Topical calcineurin inhibitors

Bibliographic informationStudy type and evidence levelNumber of patients and patient characteristicsPopulation characteristicsComparisonResults and commentsReviewer comment
Staab D;Kaufmann R;Brautigam M;Wahn U;
2005110
Study Type:
Randomised Control Trial

Evidence Level: 1+
Total number of patients = 195

Pimecrolimus cream 1%
N = 129

Vehicle
N = 66
Children included in a vehicle-controlled RCT of pimecrolimus (Breuer 2004,300 Kaufmann 2004301)Pimecrolimus cream 1% applied twice daily vs vehicle applied twice dailyOutcomes at 4 Weeks:
PQOL-AD psychosomatic wellbeing (mean score change)
+0.3 (14.6%) vs +0.1 (6.2%), p<0.05

PQOL-AD effects on social life (mean score change)*
+0.2 (6.5%) vs 0 (2%), p<0.05

PQOL-AD confidence in medical treatment (mean score change)*
+0.3 (10%) vs +0.1 (3.5%), p<0.05

PQOL-AD emotional coping (mean score change)
+0.4 (16.0%) vs +0.1 (6.5%), p<0.05

PQOL-AD acceptance of disease (mean score change)
+0.3 (19.6%) vs +0.1 (6.9%), p<0.05
Source of Funding: Novartis

*values estimated from graphs

PQOL-AD: quality of life in parents and children with atopic dermatitis
McKenna SP;Whalley D;De PY;Staab D;Huels J;Paul CF;Assche D;
2006109
Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 384

Pimecrolimus cream 1% applied twice daily
N = 283

Vehicle applied twice daily
N = 101
Quality of life data for children included in two vehicle-controlled RCTs of pimecrolimus cream 1% (Wahn 2002297 and Kapp 2002302).

154 infants included in the PIQOL-AD results
230 children in the PIQOL-AD results
144 children in the CDLQI results
Pimecrolimus cream 1% applied twice daily vs vehicle applied twice dailyOutcomes at 12 Months:
PIQOL-AD (mean score change in infants)
−4.9 (51%) vs −1.8 (21%)
OR 1.8 (95% CI 1.12 to 2.92), p=0.016

PIQOL-AD (mean score change in children)
−3.8 (41%) vs −2.3 (26%)
OR 1.46 (95% CI 1.08 to 1.98), p=0.015

CDLQI (mean score change in children)
2.12 (95% CI 0.52 to 3.71), p=0.01
Whalley D;Huels J;McKenna SP;van AD;
2002296
Study Type:
Randomised Control Trial

Evidence Level: 1+
Total number of patients = 278

Pimecrolimus cream 1%

N = 158

Vehicle
N = 83
Children aged up to 8 years who were included in the Eichenfield 2002295 study (n=278; 69% of the total study population).

Mean age about 4 years (range 1–7 years). Baseline mean PIQol-AD scores were 9.4 pimecrolimus vs 8.8 vehicle.
Pimecrolimus cream 1% applied twice daily vs vehicle applied twice dailyOutcomes at 6 Weeks:
PIQoL-AD (mean change from baseline)
−3.3 (35%) vs −1.3 (15%), p=0.023

PIQoL-AD (least squares mean change)
−3.20 vs −1.63 (difference 1.57, 95% CI 0.22 to 2.92)
Source of Funding: Novartis Pharmaceuticals Corporation

Only results for 80% were available at 6 weeks.

Following the 6-week controlled phase, children from both groups were offered treatment with pimecrolimus for up to 6 months. QOL data at 6 months [EL=3] were also shown in the report, which indicated further reductions in scores (improvement).
Reitamo S;Harper J;Dbos J;Cambazard F;Bruijnzeel-Koomen C;Valk P;Smith C;Moss C;Dobozy A;Palatsi R;
2004265
Study Type:
Randomised Control Trial

Evidence Level: 1+
Total number of patients = 624
Tacrolimus ointment 0.03% once daily
N = 207
Tacrolimus ointment 0.03% twice daily
N = 210
Hydrocortisone acetate 1%

