Evidence Table 9

Active-controlled trials of pimecrolimus

Author
Year
Country
Trial Name
(Quality Score)
Study Design SettingEligibility criteriaComorbidity (asthma, other atopic-related ailments, infections)?InterventionsRun-in/Washout PeriodAllowed other medications/interventionsMethod of Outcome Assessment and Timing of AssessmentAge (yrs)Gender EthnicityOther population characteristicsNumber screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedResultsMethod of adverse effects assessmentAdverse eventsTotal withdrawals; withdrawals due to adverse eventsComments
Luger, 2004
Europe
Fair
Double-blind, multicenter (35 centers in 9 countries)18–79 years with atopic dermatitis diagnosed according to Williams criteria; with moderate-severe disease affecting ≥5% of total BSA.

Exclusion: treatment with phototherapy; radiation therapy or systemic therapy for atopic dermatitis in the previous month; treatment with topical therapy (other than tar shampoo on the scalp) not stopped 24 hr before 1st application of study medication; malignancy or immunosuppression; known HIV-positive status; acute or chronic bacterial, viral or fungal diseases; active skin infections (ie, herpes simplex infections); and presence of skin conditions that could affect the evaluation of study treatment (ie, generalized erythoderma such as Netherton's syndrome and psoriasis)
NR (see exclusion criteria)Pimecrolimus 1% cream versus
Triamcinolone acetonide cream 0.1% (trunk and limbs) and Hydrocortisone acetate cream 1% (face and neck). Applied twice daily x 12 mos.

There was no limitation on the amount and duration of drug usage over 12 mos.
NR/NRAntihistamines and emollients onlyPrimary endpoint: Safety and tolerability: Patients were to record AE on diary cards every day.
Incidence of bacterial, viral, or fungal infections of the skin were prospectively assessed (unclear by whom and by which method-active or passive). Application site reactions were also recorded. Labs and PE were performed.

Secondary endpoint: Efficacy: EASI score, Investigator Assessment (IA), time to 1st recurrence, time to 1st remission.

Patients were assessed at baseline, days 8, 22, 43, and then monthly until end of study period. An additional visit was performed post-treatment--the day after the last application of study med).
33.4–33.5
Female 53.6–55.5
White 88.8–89.6%
Black 1.8–4.5%
Asian 3.0–4.9%
Other 2.1%
Missing 1.5%
mean %BSA involved: 26.5–27.0 (SD19.26)

% Head/neck involved: 89.6–89.7

mean EASI: 15.0–15.3 (SD10.9–10.95)

% with disease severity:
Mild (score 3–4): 2.1–3.0
Moderate (score 4.5–7.5): 63.6–65.9
Severe (score 8–9): 32–33.3

Mean height: 170.2 cm
Mean weight: 69.6–69.8 kg
NR
NR
658
Total number withdrawn-
NR
NR
658 for harms
Mean % of days on which patients needed to apply study med for pimecrolimus and triamcinolone: 88.7% vs. 83.4%

Median % of days of exposure to study med for pimecrolimus and triamcinolone: 99.5% vs.95.6%

For between-group comparisn, median EASI scores were lower with triamcoinolone than pimecrolimus at all time points, p<0.006 from baseline to study end (data reported in graph format only).

No significant differences between triamcinolone or pimecrolimus at end of study for Investigator Assessment score of 0–3: 88.8% triamcinolone vs. 81.5% pimecrolimus, p=0.067.
Patient report and investigator assessmentFor the most frequently reported skin infections (Table II), there were no statistical differences in these AE between pimecrolimus and triamcinolone except for he incidence of viral skin papilloma (treatment difference 2.1%, 95% CI −3.7, −0.6), which occurred more frequently with triamcinolone (2.1%) than pimecrolimus (0%). However, overall, none of the treatment differences exceeded 5%.

For those with >30% BSA involvement, the overall incidence of bacterial skin infections was higher with triamcinolone (19.8%) than pimecrolimus (9.6%), which was statistically significant (95% CI −19.5, −0.9). More triamcinolone-treated subjects (12.6%) reported bacterial folliculitis than pimecrolimus (4.8%) leading to statistical significant difference (treatment difference −7.8%, 95% CI − 15.2, −0.4).

