Evidence Table 5

Placebo-controlled trials of pimecrolimus

Author
Year
Country
Trial Name
(Quality Score)
Study Design SettingEligibility criteriaComorbidities (other atopic-related ailments, infections, immunodeficiencies)?InterventionsRun-in/Washout PeriodAllowed other medications/interventionsMethod of Outcome Assessment and Timing of AssessmentMean age
Gender
Race/Ethnicity
Other population characteristicsNumber screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedResults (frequency of rebound flares, reduction in sx severity, time to next flare up (treatment duration), QL, treatment failure (use of other agents)Method of adverse effects assessmentAdverse eventsTotal withdrawals; withdrawals due to adverse eventsComments
Belsito, 2004
US
Fair
Double-blind, multicenter> 18 yrs who had 6 wks or longer history of chronic hand AD; IGA score of mild to moderate disease with at least mild scaling and mild erythema of the more severely affected hand was required for enrollment. Those with the following diseases limited to the hands were eligible: dyshidrosis, atopic dermatitis, irritant and allergic contact dermatitis.

Exclusion- pregnancy; concurrent disease or treatment that could interfere with study evaluations; hypersensitivity to study drug ingredients; severe vasicullobulous dermattits of the hands; contact utricaria; latex alergey; bullous disorders; hand-foot and mouth disease; mosaic warts; history of malignant disease or current pre-malignant skin conditions of the hands; concurrent flaring of atopic dermatitis; psoriasis or other concurrent skin disease of the hands requiring therapy; patients who used systemic steroids within the previous month, or who used sytemic antibiotics for imfections of the hands or topical therapy for the hands within 7 days before screening.
NRPimecrolimus 1% cream versus vehicle; applied twice daily x 3 weeks.

The evening application was followed by occulsion for at least 6 hours using vinyl gloves. Handwashing (until 3 hours after study drug application) and irritants were to be avoided.
NRNonmedicated emollients and/or creams were allowed 1 hour before or after study drug application.Primary endpoint: IGA score (treatment success)

Baseline, day 4, 8, 14 and 22.
44.6 yrs
Female 59.9%
White: 83.7%
Nonwhite: 16.3%
IGA score for pimecrolimus and vehicle
Almost clear: 0.7% vs 0%
Mild disease: 32.5% vs. 25.9%
Moderate disease: 64.2% vs. 69.2%
Severe disease : 2.6% vs. 4.9%

Suspected etiology:
Irritant contact dermatitis: 41.6% vs. 38.5%
Endogenous disease: 30.9% vs. 33.6%
Irritant contact dermatitis + endogenouse disease: 13.4% vs. 8.4%
Irritant contact dermatitis + allergic contact dermatitis: 10.7% vs. 11.2%
NR
NR
294
22
NR
294
% of patients with IGA score of 0 to 1 (treatment success) for pimecrolimus and vehicle:
27.5% vs. 17.5%; (estimated from graph) absolute difference: 10%, p=0.68.

Subgroup:
% of patients with IGA score of 0 or 1 with palmer involvement
Presence of involvement: 23.3% vs. 17.3%
Absence of involvement: 42.9% vs. 20.0%

Disease patterns:
Palmer surface involvement: 76.8%
Dorsal involvement : 53.0%
Dermatitis on the lateral surface of the fingers: 72.2%
NRTypes of AE were not reported for either treatment arms.

"There appeared to be no appreciable differences in the rates of occurrence of common AE in the pimecrolimus-treated and vehicle-treated groups."

Application site reactions for pimecrolimus and vehicle:
0.7% vs. 2.1%
22 (7.5%)
6 (types of events not reported for either arms)
Breuer, 2004
Germany

companion to Kaufmann, 2004
Double-blind, multicenter (19 centers)

Randomization 2:1 (pimecrolimus: vehicle)
3–23 mos if they had atopic eczema affecting ≥ 5% of the body surface area and a baseline IGA score of 2 (mild disease severity) to 5 (very severe disease).

Exclusion: insufficient wash-out periods for systemic corticosteroids, antihistamines, antibiotics or other therapies that might have an effect on atopic eczema; concomitant diseases that might interfere with the study; severe concurrent skin disease in the study area, and active viral or bacterial infections.
NRPimecrolimus 1% cream vs. vehicle; applied twice daily x 4 weeks.NR/NRNRPrimary endpoint: EASI score

Secondary endpoint: IGA score, SCORAD score, intensity of pruritus/sleep loss and overall assessment of disease assessed by the caregivers
11.5–12.3 mo (SD 5.8– 6.1)
Female 28.8–37.2%
White 90.7–92.4%
Black 0–1.6%
Asian 5.4–6.1%
Other 1.5–2.3%
Height 74.4–75.3 cm (SD 7.2–8.0)
Weight 9.4 kg (SD 2.0–2.1)

IGA score
2 (mild): 9.3–12.1%
3 (moderate): 58.1–59.1%
4 (severe): 25.8–26.4%
5 (very severe): 3.0–6.2%

EASI score: 16.6–17.7 (SD 10.3–10.8)
IGA score: 3.2–3.3 (SD 0.7)
SCORAD score: 46.9–48.6 (SD 15.0– 15.9)
201
NR
196
38
NR
195
Mean EASI score for pimecrolimus and vehicle: Score at 4 weeks: −4.9 (SD 6.0) vs. +17.3 (SD 13.3)
% decrease in score from baseline: −71.5% vs. +19.4%, p<0.001 vs. vehicle
Mean IGA score: Score at 4 weeks: 1.63 (SD 1.0) vs. 3.0 (SD 1.1)
% decrease in score from baseline: −50.7% vs. −5.5%, p<0.001 vs. vehicle
Mean SCORAD score from baseline: Score at 4 weeks: 21.8 (SD 16.1) vs. 46.3 (SD 21.7)
% decrease in score from baseline: −55.2% vs. −1.1%, p=0.002 vs. vehicle