N = 207
Children aged 2–15 years (mean about 7 years) with moderate-severe AE affecting 5% or more of BSA (mean 37–39%).Tacrolimus ointment 0.03% applied once daily vs tacrolimus ointment 0.03% applied twice daily vs hydrocortisone acetate 1% applied twice dailyOutcomes at 3 Weeks:
Modified EASI (median score change)
70% vs 78.7% vs 47.2%, p<0.001 both tacrolimus groups vs HC, p=0.007 between tacrolimus groups

EASI (median score change)
66.7% vs 76.7% vs 47.6%, p<0.001 both tacrolimus groups vs HC, p=0.015 between tacrolimus groups

Physician's global evaluation (at least 90% improvement)
27.8% vs 36.7% vs 13.6%, p value not reported

Physician's global evaluation (at least 50% improvement)
74.1% vs 81% vs 52.9%, p value not stated

Patient/parent's evaluation (% better or much better) 67% vs 82.9% vs 50.7%, p value no reported

Itch (mean score change on 10cm VAS) −48% vs −57% vs −32%, p value not stated

Sleep quality (mean change on 10cm VAS +27% vs +45% vs +25%, p value not reported

Adverse effects*
23.2% skin burning
18.4% pruritus
3.9% folliculitis
2.9% flu syndrome vs
23.8% skin burning
21.4% pruritus
5.2% folliculitis
5.7% flu syndrome vs
14.5% skin burning, p=0.028 both tacrolimus groups vs HC
15.9% pruritus
3.9% folliculitis
5.3% flu syndrome
Source of Funding: Fujisawa GmbH, Munich

Treatment was given for 2 uninterrupted weeks, and for a further 7 days after clearance.
Bath oil and nonmedicated emollients were permitted.

Modified EASI includes an assessment of itch.

*the most common adverse effects (occurring in 5% or more). Additionally skin infection occurred in 1.4% vs 2.9% vs 2.9%, p=NS
Wahn U;Bos JD;Goodfield M;Caputo R;Papp K;Manjra A;Dobozy A;Paul C;Molloy S;Hultsch T;Graeber M;Cherill R;De PY;Flare Reduction in Eczema with Elidel (Children) Multicenter Investigator Study Group.; 2002297Study Type:
Randomised Control Trial

Evidence Level: 1+
Total number of patients = 713

Pimecrolimus cream 1%
N = 476

Vehicle
N = 237
Children aged 1–17 years (mean 8 years) with atopic eczema affecting at least 5% of BSA (mean 24%), and IGA score of 2 or more on a 6-point scale; at baseline 26.2% pimecrolimus vs 27.8% vehicle had mild disease (score of 2), 55.3% vs 50.6% moderate, 15.6% vs 17.7% severe, 2.7% vs 3.8% very severe.
Baseline EASI score 12.8 (mean).

Exclusions:
phototherapy or systemic therapy within 1 month
Pimecrolimus cream 1% applied twice daily (plus usual care)*
vs
vehicle applied twice daily (plus usual care)*
Outcomes at 12 Months:
% with no flares of atopic eczema 50.8% vs 28.3%, p<0.001

Time to first flare 'significantly longer' in the pimecrolimus group; p<0.001. No numerical data

EASI (median change from baseline, estimated from graph)
−60% vs −40%

% using TCS
42.6% vs 68.4%

Duration of use:
57.4% vs 31.6% used 0 days
17.1% vs 27.5% used 1–14 days
25.5% vs 41% used for >14 days

Mean % time using TCS: 4.08% vs 9.10%

Adverse effects
24.7% suspected drug-related adverse effect
28.9% nasopharyngitis
23% headache
13.2% bronchitis
14.6% influenza
19.3% cough
15.4% pyrexia
10.5% application-site burning
14.2% bacterial skin infection
12.4% viral skin infection
vs
18.7% suspected drug-related adverse effect
27.1% nasopharyngitis
21.5% headache
13.7% bronchitis
9.5% influenza
11.8% cough, p=0.04
11.8% pyrexia
9.3% application-site burning
30.9% bacterial skin infection
6.3% viral skin infection, p=0.038

RR of having a flare 0.69 (95% CI 0.61 to 0.77)

Outcomes at 6 Months: % with no flares of atopic eczema 61% vs 34.2%, p<0.001
Source of Funding: Novartis Pharma AG

Double-blind.