3 patients (0.9%) on triamcinolone reported skin striae compared with 0% pimecrolimus. 3 pimecrolimus-treated subjects reported serious skin and tissue disorders: exacerbation of AD, contact dermatitis, and infected eczema.

Application site reactions were reported more frequently wit Total 46.3% vs. 24.2% (most common was burning)
NR
Total number of withdrawals due to AE-NR, however, withdrawal due to "application site reaction" were reported (7.6% for pimecrolimus vs. 0.9% triamcinolone)
To maintain blinding, both topical steroid and pimecrolimus could be used without limitation for the total daily dose applied and for the duration of treatment.
Luger, 2001
Europe
Fair
Double-blind, multicenter (14 centers in 7 countries)≥18 yrs with atopic dermatitis diagnosed according to Hanifin and Rajka criteria; severity of the patients' atopic dermatitis was evaluated according to the grading system of Rajka and Langeland and had to be of at least moderate severity at baseline. The disease affected between 5% and 30% of the total body surface area. The use of other treatments for atopic dermatitis (including emollient use at treated sites), or corticosteroids (inhaled or oral) for the treatment of asthma during the treatment phase of the study was prohibited.

Patients with concomitant medical conditions that could interfere with the evaluation of the study were excluded, as were women who were pregnant, breast feeding, or not using medically approved contraception if they were of child-bearing potential.
NR (see exclusion criteria)Pimecrolimus 1% cream, betamethasone-17-valerate 0.1% cream, vehicle; applied twice daily (except to face) x 3 weeksNR/NRNRUsed adapted EASI scoring system (omitted scores for the head area which accounts for 10% of the total BSA).

Patients assessed pruritis using scoring system ranging from 0–3 (assessed the intensity of itch in the previous 24 hr). Patients assessed overall improvement of atopic dermatitis using a score ranging from 0–6.
28–33
Female 46.7–54.8%
White 95.3–100%
Median duration of disease: 22–25 yrs
mean EASI score: 10.12–11.28
>90% have moderate severity atopic dermatitis in all treatment arms
NR
NR
260 (130 for vehicle, pimecrolimus 1%, and betamethasone arms)
29
2
130

*data reported only for 3 arms
Median EASI scores for vehicle, pimecrolimus 1%, and betamethasone-17-valerate 0.1%: Change from baseline: 0% vs. 45%, vs. 80% (p=0.008 for vehicle vs. pimecrolimus, p-value= NR for betamethsone vs. pimecrolimus)

Patient assessment in Pruritus score (improvement) for vehicle vs. pimecrolimus, and betamethasone: Change from baseline: 18.6% vs. 46.7% vs. 81%

Patient assessment of atopic dermatitis improvement for vehicle, pimecrolimus, and betamethasone:
Change from baseline: 16.3% vs. 53.3% vs. 88.1%

EASI data were also stratified by disease severity which showed that with increasing severity, there was a decline in treatment effect (see Table 4)
Labs, PE, VS were collected; unclear who assessed adverse eventsApplication site reactions were the most commonly reported AE. For vehicle, pimecrolimus 1%, and betamethasone, the rates were: 35% vs. 49% vs. 10%. Most application site reactions began on the 1st day of treatment and resolved within the 1st 3 days of therapy.

Rates of pruritus for vehicle, pimecrolimus, betamethasone: 35% vs. 31% vs. 12%

Rates of worsening disease for vehicle, pimecrolimus, betamethasone: 21% vs. 4% vs. 2%
29
11
Per the Rajka and Langeland criteria for assessing baseline severity: A score >4 or <8 is moderate. A score 8–9 is severe.

From: Evidence Tables

Cover of Drug Class Review: Topical Calcineurin Inhibitors
Drug Class Review: Topical Calcineurin Inhibitors: Final Report [Internet].
Lee NJ, McDonagh M, Chan B, et al.
Portland (OR): Oregon Health & Science University; 2008 Oct.
Copyright © 2008, Oregon Health & Science University, Portland, Oregon.

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