Mean pruritus score: Score at 4 weeks: 2.1 (SD 2.3) vs. +5.2 (SD 3.3), p<0.001 vs. vehicle

Mean sleep loss score: Score at 4 weeks: 1.6 (SD 2.3) vs. +4.1 (SD 3.3), p<0.001 vs. vehicle
NRNR (reported in Kaufmann, 2006)38
NR
Ho, 2003
Austrailia, Brazil, Canada, Germany, S. Africa, Spain
Fair
Double-blind, multicenter (25 sites)

Randomization 2:1 (pimecrolimus vs. vehicle)
3–23 mos; clear diagnosis of AD, affecting ≥ 5% of total body surface area and with a baseline IGA of 2 or 3 (mild to moderate), based on the degree of erythema and infiltration/papulation.

Exclusion-immunocompromised; other concurrent or active skin disease or viral skin infections or known sensitivity to study drug; subjects who received phototherapy or systemic treatment known to affect AD within the previous month; topical therapy within the previous week, or sedative antihistamines to treat pruritus within the previous week.
NRPimecrolimus 1% cream versus vehicle; applied twice daily x 6 weeks.NR/NRBland emollients on areas untreated with study medication.Primary endpoint: IGA score
Secondary endpoint: EASI score; severity of pruruitus made by the caregiver; assessment of the disease by the caregiver
Baseline, days 8, 15, 22, 29 and 43.
12.6–12.7 mos (SD 6.25–6.29)
Male 54.0–55.3%
White 52.8–69.8%
Black 6.3–13.0%
Asian 1.6–2.4%
Other 22.2–31.7%
Height: 74.7–75.0 cm (SD 7.54–8.52)
Weight: 9.5–9.8 kg (SD 1.84–1.94)

IGA score: 2 (mild): 32.5–33.3%
3 (moderate): 66.7–67.5%

mean EASI score: 10.2–11.2 (SD 7.75–7.88)
NR
NR
186
44/
NR/
186
IGA score of 0 or 1 at 6 weeks for pimecrolimus and vehicle: 54.5% vs. 23.8%; p<0.001

mean EASI score decreased by: 6.8 points vs. 0.75 points, p<0.001

% decline in overall MEDIAN EASI score: 81.6% vs. 25%

% achieving pruritus severity (absent or mild): 72.4% vs. 33.3%; p<0.001

% of caregivers reporting complete or good control of disease: 71.5% vs. 27.0%; p<0.001

Subgroup
For those with moderate severity (for pimecrolimus and vehicle): 70% improved/5% worsened vs. 36% improved/14% worsened; p-value=NR

For those with mild disease: 65% improved/7.5% worsened vs. 48% improved/43% worsened

For those 3 mo to 1 yr with IGA score of 0 to 1 (for pimecrolimus and vehicle): 65.5% vs. 25%
For those 1 to 2 yrs with IGA score of 0 to 1: 46.3% vs. 22.6%
Investigators sought to identify the cause of AE74.8% of pimecrolimus-treated patients vs. 65.1% of vehicle- treated patients experienced at least 1-treatment emergent AE.

% of AE related to study medication for pimecrolimus and vehicle: 5.7% vs. 12.7%

Most common AE were typical childhood infections and ailments (pyrexia, upper respiratory tract infection, nasopharyngitis, teething, and diarrhea); none of these was considered to be study medication related.

Pyrexia (31.7% vs. 12.7%) and diarrhea (8.1% vs. 0%) were the only common AE more frequent in the pimecrolimus arm than vehicle arm. None of these was suspected to be treatment- related.

Application site reactions occurred <5% for both arms.

Rate of bacterial skin inection for pimecrolimus and vehicle: 0.8% vs. 6.3%
44 (23.7%)
NR
Withdrawals due to AE were not reported.

20-week open-label extension was conducted in this trial (but was not abstracted because it does not meet inclusion criteria)
Kapp, 2002
Europe, Canada, New Zealand, S. Africa
Fair
Double-blind, multicenter (41 centers)

Randomization 4:1 (pimecrolimus: vehicle/conventional therapy)
3–23 mo with clinical diagnosis of atopic dermatitis according to criteria of Seymour, et al; affecting ≥5% of total BSA; IGA score of ≥2

Exclusion: phototherapy or systemic therapy known or suspected to affect AD ≤1 mo before the first application of study medication; topical therapy known or suspected to affect AD ≤7 days before the first application of study medication, and systemic antibiotics ≤2 weeks before the first application of study medication; were immunocompromised or had a history of malignant disease; had active skin infections; had other infections that required treatment with prohibited medications (ie, generally medication that could affect a patient’s AD), and had other skin conditions that could affect the evaluation of study treatment.
NRPimecrolimus 1% cream vs. vehicle; applied twice daily x 12 mos; emollients were mandated and moderately potent topical steroids were allowed for flares not controlled by study medication. Topical steroids were to be administered until clearance or until the maximum treatment duration allowed by the local country label was reached. Treatment with corticosteroid was followed by a week of treatment with study medication for residual disease.

Corticosteroids used were: 0.02% difluprednate cream, 0.1% hydrocortisone butyrate cream, 0.05% clobetasone butyrate cream, 0.02% triamcinolone acetonide cream, and 0.2% hydrocortisone valerate cream.