*treatment was applied to the affected areas at the first sign (erythema) or symptom (pruritus) of atopic eczema, to prevent progression to flare. Emollients were used in both groups to treat dry skin. Moderately potent TCS were mandated in both groups for flares not controlled by study medication (i.e. at least severe erythema and severe infiltration/papulation; IGA score of 4 or more). Treatment with TCS was followed by 1 week of treatment with study medication for 'residual disease'.

14.2% vs 7.0% used study mediation continuously.

Antihistamines were permitted if the dosages used was stable; they were used by 57.2% of the pimecrolimus group vs 62.9% vehicle.

Discontinuation rates at 12 months were 31.6% pimecrolimus vs 51.5% vehicle; p value was not reported, but the difference between groups was reported to be 'significant'. The main reason for discontinuation was unsatisfactory therapeutic effect (12.4% vs 30.4%).

IGA was also measured as an outcome but no data were reported.

Other than the adverse effects for which p values are given, no other statistically significant differences were reported between groups.
Kapp A;Papp K;Bingham A;Folster-Holst R;Ortonne JP;Potter PC;Gulliver W;Paul C;Molloy S;Barbier N;Thurston M;De PY;Flare Reduction in Eczema with Elidel (infants) multicenter investigator study group.; 2002302Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 250

Pimecrolimus cream 1% applied twice daily*
N = 204

Vehicle*
N = 46
Children aged 3–23 months (mean 12 months) with AE affecting at least 5% of BSA (mean 28%), and IGA score of 2 or more: 32.8% pimecrolimus vs 39.1% vehicle groups had mild disease, 57.4% vs 47.8% moderate, 8.3% vs 10.9% severe, 1.5% vs 2.2% very severe. Baseline EASI score was 12 (mean).

Exclusions: immunocompromised, active skin infections, other skin infections or other infections that might interfere with the study.
Pimecrolimus cream 1% applied twice daily* vs vehicle applied twice daily*Outcomes at 12 Months:
% with no flares of AE
56.9% vs 28.3%

Time to first flarepimecrolimus was associated with a significantly longer flare-free period’, p<0.001

Number of flares per person (mean) 1.0 vs 2.2, p<0.001

% using TCS
63.7% vs 34.8% used none.
Duration of use 3.2% vs 6.2%

IGA (score of 0 or 1)
53.9% vs 47.8%, p=NS

EASI (mean score change)
−7.3 (59%) vs −5.7 (45%)

Pruritus (score of 0 or 1)
77% vs 63%, p=0.337

Adverse effects 6.5% application-site reactions
27% at least one skin infection vs 14.7% application-site reactions, p=0.104
27.6% at least one skin infection, p=0.728

Outcomes at 6 Months:
IGA (score of 0 or 1)
52.9% vs 37.0%, p=0.03

% with no flares of AE
67.6% vs 30.4%
Source of Funding: Novartis Pharma AG

Double-blind.

*study medication was applied at the first sign (erythema) or symptom (pruritus) of AE, to prevent progression to flares. Emollients were used in both groups to treat dry skin. Moderately potent TCS were allowed in both groups for flares not controlled by study medication (IGA score of at least 4). Treatment with TCS was followed by a week of treatment with study medication for residual disease.

15.7% pimecrolimus vs 34.8% vehicle withdrew at 6 months, and 24.5% vs 39.1% at 12 months, p=0.016.

IGA, pruritus and caregiver assessment all measured on a scale of 0–3.
Boguniewicz M;Fiedler VC;Raimer S;Lawrence ID;Leung DY;Hanifin JM; 1998292Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 180
Tacrolimus ointment 0.03%
N = 43
Tacrolimus ointment 0.1%
N = 49
Tacrolimus ointment 0.3%
N = 44
Vehicle N = 44
Children aged 7–16 years (mean about 10 years) with 5–30% BSA affected with AE (mean ranged from 15–19% across groups, p=0.049).

