A double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of thymopentin as an adjunctive treatment in atopic dermatitis

Journal of the American Academy of Dermatology Volume 30, Number 4

epidermal autografts bearing melanocytes. 1 AM ACAD DERMATOL 1992;26:23~. 13. Halaban R, Rubin1S, FunasakaY, et a1. Met and hepatocyte growth factor/scatter factor signaltransduction in normalmelanoeytes andmelanoma cells. Oncogene 1992;7: 2195-206. 14. Olsson MJ, Juhlin L. Melanocyte transplantation in vitiligo. Lancet 1992;340:981. 15. Olsson MJ, Juhlin L. Repigmentation ofvitiligo by transplantation ofcultured autologous melanocytes. Acta Derm Venereol (Stockh) 1993;73:49-51. 16. Moellmann GE, Klein-Angerer S, Scollay DA, et a1. Extracellular granular material and degeneration of keratinocytes in the normally pigmented epidermis of patients with vitiligo. J Invest Dermatol 1982;79:321-30. 17. Bhawan 1, Bhutani LK. Keratinocyte damagein vitiligo. J Cutan PathoI1983;10:207-12.

Stiller et al. 18. Halaban R, Langdon R, BirchallN, et a1. Basic fibroblast growth factorfromhuman keratinocytes is a natural mitogen for melanocytes, J Cell Bioi 1988;107:1611-9. 19. Scott G, StolerM, Sarkar S, et al, Localization of basicfibroblastgrowth factormRNA in melanocytic lesions byin situ hybridization. 1 InvestDermatoI1991;96:318-22. 20. Longley BJ, Morganroth GS, Tyrrell L, et a1. Alteredmetabolism ofmastcellgrowthfactor (c-KIT ligand)in cutaneous mastocytosis. N Engl 1 Med 1993;328:1302-7. 21. Yohn11,Morelli 1G, WalchakS1, et al. Cultured human keratinocytes synthesize and secreteendothelin-l. J Invest Dermatol 1993;100:23-6. 22. MedranoEE, Nordlund JJ. Successful culture ofadult humanmelanocytes obtained fromnormaland vitiligo donors. J InvestDennatol 1990;95:441-5.

A double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of thymopentin as an adjunctive treatment in atopic dermatitis Matthew J. Stiller, MD, Jerome L. Shupack, MD, Clare Kenny, RN, Lorrie Jondreau, RN, David E. Cohen, MD, MPH, and Nicholas A. Soter, MD New York, New York Baekground: Multiple immunologic abnormalities such as impaired T-cell function, elevated serum 19Blevel, and increased interleukin 4 production have been demonstrated in patients with atopic dermatitis. Objective: As part of a 12-week, multicenter, double-blind, placebo-controlled clinical trial, we evaluated the safety and efficacy of thymopentin (Timunox) as an adjunctive treatment in patients with severe atopic dermatitis, Methods: Thirty-nine patients at least 2 years old with severe atopic dermatitis on a minimum of 200/0 of their cutaneous surface area were randomly selected to receive either thriceweeklysubcutaneous injections of thymopentin, 50 mg, or placebo. Use of triamcinolone 0.1 % or hydrocortisone 1.00/0 cream and oral antihistamines were permitted during this trial. Results: After 12 weeks, thymopentin-treated patients had significantly greater improvement than those receiving placebo. No thymopentin-related adverse events occurred. Conclusion: Thymopentin may be a safe effective adjunct to therapy in patients with severe atopic dermatitis. (J AM ACAD DERMATOL 1994;30:597-602.) From the Ronald O. Perelman Department of Dermatology, New York University School of Medicine, and the Dennatopharmacology Section, Charles C. Harris Skin and Cancer Pavilion, New York University Medical Center. Supported by a grant from the Immunobiology Research Institute, Annandale, N.J. Presented in part at the Eastern Regional Society for Investigative Dermatology, New York, Oct. 9-10, 1992 and the annual meeting of the Society for Investigative Dermatology, Washington, D.C., Apri128May 1,1993. Reprint requests: Matthew J. Stiller, MD, The Ronald O. Perelman Department of Dermatology, 562 First Avenue, New York, NY 10016. Copyright @I 1994 by the American Academy of Dermatology, Inc. 0190-9622/94 S3.00 + 0