Patients whose AD flares were not controlled by the topical corticosteroid could leave the study.
NR/NRNonmedicated emollientsPrimary endpoint: rate of flares at 6 mos

Secondary endpoints: IGA score, EASI score, caregiver's assessment of pruritus and overall assessment of disease control
11.8–12.2 mos
Female 33.3–39.1%
NR
Mean total BSA involved: 27.3–28.8% mean EASI: 12.3–12.6

IGA score:
1 (almost clear): 0%
2 (mild): 32.8–39.1%
3 (moderate): 47.8–57.4%
4 (severe): 8.3–10.9%
5 (very severe) 1.5–2.2%
280
251
251
69
14
250
% of patients without a flare for pimecrolimus and vehicle:
At 6 mo: 67.6% (95% CI 61.2–74.1%) vs. 30.4% (95% CI 17.1–43.7%)
At 12 mo: 56.9% (95% CI 50.1–63.7%) vs. 28.3% (95% CI 15.2–41.3%)

% achieving IGA score of 0 to 1:
At 6 mo: 52.9% vs. 37.0%, p=0.03
At 12 mo: 53.9% vs. 47.8%, p= NSD

EASI mean total score:
At 6 mo: 5.0 vs. 6.9, p=0.076
At 12 mo: 5.0 vs. 5.9, p=0.487

% with pruritus score of 0 or 1 (none or mild):
At 6 mo: 73.0% vs. 54.4%, p=0.008
At 12 mo: 77.0% vs. 63.1%, p=0.074

% with complete of good control of disease as measured by caregiver:
At 6 mo: 70.6% vs. 51.0%, p=0.016
At 12 mo: 71.0% vs. 63.0%, p=0.337
NRCommonly reported AE for pimecrolimus and vehicle:
Nasopharyngitis 56.9% vs. 46.2%
Pyrexia 44.8% vs. 40.5%
Teething 31.6% vs. 32.8%
Diarrhea NOS 27.6% vs. 26.3%
Upper respiratory tract infection NOS 27.3% vs. 25.3%
Cough 26.0% vs. 16.5%
Rhinitis NOS 24.0% vs. 15.8%
Ear infection NOS 21.7% vs. 20.8%
Chickenpox 19.6% vs. 15.6%
Vomiting NOS 16.1% vs. 8.2%
Otitis media NOS 14.9% vs. 15.5%
Gastroenteritis NOS 14.8% vs. 14.9%
Bronchitis NOS 14.6% vs. 16.2%
Conjunctivitis NOS 13.9% vs. 13.9%

Bacterial and viral skin infections:
Total Bacterial 12.7% vs. 9.1%
Impetigo NOS 9.1% vs. 6.8%

Bacterial infection NOS 1.6% vs. 0%
Folliculitis 0.5% vs. 0%
Furuncle (exc genital) 0.5% vs. 0%
Bacterial genital infection NOS 0.6% vs. 0%
Stye 0.6% vs. 0%
Erysipelas 0% vs. 2.3%
Total Viral 3.3% vs. 6.9%
Herpes simplex 1.1% vs. 3.4%
Eczema herpeticum 0.5% vs. 0%
Molluscum contagiosum 1.2% vs. 0%
Skin papilloma 0.5% vs. 0%
Viral rash NOS 0% vs. 3.4%
24.5% vs. 40.4%, p=0.016
NR
Withdrawals due to AE were not reported
Kaufmann, 2004
Germany
Fair
Double-blind, multicenter (19 centers)

Randomization 2:1 (pimecrolimus: vehicle)
3–23 mos if they had atopic eczema affecting ≥5% of the body surface area and a baseline IGA score of 2 (mild disease severity) to 5 (very severe disease).

Exclusion: insufficient wash-out periods for systemic corticosteroids, antihistamines, antibiotics or other therapies that might have an effect on atopic eczema; concomitant diseases that might interfere with the study; severe concurrent skin disease in the study area, and active viral or bacterial infections.
NRPimecrolimus 1% cream vs. vehicle; applied twice daily x 4 weeks.NR/NRNRPrimary endpoint: EASI score

Secondary endpoint: IGA score, intensity of pruritus/sleep loss and overall assessment of disease assessed by the caregivers (using part of SCORAD)
11.5–12.3 mo (SD 5.8– 6.1)

Female 28.8–37.2%
White 90.7–92.4%
Black 0–1.6%
Asian 5.4–6.1%
Other 1.5–2.3%
Height 74.4–75.3 cm (SD 7.2–8.0)
Weight 9.4 kg (SD 2.0–2.1)

IGA score
2 (mild): 9.3–12.1%
3 (moderate): 58.1–59.1%
4 (severe): 25.8–26.4%
5 (very severe): 3.0–6.2%

EASI score: 16.6–17.7 (SD 10.3–10.8)
IGA score: 3.2–3.3 (SD 0.7)
SCORAD score: 46.9–48.6 (SD 15.0– 15.9)
201
NR
196
38
NR
195
Mean EASI score for pimecrolimus and vehicle:
Score at 4 weeks: −4.9 (SD 6.0) vs. +17.3 (SD 13.3)
% decrease in score from baseline: −71.5% vs. +19.4%, p<0.001 vs. vehicle

% achieving IGA score of 0 to 1 (treatment success):
53.5% vs. 10.6%; p<0.001 for between-group comparison)

Caregiver's assessment of disease response as "good or complete":
80.6% vs. 22.7%, p<0.001 vs. vehicle

Mean pruritus score:
Score at 4 weeks: 2.1 (SD 2.3) vs. +5.2 (SD 3.3), p<0.001 vs. vehicle

Mean sleep loss score:
Score at 4 weeks: 1.6 (SD 2.3) vs. +4.1 (SD 3.3), p<0.001 vs. vehicle
NR3 patients discontinued due to serious AE: 1-patient from pimecrolimus arm discontinued due to moderate case of eczema herpeticum; 1 pimecrolimus-treated and 1- vehicle patient experienced super infection on top of aggravated AD.