Exclusions: in need of antimicrobial treatment
Tacrolimus ointment 0.03% applied twice daily vs tacrolimus ointment 0.1% applied twice daily vs tacrolimus ointment 0.3% applied twice daily vs vehicle applied twice dailyOutcomes at 22 Days:
75% improvement or more in physician’s global assessment
69% vs 67% vs 70% vs 38%, p<0.004 for all tacrolimus groups vs vehicle

EASI (% improvement in scores)
72% vs 77% vs 81% vs 26%, p<0.001 all tacrolimus group vs vehicle

Head & neck total score (% improvement)
65% vs 83% vs 81% vs −2%, p<0.001 all tacrolimus groups vs vehicle

Patients global assessment (% feeling better or much better)
76% vs 91% vs 91% vs 52%, p<=0.025 all tacrolimus groups vs vehicle

Pruritus (% reduction in scores)
no numerical data; ‘significantly’ greater for tacrolimus-treated patients vs the vehicle group, p=0.027

Adverse effects
20.9% burning
25.6% pruritus
0 erythema vs 10.2% burning
20.4% pruritus
2% erythema vs 6.8% burning
15.9% pruritus
4.5% erythema, p=NS for all between group differences

Mean tacrolimus blood concentrations
0.07 ng/ml (SD 0.10) vs
0.09 ng/ml (SD 0.31) vs
0.18 ng/ml (SD 0.21) vs

Outcomes at 4 Days:
Mean tacrolimus blood concentrations
0.10 ng/ml (SD 0.17) vs
0.21 ng/ml (SD 0.32) vs
0.31 ng/ml (SD 0.41)
Drake L;Prendergast M;Maher R;Breneman D;Korman N;Satoi Y;Beusterien KM;Lawrence I; 2001294Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 323

Tacrolimus ointment 0.03%
N = 1171

Tacrolimus ointment 0.1%
N = 118

Vehicle
N = 116
Children and toddlers included in the Paller 2001293 study.
178 children mean age 9 years
145 toddlers (not defined), mean age 3 years.
Tacrolimus ointment 0.03% applied twice daily
vs
Tacrolimus ointment 0.1% applied twice daily
vs
Vehicle applied twice daily
Outcomes at 12 Weeks:
CDLQI in children (mean score change)*
−24.4 vs −24.1 vs −8.1, p=0.000 both tacrolimus groups vs vehicle, p=0.937 between tacrolimus groups

CDLQI in toddlers (mean score change)*
−30.8 vs −35.6 vs −7.9, p=0.000 both tacrolimus groups vs vehicle, p=0.224 between tacrolimus groups
Source of Funding: Fujisawa Healthcare

*adjusted for baseline score. For the toddlers, relatives completed a version of the CDLQI (Toddler survey) modified based on recommendations from the developer.
Eichenfield LF;Lucky AW;Boguniewic z M;Langley RG;Cherill R;Marshall K;Bush C;Graeber M; 2002295Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 403

Pimecrolimus cream 1%
N = 267

Vehicle
N = 136
Children aged 1–17 years (mean 6.7 years) with atopic eczema affecting at least 5% of BSA (mean 26%), and IGA score of 2 or 3 (mild to moderate disease) on a 6-point scale. At baseline 30% pimecrolimus vs 31.6% vehicle had mild disease, 60.3% vs 57.4% moderate, 8.6% vs 8.1% severe, 1.1% vs 2.9% severe.
Baseline EASI score 12.8 (mean).
Pimecrolimus cream 1% applied twice daily vs vehicle applied twice dailyOutcomes at 6 weeks:
IGA (% with score of 0 or 1)
34.8% vs 18.4%, p <=0.05

Change in IGA score
59.9% vs 33.1% improved by 1 IGA score or more
36% vs 47.1% maintained baseline score
4.1% vs 19.9% worsened

Change in EASI score −45% vs −1%, p<=0.001

Pruritus severity (% with score of 0 or 1; estimated from graph) 55% vs 33%, p<0.001

Patients assessment of disease control (% reporting complete or good control; estimated from graph) 61% vs 40%, p<0.05

Adverse effects
44% reported one or more
28% local adverse effects
14.2% URTI
13.9% headache
11.6% cough
10.1% nasopharyngitis
10.4% application-site burning
1.9% discontinuation due to adverse effects vs
42.6% reported one or more
35% local adverse effects
13.2% URTI
8.8% headache
8.1% cough
7.4% nasopharyngitis
12.5% application-site burning
2.9% discontinuation due to adverse effects
Source of Funding: Novartis Pharmaceuticals Corp

This report represents pooled analysis from 2 RCTs.