16/1/50797

Atopic dermatitis (AD) affects more than 5% of the population.!" Although its pathogenesis is uncertain, immunologic abnormalities are a prominent feature. These include defective T-cell function.v'' an elevated serum IgE level." as well as decreased interferon gammaf and increased interleukin 4 (IL-4)9 production by mononuclear cells. The synthetic inununomodulatory pentapeptide, thymopentin, (Timunox, TP-5) is composed of ammo acids 32-36 (Arg-Lys-Asp-Val-Tyr) of the 52 amino acid thymic hormone thymopoietin. 10-12 Thymopentin appears to have all the biologic and phar-

597

Journal of the American Academy of Dermatology April 1994

598 Stiller et al.

Table I. Demographic comparison of thymopentin- and placebo-treated groups

I Sex Male Female Age (yr)* Race White Black Other ethnicity* Height (em)" Weight (kg)" Duration of AD (yr)* Extent of involvement (%)* Total severity score*

Thymopentin

1

9 9 42 ± 3.8 (21-68) 12 5 I 171 ± 75 ± 32 ± 54.9 ± 6.06 ±

2.3 3.3 4.5 3.4 .25

PIa_cebo

........

P Value

9 8 38 ± 3.7 (11-68)

0.52

13 2

0.51

2 170 ± 70 ± 30 ± 57 ± 6.32 ±

3.3 3.4 4.7

5.6 .27

_

1.00

0.95 0.31 0.77 0.70 0.47

"Mean ± SEM .

macologic effects of the parent compound and influences both the differentiation ofthymocytes and function of mature T cells. 13, 14 Immunoregulatory effects of thymopentin include enhancement of in vivo interleukin 2 (IL-2) production I 5 and of in vitro mitogen-induced interferon gamma production. 16 Thymopentin also decreases in vitro and in vivo IgE production by peripheral blood monocytes of patients with AD. Its immunoregulatory effects are dependent on both dosage and route of administration. Higher intravenous doses suppress whereas lower subcutaneous doses stimulate the immune system. I? Leung et al. 5 reported that subcutaneous thymopentin, 50 mg daily, was significantly more effective than placebo in reducing pruritus and total severity score and severity index in patients with

AD.18 As part of a multicenter clinical trial, we evaluated the safety and efficacy of thrice-weekly subcutaneous thymopentin as an adjunctive therapy in patients with severe AD.

MATERIAL AND METHODS Thirty-nine patients with chronic, severe AD were entered into this 12-week, double-blind, randomized, placebo-controlled multicenter clinical trial. Patients were at least 2 years of age and had AD affecting at least 20% of their cutaneous surface. Patients known to be positive for HIY and those suspected of having HIY infection were excluded. Systemic corticosteroids, immunomodulatory drugs, and phototherapy were discontinued at least 4 weeks before initiation of thymopentin treatment. Topical corticosteroid creams other than triamcinolone acetonide 0.1% or hydrocortisone 1.0% were discontinued 7

days before entry; patients were permitted to use these preparations during the study. The creams were dispensed to patients in I-pound jars that were weighed on subsequent visits to determine the amount used. New jars were dispensed as needed on each study visit. Oral antihistamines and topical emollients were permitted. Diagnostic criteria for atopic dermatitis were those of Hanifin and Rajka.'? Pruritus, erythema, and induration were graded on a scale of 0 to 3 in O.5-unit increments (0 = absent, 1 = mild, 2 = moderate, and 3 = severe). The sum of pruritus, erythema, and induration was designated the total severity score. Admission into the study required a severity score greater than or equal to 4. In addition, pruritus and erythema each had to be greater than or equal to 2. Lichenification (0-3) and scaling/dryness (0-3) in O.S-unit increments were also rated. The percentage of each patient's total cutaneous surface area involved was evaluated with the rule of nines.i? In addition, patient and physician overall assessments were obtained at each visit (excellent = 1, good = 2, fair = 3, poor = 4, and very poor = 5). Patients satisfying eligibility requirements were randomly assigned to receive either thymopentin, 50 mg, or placebo, subcutaneously, three times weekly for 12 weeks. Thyrnopentin and placebo were supplied in identical single-dose ampules each containing 1.0 mt. After the injections were stopped, patients were observed for an additional month . Thymopentin (or placebo) was administered under the supervision of a physician or nurse until patients or parents were competent to give the subcutaneous injections. Assessment of efficacy parameters and review of patient diary cards were performed 1 week before initiation of treatment (day 7), on the day therapy began (day 0), and on days 7, 21,42,63,84, and 112 (4 weeks after cessation of study medication). In addition to a physical examination, a complete blood cell count (CBC), serum

Journal of the American Academy of Dermatology Volume 30, Number 4

Stiller et al. 599

•

T PS

0

P LA C E B O

.. ... (p ~ q. q2 9) ..... .. 2 '

1.5

0.5 Q lC-.

-J

-L

BASELINE

DAY 84

Fig. 1. Comparison of lichenification (0-3 ± SEM) for thymopentin- and placebo-treated groups at baseline and after 12 weeks.