Most common AE were typical childhood ailments (see Table 2 in trial). There was no difference in treatment arms after adjusting for time.
38 (19.4%)
NR
Authors did not specify total # of withdrawals due to AE (they reported the withdrawal of 3 patients due to serious AE)
Meurer, 2002
Germany
Fair
Double-blind, multicenter (16 sites)Adults with a clinical diagnosis of AD according to the criteria of Rajka; required to have AD affecting at least 5% of the total body surface area; an Investigator’s Global Assessment (IGA) score of 3 or 4.

Exclusion: PUVA, high-dose UVA or systemic therapy with corticosteroids, immunosuppressants or cytostatics (previous 3 months); topical therapies for AD (previous 2 weeks); systemic antibiotics (previous 2 weeks); systemic steroids for indications other than AD (previous 1 month). Other exclusion criteria comprised: pregnancy or lactation; women of child-bearing age not using reliable contraception; need for treatment with potent topical steroids for control of AD; severe concurrent allergic diseases; diseases associated with immunosuppression or malignancy; presence of skin conditions that could affect the evaluation of study treatment; active skin infections requiring treatment with a prohibited medication, or active herpes simplex infections.
NRPimecrolimus 1% cream vs. vehicle; applied twice daily in order to prevent disease flare x 6 mos

Nonmedicated emollients were applied to dry skin after study medication.

A moderatley potent topical steroid, prednicarbate 0.25% cream if the patient experienced unacceptable itcing and clinical signs (oozing/crusting or excessive scratch marks or severe erythema) despite study medication.

Topical steroid was to be used for a max of 7 days twice daily followed by a further 7 days every other day or until marked reduction of the signs of AD were achieved. After each course of sterid there was a mandaory treatment for 7 days with the study drug.
NR/NRNonmedicated emollients and cetirizine.Primary endpoint: % of days on topical steroids (to assess pimecrolimus in preventing disease flares)

Secondary endpoint: # of flares, time to 1st flare, IGA score, EASI score, pruritus assessment, patient's self-assessment, DLQI QoLIAD

Baseline, weeks 1, 3, 6, 12, and 24. There was additional telephone contact during weeks 9 and 18 and unscheduled visits in the event of flares.
31.8–32.5 (SD 10.7–11.1)
Female 57.3–62.5%
NR
Total BSA involved: mean 16.9–17.0% (SD 7.6–10.7)

mean EASI: 10.8–11.2 (SD 5.1–6.1)

IGA score:
3 (moderate): 64.6–70.8%
4 (severe): 29.2–34.4%
5 (very severe): 0.0–1.0%
197
192
192
58
4
192
% of days of topical steroid for pimecrolimus and vehicle:
All patients: (mean) 14.2% (SD 24.2) vs. 37.2% (SD 34.6), p<0.001
All patients: (median) 2.1% vs. 27.8%
For those with moderate disease: (mean) 9.5% (SD 19.8) vs. 37.0% (SD 36.3), p<0.001
For those with moderate diseae: (median) 0.0% vs. 23.5%
For those with severe disease (IGA 4): (mean) 23.1% (SD 29.5) vs. 37.8 (SD 30.4), p=0.027
For those with severe disease: (median) 7.7% vs. 35.2%

% of patients with no steroid use: 49% vs. 21.9%

Mean # of flares at study end: 1.1 flares (95% CI 0.7–1.4) vs. 2.4 (95% CI 2.0–2.8), p<0.001 vs. vehicle

% of patients with no flare at study end: 44.8% vs. 18.8%

% of patients classified as treatment success per IGA score of ≤2: 68.6% vs. 36.5%, p-value=NR

Patient's self assessment of their disease as completely or well-controlled: 64.6% vs. 35.4%, p-value=NR

Pruritus score at week 24: not reported; scores from day 1–7 were reported instead (see Fig 4 in trial)

% EASI score declined from baseline: 48.3% vs. 15.9%, p<0.001
NRFive patients discontinued due to AE (1 patient in the pimecrolimus arm had an aneurysm, which was not suspected to be study drug-related; 3 patients in the vehicle arm had contact dermatitis and 1 had application site reaction).

10 pimecrolimus-treated patients vs. 3-vehicle treated patients experienced application site burning which resolved within 1–7 days.

18.8% vs. 9.4% of pimecrolimus-and vehicle-treated patients had at least 1 skin infection by month 6 (95% CI −19.1 to 0.4). This was mainly due to higher herpes infection rates in the pimecrolimus than vehicle arms (10 vs. 5) whereas the rates of bacterial (4 vs. 3) and fungal (2 vs. 1) infections were similar. 6 of 10 cases in the pimecrolimus arm were due to herpes labialis (areas not treated with study medication) compared with 1 of 5 in the vehicle arm.

There were 2 cases of eczema herpeticum in the vehicle group.

(No other AE data were reported)
58 (30.2%)
5
Pruritus score at the end of study were not reported.

Authors did not report what type of herpes infections occurred for the remaining 4 patients in the pimecrolimus arm or the remaining 2 patients in the vehicle arm.
Meurer, 2004
Germany

companion to Meurer, 2002
(only patients with moderate disease were included in this analysis)
Double-blind, multicenter (16 sites)Adults with a clinical diagnosis of AD according to the criteria of Rajka; required to have AD affecting at least 5% of the total body surface area; patient's with an Investigator’s Global Assessment (IGA) score of 3 were included for this analysis.

Exclusion: PUVA, high-dose UVA or systemic therapy with corticosteroids, immunosuppressants or cytostatics (previous 3 months); topical therapies for AD (previous 2 weeks); systemic antibiotics (previous 2 weeks); systemic steroids for indications other than AD (previous 1 month). Other exclusion criteria comprised: pregnancy or lactation; women of child-bearing age not using reliable contraception; need for treatment with potent topical steroids for control of AD; severe concurrent allergic diseases; diseases associated with immunosuppression or malignancy; presence of skin conditions that could affect the evaluation of study treatment; active skin infections requiring treatment with a prohibited medication, or active herpes simplex infections.
NRPimecrolimus 1% cream vs. vehicle; applied twice daily in order to prevent disease flare x 6 mos

Nonmedicated emollients were applied to dry skin after study medication.