Double-blind.

IGA scored on a 6-point scale of 0–5, none to very severe.

Pruritus was measured on a scale of 0–3, no itching/scratching to bothersome itching/scratching that disturbs sleep.

Children also received stable doses of an additive-free basic, bland emollient for at least 7 days before baseline.
Eichenfield LF;Lucky AW;Langley RG;Lynde C;Kaufmann R;Todd G;Lindsley L;Barbier N;Felser JM; 2005306Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 589

Pimecrolimus cream 1%
N = 390

Vehicle
N = 199
Children included in vehicle-controlled RCTs of pimecrolimus cream 1% (Ho 2003299 and Eichenfield 2002295).

Results for children of Caucasian origin (54%) were compared with those for children of non-Caucasian origin (41.8% Black, 11.6% Asian, 46.6% ‘other’, mainly Hispanic)
Pimecrolimus cream 1% applied twice daily vs vehicle applied twice dailyOutcomes at 6 weeks:
IGA score of 0 or 1 (Caucasian group)
45% vs 23.6%, p<0.02
(treatment effect 21.4, 95% CI 0.03 to 0.41)

IGA score of 0 or 1 (non-Caucasian group)
36.3% vs 15.7%, p<0.001
(treatment effect 20.6, 95% CI 0.09 to 0.30)

EASI (mean score change, Caucasian group)
−6.56 (SD 8.24) vs −1.22 (SD 6.04), p<0.001
(treatment effect −4.35 95% CI −5.65 to −3.04)

EASI mean score change (non-Caucasian group)
−5.83 (SD 7.9) vs −0.49 (SD 9.34), p<0.001
(treatment effect −5.37, 95% CI −7.44 to −3.29)

Adverse effects
application-site burning:
9% (Caucasian)
5.6% (non-Caucasian) vs
application-site burning:
9.1% (Caucasian)
10.1% (non-Caucasian)
Source of Funding: Novartis Pharmaceuticals Corp

The proportions of children with an IGA score of 0 or 1 in the three non-Caucasian subgroups were also reported, as was the % change in EASI scores.

IGA score of 0 or 1 (pimecrolimus vs vehicle):
34.2% vs 20.5% Black
42.9% vs 0% Asian
36.5% vs 15.0% other

Mean EASI score change:
−3.85 vs +0.28 Black
−6.33 vs −0.32 Asian
−7.41 vs +0.75 other
Ho VC;Gupta A;Kaufmann R;Todd G;Vanaclocha F;Takaoka R;Folster-Holst R;Potter P;Marshall K;Thurston M;Bush C;Cherill R; 2003299Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 186

Pimecrolimus cream 1%
N = 123

Vehicle
N = 63
Children aged 3–23 months (mean 12.6 months) with atopic eczema affecting 5% or more of BSA, and IGA score of 2 or 3 (mild or moderate) based on degree of erythema and infiltration/papulation; 32.5% pimecrolimus vs 33.3% vehicle groups mild, 67.5% vs 66.7% moderate.
Baseline EASI score 11.2 vs 10.2.