Table II. Comparison of baseline and day 84 values far thymopentin efficacy parameters Day 84

(change from baseline)

Baseline Parameter

Acute manifestations Pruritus Erythema Dermal induration

Treatment

Chronic manifestations Lichenification Scaling/dryness

I

SEM

I

p Value

0.14 0.16 0.09 0.08 0.15 0.15 0.25 0.27

0.789

Placebo

2.03 ± 1.97 ± 2.06 ± 2.15 ± 1.97 ± 2.21 ± 6.06 ± 6.32 ±

Thymopentin Placebo Thymopentin Placebo

2.19 ± 2.18 ± 1.94 ± 2.09 ±

0.15 0.20 0.11 0.17

0.942

Thymopentin Placebo Thymopentin Placebo

Thymopentin Placebo

Total severity score

Mean

Thyrnopentin

chemistry profile (SMA-IS), urinalysis, and serum immunoglobulins were obtained on day 7. The physical examination, CBC, SMA-IS, and urinalysis were repeated on day 84. The serum immunoglobulins and physical examination were repeated on day 112. This clinical trial was approved by the Institutional Board of Research Associates of the New York U niversity School of Medicine before its initiation. Informed consent was obtained from all subjects or from a responsible parent/guardian. A separate statistical analysis for each center was performed. Demographic variables were evaluated at baseline with the Wilcoxon rank sum test for age, weight, height, duration of AD, exten t of body involvement, and

0.460 0.275 0.465

0.478

Mean

I

SEM

± 0.10

-0.37 -0.22 -0.47 -0.22 -0.43 -0.30 -1.27 -0.75

± ± ± ± ± ± ±

-0.51 -0.16 -0.50 -0.16

± 0.09 ± 0.13 ± 0.11 ± 0.11

0.11 0.09 0.09 0.08 0.12 0.17 0.22

I

p Value

0.397 0.028 0.171 0.055

0.029 0.011

total severity score. Fisher's exact test (for sex), the chisquare test (for race), and Student's t test (for other variables) were 11Sed to assess the relation between treatment results and demographic data. Changes in efficacy parameters were analyzed by analysis of covariance with box line response variable as the covariate. Changes in laboratory values were assessed with the Wilcoxon rank sum test. 21 RESULTS

At New York University Medical Center, 39 patients were entered into the study (20 thymopentin/19 placebo), of whom 35 evaluable patients (18

600

Journal of the American Academy of Dermatology April 1994

Stiller et al.

•

"

0.7

TP 5

0

P LAC EB O

(p ::;; O:001 ) T

0.6 . 0 .5 .

0.4 .

0.3 . 0.2 . 0. 1 .

Ol.!..-- - -BASE - -LINE - - - - ..L-- - - DAY - - 84- - - --/ Fig. 2. Comparison of severity index for thymopentin- and placebo-treated groups (mean ± SEM)-.Severity index is based 70% on severity score and 30% on total cutaneous surface area covered with AD.

thymopentin, 17 placebo) completed 12 weeks of participation. Two patients in the placebo group were lost to follow-up, as was one in the active group. One patient was removed from the study after receiving thymopentin for 3 weeks because of a non-thymopentin-related HIV -induced leukopenia present but undiagnosed at the start of the study. The thymopentin- and placebo-treated groups were demographically comparable with respect to sex, age, weight, height, ethnic origin, duration of AD, and percentage of cutaneous surface area involved (Table I). Erythema improved significantly in the thymopentin-treated group compared with the placebotreated group by day 84(p ::;; 0.028). Both lichenification (p =;:: 0.029) and scaling/dryness (p = 0.011) improved significantly in the thymopentintreated group (Fig. 1). Baseline values and the change from baseline after 12 weeks for acute and chronic signs and symptoms are shown in Table II. The total severity score improved in the thymopentin-treated group from 6.06 ± 0.25 at baseline to 4.79 on day 84 (p = 0.055). There was a smaller change in the total severity score in patients receiving placebo (baseline, 6.32 ± 0.27; day 84, 5.57). The difference between the two groups was not statistically significant (p = 0.055). The percentage of the cutaneous surface area affected by AD decreased from 54.94% ± 3.38% at baseline to 42.04% in the thymopentin-treated subset of patients compared with 57.42% ± 5.57% at baseline and