A moderatley potent topical steroid, prednicarbate 0.25% cream if the patient experienced unacceptable itcing and clinical signs (oozing/crusting or excessive scratch marks or severe erythema) despite study medication.

Topical steroid was to be used for a max of 7 days twice daily followed by a further 7 days every other day or until marked reduction of the signs of AD were achieved. After each course of sterid there was a mandaory treatment for 7 days with the study drug.
NR/NRNonmedicated emollients and cetirizine.Primary endpoint: % of days on topical steroids (to assess pimecrolimus in preventing disease flares)

Secondary endpoint: # of flares, time to 1st flare, IGA score, EASI score, pruritus assessment, patient's self-assessment, DLQI QoLIAD

Baseline, weeks 1, 3, 6, 12, and 24. There was additional telephone contact during weeks 9 and 18 and unscheduled visits in the event of flares.
29.2–31.4 (SD 9.7–10.0)
Female 59.7–63.2%
White 97.9–100%
Total BSA involved: mean 12.7–13.9% (SD 5.8)

mean EASI: 8.6–9.3 (SD 3.9–4.0)

IGA score:
3 (moderate): 64.6–70.8%
4 (severe): 29.2–34.4%
5 (very severe): 0.0–1.0%
197
192
192
130 (had moderate disease)
32
NR
130
% of days of topical steroid for pimecrolimus and vehicle: 9.7% vs. 37.8%, p<0.001
% of patients with no steroid use: 59.7% vs. 25%

Mean # of flares at study end: 1.0 flares (SD 1.5) vs. 2.3 (SD 2.5), p<0.001

% of patients with no flare at study end: 59.7% vs. 22.1%, p<0.001

% of patients classified as treatment success per IGA score of ≤2: 80.6% vs. 36.8%, p<0.001

Patient's self assessment of their disease as completely or well-controlled: 72.6% vs.38.2%, p<0.001

% decrease in pruritus score at week 24: 69.3% vs. 35.3%, p<0.001

% EASI score declined from baseline: 71.1% vs. 11.6%
Raw scores for pimecrolimus: from 8.8 to 2.1
Raw scores for vehicle: from 8.5 to 5.2

Mean decrease (ie, improvement) in QoLIAD score: 34.9% vs. 10.5%
Mean decrease (ie, improvement) in DLQI score: 22.9% vs. 0.9%
Data were not shown
NRNo patients in the pimecrolimus group and only 3 patients in the vehicle arm withdrew due to AE. Local application site reactions were the most common AE: 14.5% pimecrolimus vs. 8.8% vehicle arm. A total of 21.0% of pimecrolimus and 11.8% vehicle-treated patients experienced skin infections during the study. Herpes simplex infection occurred in 11.3% pimecrolimus vs. 4.4% vehicle.

Table 3 in the trial provides more detail of AE.
32 (24.6%)
3
Siegfried, 2006
US
Fair
Double-blind, multicenter (35 centers)

Randomized 2:1 (pimecrolimus: vehicle)
3 mos-11 yrs with mild to severe AD; at least 5% of total BSA; AD diagnosed using Sampson’s criteria for subjects <2 yrs and Williams’ criteria for > 2 yrs; AD severity determined using Investigator’s Global Assessment (IGA).

Exclusion criteria were immunocompromised children; those with a concurrent skin disease that could interfere with evaluations; patients with AD triggered by a known, unavoidable allergen or irritant; and those with an active viral or bacterial infection. Excluded therapies for the duration of the study were all topical and systemic agents known or thought to be effective in treating AD, including sedating antihistamines.
NRPimecrolimus 1% cream versus vehicle' applied twice daily x 6 months.

After 7 days, if the AD had not improved or had worsened to the point at which the investigator judged it was severe (IGA>4), a major flare regimen was introduced. In this flare regimen, the evening study drug dose was replaced with a mid-potency topical CS with demonstrated once-daily (qd) efficacy in AD.

Rescue steroids for major flare-ups:
fluticasone propionate 0.05% cream for all patients and mometasone furoate 0.1% cream for subjects >2 yrs x 3 weeks maximum.

A mandatory 7-day CS-free period must have elapsed before another 3 weeks of the flare regimen could be started. The subject or caregiver was contacted by telephone each week during periods of the major flare to monitor compliance, flare duration, and steroid use.
Run-in: NR

Washout: 1-month for systemic anti-inflammatory agents or phototherapy; 1-week for all topical agents except low-or mid-potency steroids; 2-week for all systemic antibiotics
Nonmedicated emollientsIGA, EASI, pruritus severity score (4-point scale).

IGA and EASI scores recorded weekly x 1st month then monthly to the end of the study (at 6 months). Pruritus score recorded daily on diary cards for 1st 3 weeks.

Primary endpoint: % of patients with no major flares over 6 months. Definition of flare: after 7 days, if the AD had not improved or had worsened to the point at which the investigator judged it was severe (IGA>4), a major flare regimen was introduced.