54.64% ± 1.68% on day 84 for placebo (p < o.oon The severity index.' based 70% on the total severity score and 30% on the cutaneous surface area involved, decreased significantly in the thymopentintreated group compared with the placebo-treated group. The severity index decreased from 0.64 at baseline to 0.50 on day 84 in thymopentin-treated subjects compared with 0.66 ± 0.03 at baseline and 0.59 on day 84 in the placebo-treated group (p ::;; 0.012, Fig. 2). There was a statistically significant improvement in the physicians' overall assessment of severity; this decreased from 3.61 ± 0.14 at baseline to 2.93 on day 84 in thymopentin-treated patients. Placebo-treated patients had a physician's global assessment of 3.71 ± 0.22 at baseline and 3.42 after 12 weeks (p = 0.006). The patient overall assessment improved in patients receiving thymopentin from 3.11 ± 0.21 initially to 2.78 on day 84, whereas patients receiving placebo rated their overall disease severity as changing from 3.00 ± 0.19 to 2.92 (p = 0.072). There was no difference in the type or frequency of adverse experiences between active- and placebotreated subjects. Fifteen thymopentin-treated patients experienced adverse events, as did 16 receiving placebo. None of these adverse events was believed to be related to thymopentin administration. There was no difference between thymopentinand placebo-treated patients in occurrence of noncutaneous infections. However, five thymopentintreated patients had six cutaneous infections com-

Journal of the American Academy of Dermatology Volume 30, Number 4

pared with 13 cutaneous infections in nine patients receiving placebo. Seven staphylococcal skin infections occurred in five patients receiving placebo compared with only two cutaneous staphylococcal infections in two patients receiving thymopentin. Other cutaneous infections included plantar warts and verruca vulgaris in two thymopentin-treated patients and two episodes of cellulitis in a third. One placebo-treated patient had two episodes of tinea cruris, and another had a single episode of tinea cruris, all caused by Trichophyton rubrum. One placebo-treated patient had two episodes of Candida intertrigo; another had herpes zoster. There was no difference in antihistamine or topical corticosteroid use between patients treated with thymopentin or placebo. There were no significant changes in laboratory values including serum immunoglobulin level in either thymopentin- or placebo-treated patients. DISCUSSION

Thymopentin appears to be a safe adjunctive therapy with limited efficacy in severe AD. Patients were permitted unlimited use of antihistamines and topical glucocorticoid creams. This may account for our failure to observe a difference in the degree of pruritus between treatment groups, as did Leung et al. 5 in a study permitting topical corticoids but not supplying them freely to patients. Clinical trials evaluating adjunctive drugs rather than monotherapies for AD are difficult to conduct. 4, 22 Our patients had, on average, more than 50% cutaneous involvement. To treat such patients effectively with a single agent is difficult. Only two centers in this multicenter clinical trial reported statistically significant efficacy for thymopentin versus placebo-'; we attribute this to patient selection and study design. Subjects who previously had limited access to topical glucocorticoids were given pound jars of triamcinolone or hydrocortisone cream the week before initiation of thymopentin treatment. This could have produced rapid initial improvement in both thymopentin- and placebo-treated patients. Perhaps investigators at some centers allowed patients significantly greater than prestudy access to antihistamines. This might explain the unexpected improvement in placebotreated subjects at these centers. We attempted not to alter the pattern of topical corticoid or oral antihistamine use by patients before or during this clinical trial anticipating the predictably less impressive

Stiller et al. 601 difference between thymopentin- and placebotreated subjects observed by other investigators. Most systemic drugs used in AD have major side effects. Thymopentin, in contrast, is remarkably safe with a half-life of 30 seconds caused by rapid degradation by peptidases." Thymopentin, currently approved for use in some countries but not in the United States or United Kingdom, has shown efficacy in the treatment of rheumatoid arthritis,25,26 sarcoidosisj? Sezary syndrome, 28 HIV infection,29,30 and lepromatous leprosy. 31 Peripheral blood mononuclear cells of patients with AD produce decreased amounts of interferon gamma'' and increased amounts of IL-4. 9 IL-4 increases IgE synthesis.F a prominent feature of AD.7 These immunologic abnormalities have been reversed in vitro by thymopentin.P- 17 Primary and secondary immunodeficient states including the Wiskott-Aldrich syndrome" and HIV infection 29, 30, 34 may be associated with eczematous dermatitis. The dermatitis frequently decreases in severity or resolves when immunologic function improves.29, 30, 33, 34 Although thymopentin does not improve AD as dramatically as glucocorticoidsf and cyclosporine,36 its superior safety profile is an advantage. Thymopentin in combination with antihistamines, topical corticosteroids, and possibly phototherapy may offer a partial solution to the treatment of refractory cases of AD. REFERENCES 1. Hanifin 1M. Atopic dermatitis. J AM ACAD DERMATOL

1982;6:1-13. 2. Leung DYM, Rhodes AR, Geha RS, et aJ. Atopic dermatitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al, eds. Dermatology and general medicine. 3rd ed. New York: McGraw-Hill, 1986:1385-408. 3. Taylor B, Wadsworth M, Wadsworth J, et al, Changes in the reported prevalence of childhood eczema since 1939-45. Lancet 1984;2:1255-8. 4. Shupack J, Stiller M, Meola T, et aI. Papaverine hydrochloride in the treatment of atopic dermatitis: a doubleblind, placebo-controlled crossover clinical trial to reassess safety and efficacy. Dermatologica 1991; 183:21-4. 5. Leung DYM, Hirsch RL, Schneider L, et al. Thymopentin therapy reduces the clinical severity of atopic dermatitis. J Allergy Clio Immunol 1990;85:927-33. 6. Leung DYM, Geha RS. Immunoregulatory abnormalities in atopic dermatitis. Clin Rev Allergy 1986;4:67-86. 7. Juhlin L, Johansson SGO, Bennich H, et al. Immunoglobulin E in dermatoses: levels in atopic dermatitis and urticaria. Arch Dermatol 1969;100:12-6. 8. Reinhold V, Pawelec G, Wehrmann W, et al. Immunoglobulin E and immunoglobulin G subclass distribution ill vivo and relationship to invitro generation of interferon-gamma

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Journal of the American Academy of Dermatology April 1994

placebo-controlled cross-over study. Br J Derrnatol 1990; 122:553-7. 23. Schneider LC, Barlan I, Kamada MM , et a1. Treatment of atopic dermatitis AD with thymopentin (Timunox) [Abstract). 1 Allergy Clin Immuno11993;9l:245. 24. Tischio J, Patrick 1, Weintraub H, et aI. Short in vitro half-life of thyrnopoietin 32-36 pentapeptide in human plasma. Int J Pept Prot Res 1979;14:479-84. 25. Malaise M, Franchirnont P, Bach-Andersen R, et al. Treatment of active rheumatoid arthritis with slow intravenous injections of thymopentin. Lancet 1985;1:832-6. 26. Kantharia B, Goulding N, Hall N, et al. Thymopentin (TP-5) in the treatment of rheumatoid arthritis. Br 1 Rheum 1989;28:118-23. 27. Thivolet J, Faure M, Nicolas J, et al. Therapeutic use of TP5 (thymopentin 32-36) in sarcoidosis of the skin. Clin Immuno1ImmunopathoI1983;26:35Q-60. 28. Bernego M, Doveil G, McregaJl M, et al. Immunomodulation and Sezary syndrome: experiencewith thymopentin (TP-5). Br 1 DermatoI1988;119:207-2J. 29. Barcellini W, Meroni P, Frasca D, et al, Effect of subcutaneous thymopentin treatment in drug addicts with persistent generalized lymphadenopathy. Clin Exp Immunol 1987;67:537-43. 30. Clumeck N, Van de Perre P, Mascart-Lernone F, et al. Preliminary resultson clinicaland immunologicaleffectsof thymopentin in AIDS. lnt 1 Clin Pharm Res 1984;4:45963. 31. Munno I, PellegrinoNM, Fumo G, et al. Effects of a synthetic extract (thymopentin) on the immune system of lepromatous leprosypatients. Cytobios 1987;52:167-73. 32. Del Prete G, Maggi E, Paronchi P, et al. IL-4 is an essential factor for the IgE synthesisinduced in vitro by human T-cell clonesand their supernatants. 1 Immunol 1988;]40: 4193-8. 33. Saurat I-H. Eczema in primary immune deficiencies: clues to the pathogenesisof atopic dermatitis with special reference to Wiskott-Aldrich syndrome. Acta Derm Venereal (Stockh) 1985;114:125-8. 34. Silvestris F, GernomeA, Frassanito M, et al. Immunologic effectsof long-termthymopentintreatment in patients with HIV-induced lymphadenopathy syndrome. 1 Lab Clin Med 1989;113:139-44. 35. DuvoneCA, AzarnoffDC. Clinicalcomplicationsof corticosteroid therapy. Med Clin North Am 1973;57:1331-42. 36. Wahlgren GF, Scheynius A, Hagermark O. Antipruritic effect of oral cyclosporin -A in atopic dermatitis . Acta Derm Venereol(Stockh) 1990;70:323-9.