Secondary endpoints: # of days of steroid use; change in EASI score; daily pruritus score; # of major flares over 24-weeks; # of days to onset of 1st flare; # of days between 1st and 2nd flare; time to reach pruritus score improvement by at least 1 point
59.9 (SD 38.98)
NR
NR
IGA mean score: 2.9 (moderate severity)
Pruritus severity score (mean): 1.9
Total body surface area affected: 29%
NR
NR
275
59
20
272 (98.9%)
% of those with no single major flare x 6 mos for pimecrolimus and vehicle: 51.9% vs. 34.1%, p=0.007
% of those with at least 1 major flare x 6 mos: 40.3% vs. 56%, p= NR
% of those with > 2 major flares x 6 mos: 7% vs. 23%, p= NR

# of days to onset of first major flare (median): 53 days vs. 13 days, p<0.001 between groups
# of days between first and second major flares (median): 31 days vs. 15 days, p=0.003
# of days of topical steroid use (mean): 10.9 days vs. 17.3 days, p=0.002
EASI score at 6 mos: NR
IGA scores at 6 mos: NR
EASI and IGA scores were reported for day 8 instead (see study)

The difference in EASI and IGA narrowed over time and lost significance, subsequent to introduction of topical steroid.
Did not report who assessed AE; confirmatory viral culture for all suspected cases of eczema herpeticum were takenAE were similar in overall incidence and type. Most AE represented typical childhood illnesses. There was no statistically significant between-treatment difference by crude incidence or time-adjusted analysis except for rhinorrhea (pime 9.8% vs. 2.2% vehicle, p=0.025). AE types: diarrhea, vomiting, ear infection NOS, impetigo, otitis media NOS, upper respiratory tract infection, pyrexia, cough, nasal congestion, nasopharyngitis, rhinorrhea

The most common suspected drug-related AE: application site reaction in 2.2% in each arm)

1-case of impetigo in pime arm was considered severe; no cases of eczema herpeticum were reported in either arm; crude incidence of each type of skin infection was usually <2% and none showed statistically significant between-treatment difference.
59 (Pime:28%, Vehicle: 18%)
NR
Withdrawals due to AE were not reported; EASI and IGA scores at end of the study were not reported
Staab, 2005
Germany

companion to Kaufmann, 2004
same as Kaufmann, 2004same as Kaufmann, 2004same as Kaufmann, 2004same as Kaufmann, 2004same as Kaufmann, 2004same as Kaufmann, 2004In addition to the above outcomes:
Parent's QoL was measured at baseline and at 4 weeks using the PQoL-AD (different from PIQoL-AD) and % change in SCORAD index was reported for this paper.
same as Kaufmann, 2004same as Kaufmann, 2004same as Kaufmann, 2004same as Kaufmann, 2004Mean % change from baseline in SCORAD index for pimecrolimus and vehicle: −55.2% vs. +1.1%, p=0.002

Mean % change from baseline: all 5 domains, p<0.05 vs. vehicle
Most notable were:
Psychosomatic well-being: 14.6% change vs. 6.22%
Emotional coping: 16.1% vs. 6.5%
Acceptance of disease: 19.6% vs. 6.98%

Analysis of the relationship between various scoring methods (IGA, EASI, SCORAD) and QoL showed weak correlations.
NRNot primary focus. Data were not shown. Authors only report that parent's reports of application site reactions were rare, occurring in only 1-patient in each group.same as Kaufmann, 2004
Van Leent, 1998
Netherlands
Fair
Double-blind, single- center

(proof of concept)
All patients had AD according to the criteria of Hanifin and Rajka with at least 1% of the body surface area affected on both arms. For assessment of severity of the dermatitis weused the Atopic Dermatitis Severity Index (ADSI).

Exclusion criteria were as follows: patients receiving radiation therapy, systemic therapy with cytostatics, or immunosuppressive drugs within 24 weeks before randomization; receiving phototherapy or systemic therapy for AD within 1 month before randomization; receiving antibiotics or topical therapy for AD within 2 weeks before randomization (however, the once- daily use of 1% hydrocortisone acetate was allowed on all lesions with the exception of the test sides selected for the study, and emollients were allowed to be used liberally but not on the test sides); taking antihistamines within 1 week before randomization; and acute skin infection (superinfection) at randomization.
NRPimecrolimus 1% cream vs. vehicle; applied twice daily or once daily; applied to either the left arm or right arm x 3 weeks.NR/NRHydrocortisone acetate 1% on all other leisons except the study specific onesADIS scoring method

Baseline, days 4, 11, 21
29.1–35.8 (SD 13.2– 13.7)
43.7–61.1%
NR
Mean ADSI score for pimecrolimus and vehicle:
Twice daily arm: 8.1 (SD 1.2–1.4)
Once daily arm: 7.7–7.8 (SD 1.2–1.3)
38
NR
34
7
NR
34
For twice daily dosing arm:
Mean % change in ADSI score from baseline for pimecrolimus and vehicle: 71.9% vs. 10.3%, p<0.001

For once daily dosing arm:
Mean % change in ADSI score from baseline: 37.7% vs. 6.2%
NRDetailed report of AE were not reported. Authors state that "no skin irritations or any other local adverse events were observed. No relevant changes were observed in the patients' lab test values…all vital signs and results of physical examinations were normal. There were no clinically signficant adverse effects (ie, drug-related adverse events)."7
NR
Wahn, 2002
europe, US, Canada, S.
Africa, Austrailia
Fair
Double-blind, multicenter
(53 centers)

Randomization 2:1
(pimecrolimus:vehicle)
2–17 yrs; had a diagnosis of AD according to the criteria of Williams et al; AD affecting at least 5% of total body surface area and an Investigators’ Global Assessment (IGA) score of ≥2.

Excluded if they had received phototherapy or systemic therapy known or suspected to affect AD up to 1 month before the first application of study medication, topical therapy known or suspected to affect AD up to 7 days before the first application of study medication, or systemic antibiotics up to 2 weeks before the first application of study medication. Also excluded were patients who had infections that required treatment with prohibited medications (ie, generally medication that could affect a patient’s AD) or skin conditions that could affect the evaluation of study treatment.
NRPimecrolimus 1% cream vs. vehicle; applied twice daily x 12 mos; emollients were mandated and moderately potent topical steroids were allowed for flares not controlled by study medication. Topical steroids were to be administered until clearance or until the maximum treatment duration allowed by the local country label was reached. Treatment with corticosteroid was followed by a week of treatment with study medication for residual disease.

Corticosteroids used were: 0.02% difluprednate cream, 0.25% prednicarbate cream, 0.1% hydrocortisone butyrate cream, 0.05% clobetasone butyrate cream, 0.02% triamcinolone acetonide cream, and 0.2% hydrocortisone valerate cream.
NR/NRAntihistamines/H1 blockers if stable dose throughout study could be ensuredPrimary endpoint: rate of flares at 6 mos

Secondary endpoints: rate of flares at 12 mos, IGA score, EASI score
7.9–8.0 yrs
Female 52.7%
NR
mean EASI: 13.3–13.8

% of mean total BSA affected: 23.8– 24.2%

IGA score:
1 (almost clear): 0–0.2%
2 (mild): 26.2–27.8%
3 (moderate): 50.6–55.3%
4 (severe) 15.6–17.7%
5 (very sever) 2.7–3.8%

Note: 1 patient had an IGA score of 1 at baseline; however, this patient had a baseline EASI score >10 (ie, mild- moderate disease)
733
713
713
272 (38.1%)
22
711 (99.7%)
% of patients without a flare for pimecrolimus and vehicle:
At 6 mo: 61.0% vs. 34.2%
At 12 mo: 50.8% vs. 28.3%

% achieving IGA score of 0 to 1: not reported (Authors report that the results were similar to EASI scores)

% reduction in median EASI score: (data not reported; estimated from graph) approx −61% vs. approx −39%

Outcomes that were not prespecified in the methods but were reported in the results section were: the % requiring steroids, % of days on steroids (see study for more details)
NRMost frequent AE were common childhood infections and ailments such as: nasopharyngitis, headache, bronchitis, influenza, cough, pyrexia, application site burning (10.5% pimecrolimus vs. 9.3% vehcile). The authors reported AE with ≥10% incidence (see Table 3 in study for more details).

There was slightly greater incidence of viral skin infections in the pimecrolimus- than vehicle arm (total rate: 12.4% vs. 6.3%, p=0.038; see Table 4 in study for more details).

10 patients in pimecrolimus arm vs. 2 patients in the vehicle arm had eczema herpeticum.
272
NR
IGA scores were not reported and other unprespecified outcomes were reported.

Withdrawals due to AE were not reported.
Zuberbier, 2007
Germany
Fair
Double-blind, multicenter (22 dermatologic and pediatric centers)2–17 yrs; history of severe AD determined by score of 8 or 9 in the Rajka and Langeland grading; in cases of active symptoms those who responded to prednicarbate cream 0.25% (max 21 day therapy) during the screening phase were eligible.

Those who received topical steroids within 7 days or phototherapy or systemic corticosteroids/immunosuppressantswithin 1 month prior to study entry were excluded; children with active acute viral infection or those who were immunocompromised were also excluded.
NRPimecrolimus 1% cream or vehicle; applied twice daily x 24 weeks
For flare-up, treatment with prednicarbate cream (topical steroid) 0.25% was reinstated twice per day in place of pimecrolimus cream till flare was controlled.

In case of a flare, treatment with prednicarbate cream was reinitiated by the patient instead of treatment with the study medication. Once flare was controlled, topical steroid was discontinued and study medication was resumed.
Run in: during in screening phase, patients were treated with prednicarbate 0.25% for at least 7 days (max 21 days). If there was no significant improvement after 21 dyas, patient was not eligible.

Washout: none. Patients were switched from prednicarbate cream to the study medication for at least 7 days.
Nonmedicated emollientsPrimary endpoint: was the need for topical steroid during the time between randomization and the end of the study. This was measured as the % of days on which pateints decided to use topical steroids instead of study medication.

Secondary endpoints: EASI score, the patient's overall self assessment scores, QOL measured at screening, 6 weeks of treatment and end of study using Children's Dermatological Life Quality Index, and Parents Index of quality of Life-AD
7.6 (SD 4.9), Female 52%
White 93%
Black 1%
Asian 5%
Other 1%
Rajka and Langeland score at screening: 8.3

IGA scores
3 (moderate disease): 39%
4 (severe disease): 42%
5 (very severe disease): 6%
195
NR
184
29
NR
NR
% of days that patients required additional steroids for pimecrolimus vs. vehicle: 29% of days (SD 25) vs. 35% of days (SD 25), (absolute difference 6%; 95% CI 11.8 to −2.3%, p=0.1841)

EASI score:
7 (SD 6) vs. 9 (SD 8), p=0.0827

Patient's Overall Self Assessment score: not reported

Parent's QoL (mean score) at week 24:
4.2 (SD 5.2) vs. 6.2 (SD 5.9)
Between-group difference: −2.0, p=0.047

Patient's (mean score) QoL at week 24:
3.6 (SD 3.7) vs. 4.6 (SD 4.6), p=0.225

Subgroup
% of days that patients required additional steroids for pimecrolimus vs. vehicle (for head/neck):
10% of days (SD 14) vs. 19% of days (SD 22), (95% CI 14.1 to 3.7%, p=0.0009)

% of days for the rest of the body
27% of days (SD 25) vs. 30% (SD 24), p=0.64

For subgroup with IGA score of 4 or 5 (severe to very severe disease): % of days of steroid application: 28% of days (SD 21) vs. 45% (SD 27), (absolute difference 17%; 95% CI 24.8 to 5.6%, p=0.0024)
Mean EASI score: 9 (SD 7) vs 13 (SD 10), p=0.0041
Patient's overall self-assessment score: 2.3 (SD 0.7) vs. 2. (SD 0.9), absolute difference −0.4; p=0.029
Did not report who assessed AE; patient and caregiver interviews were conducted and diary cards were utilized5 AE with suspected drug relationship occurred in 5 pimecrolimus-treated subjects compared with 10 AE in 4 vehicle-treated subjects.

1-patient randomized t vehicle had 6 allergic eye disorders.

2 patients on pimecrolimus reported application site reaction compared wit 1 patient (did not report how often these reactions occurred nor the types of reactions that were observed).
29/
NR
Rajka and Langeland scores did not corelate closely with active severe disease. 48% had severe to very severe AD at screening (IGA score of 4 and 5).

Patient's overall self-assessment score for the entire population was not reported. It was selectively reported for the subgroup analysis.

Withdrawals due to AE were not reported
Eichenfield, 2002
US
Fair
Double-blind, multicenter

This pooled study includes data from 2 larger unpublished trials. Both trials were of identical study design.

These 2 trials were later identified in the FDA dossier as study #305 and #307.
1–17 yrs; AD diagnostic criteria of Williams et al; AD affecting at least 5% of total body surface area (TBSA); an Investigator’s Global Assessment (IGA) score of 2 or 3, corresponding to mild to moderate disease; and receiving stable doses of an additive-free, basic bland emollient for at least 7 days before baseline (day 1).

Reasons for exclusion: pregnancy or nursing; phototherapy (eg, UVB, PUVA) or systemic therapy (eg, immunosuppressants, cytostatics) for AD within 1 month, or topical therapy (eg, tar, topical corticosteroids) within 7 days before the first application of study medication; systemic antibiotics in the 2 weeks before the first application of study medication; and significant concurrent disease.
NRPimecrolimus 1% cream, vehicle cream; applied twice daily x 6 weeks

2: 1 randomization
NR/NRBland emollientsIGA score ≤1, EASI, patient assessment of pruritus (score system), patient assessment of overall disease control

Baseline, and on days 8, 15, 22, 29, and 43.
Pooled results: 6.6–6.8 yrs
Female 47.6–54.4%
White 48.5–54.7%
Non-white: 45.3–51.5%
IGA
Mild 30.0–31.6%
Moderate 57.4–60.3%
Severe 8.1–8.6%
Very severe 1.1–2.9%

%TBSA
25.5–26.1%

Mean EASI: 12.7–12.9
Pooled

NR
NR
403
Pooled

64 (15.8%)
NR
403
NR
Pooled:D
Reported as pimecrolimus vs. vehicle

% achieving IGA score ≤ 1: 34.8% vs. 18.4%, p≤0.05

% improvement in EASI score: −45% vs. −1%, p≤0.001

Actual data not reported for patients who reported mild or no pruritus. Authors report that more pimecrolimus-treated patients reported mild-no pruritus than placebo-treated patients. Data at day 43 were not provided for both treatment arms. An estimate based on figure 4: 56% vs. 35%, p<0.001

Actual data not reported for % of patients reporting good or complete control of their disease. An estimate from Figure 5 (3-dimensional bar graph): 60% vs. 40%, p<0.05
NRFor pimecrolimus vs. vehicle:

Application site burning: 10.4% vs. 12.5%
Nasopharyngitis: 10.1% vs. 7.4%
Cough 11.6% vs. 8.1%
Headache NOS 13.9% vs. 8.8%
Upper respiratory tract infection 14.2% vs. 13.2%
64 (15.8%)
9 (2.2%)
Study #305 (From FDA reviews)see abovesee abovesee abovesee abovesee abovesee abovesee above6.4–6.9 yrs
Female 48.5–51.5%
White 50.0–58..5%
Black 14.6–17.6%
Asian 10.0–11.8%
Other 16.9–20.6%
Weight 27.9–28.9 kg
Height 117.5–121.4 cm

IGA score
Mild 21.5–26.5%
Moderate 55.9–63.8%
Severe 11.8–12.3%
Very severe 2.3–5.9%
% TBSA: 27.4–29.7%
219
NR
198
36 (18.2%)
6 (3%)
198
For pimecrolimus vs. vehicle:

IGA score ≤1: 37.7% vs. 16.2%, p=0.002

Frequency of pruritus score:
Score of 0 (absence of itch): 13.8% vs. 0.0%, p=0.001
Score of 1 (mild presence of itch): 36.2% vs. 32.4%, p=NR
see abovesee above12.3% vs. 29.4% (total 18.2%)
NR
Primary reason for withdrawal lack of efficacy 4.6% vs. 23.5% (total 11.1%), p=0.001
Study #307
(From FDA reviews)
see abovesee abovesee abovesee abovesee abovesee abovesee above6.7–6.9 yrs
Female 43.8–60.7%
White 47.1–51.1%
Black 27.7–33.8%
Asian 1.5–3.6%
Other 17.5%
Weight 30.2–31.3 kg
Height 121.7–123.5 cm

IGA score
Mild 36.8–38%
Moderate 56.9–58.8%
Severe 4.4–5.1%
%TBSA 22.7–23.6
272
NR
205
28 (13.7%)
8 (3.9%)
205
For pimecrolimus vs. vehicle:

IGA score ≤1: 32.1% vs. 20.6%, p=0.076 (NSD)

Frequency of pruritus score:
Score of 0: 17.5% vs. 4.4%, p=0.009
Score of 1: 45.3% vs. 30.9%, p=NR
see abovesee above10.2% vs. 20.6% (total 13.7%), p=0.047

2.2% vs. 2.9% (total 2.4%), p=NSD
Primary reason for DC was unsatisfactory therapeutic effect: 0.7% vs. 7.4% (total 2.9%)

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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