Exclusions: phototherapy or systemic therapy for AE within 1 month, topical treatment or sedating antihistamine within 1 week, immunocompromised, concurrent or active skin disease or viral skin infections.
Pimecrolimus cream 1% applied twice daily vs vehicle applied twice dailyOutcomes at 6 weeks:
IGA (score of 0 or 1)
54.5% vs 23.8%, p<0.001

EASI (mean score change)
−6.81 vs −0.75, p<0.001

EASI (median % change)
−81.6% vs −25%

Pruritus severity (score of 0 or 1)
72.4% vs 33.3%, p<0.001

Carers assessment (complete or good control)
71.5% vs 27%, p<0.001

Adverse effects
31.7% pyrexia
23.6% URTI
14.6% nasopharyngitis
8.1% teething
8.1% diarrhoea
8.1% restlessness
7.3% gastroenteritis
5.7% bronchitis
5.7% influenza
4.9% rhinitis
5.7% asthma
0.8% bacterial skin infection
vs
12.7% pyrexia, p<0.05
14.3% URTI
7.9% nasopharyngitis
4.8% teething
0% diarrhoea
4.8% restlessness
3.2% gastroenteritis
4.8% bronchitis
3.2% influenza
7.9% rhinitis
3.2% asthma
6.3% bacterial skin infection

Outcomes at 26 Weeks:
54.7% had IGA score of 0 or 1
EASI score remained at about 80% below baseline about 67% had absent/mild pruritus
27% pyrexia
21% URTI
16% nasopharyngitis
10% teething
9% bronchitis
9% otitis media
Source of Funding: Novartis Pharmaceuticals Corp

The 6-week randomised phase was double-blind. Following this, children were offered treatment with pimecrolimus cream 1% in an open, unblinded way.
Emollients were permitted only on areas untreated with study medication. During weeks 7–26, emollients were permitted on all skin areas, but applied to treated areas after study medication had been fully absorbed.

88.6% in the pimecrolimus group vs 52.4% in the vehicle group completed the 6-week DB phase.

Pruritus score was measured on a scale of 0–3, no itching/scratching to bothersome itching/scratching that disturbs sleep.
Kempers S;Boguniewicz M;Carter E;Jarratt M;Pariser D;Stewart D;Stiller M;Tschen E;Chon K;Wisseh S;Abrams B; 2004305Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 141

Tacrolimus ointment 0.03% applied twice daily
N = 70

Pimecrolimus cream 1% applied twice daily
N = 71
Children/young people aged 2–17 years with moderate atopic eczema (Investigator’s Global Assessment [IGA] score of 3 or more on a scale of 0–5). 83.6% were aged 2–12 years.

Exclusions: treatment with phototherapy or systemic corticosteroids within 1 month, topical therapy (not specified) within 1 week, or systemic antibiotics within 2 weeks.
Tacrolimus ointment 0.03% applied twice daily vs pimecrolimus cream 1% applied twice dailyOutcomes at 4 Days:
Application-site reactions
26% vs 24%

Warmth/burning/stinging
17% vs 2−%, p=0.931
(% with duration >30 mins: 67%) vs 0, p<0.001)

Erythema or irritation
19% vs 8%, p=0.039
(% with duration >30 mins: 85%) vs 0, p<0.001)

Increased itching
20% vs 8%, p=0.073
(% with duration >30 mins: 60%) vs 17%, p=0.559)

Outcomes at 6 weeks:
IGA score of clear or almost clear
42% vs 30%, p=0.119

Pruritus score of absent or mild
70% vs 64%, p=0.493

% body surface area affected
% change from baseline:
−45% whole body
−35% head/neck
−42% lower limbs
−38% upper limbs
−36% trunk
vs
% change from baseline:
−43% whole body
−54% head/neck
−29% lower limbs
−35% upper limbs
−40% trunk
Source of Funding: Novartis Pharmaceuticals Corporation

The primary outcome in the study was local tolerability. Data for day 4 were presented in detail in the report because these reactions ‘are most common during the first few days of therapy’. Incidence appeared to fall with time in both groups over the 6-week study period (data shown in graphs only).

Ease of application also reported. Data not reproduced here.

Discontinuation rates 4% tacrolimus vs 18% pimecrolimus.
Paller A;Eichenfield LF;Leung DY;Stewart D;Appell M; 2001293Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 351
Tacrolimus ointment 0.03%
N = 117
Tacrolimus ointment 0.1%
N = 118
Vehicle
N = 116
Children aged 2–15 years (61% aged 2–6 years, 39% 7–15 years), with moderate (38%) or severe (62%) AE involving 10–100% BSA (mean 45–49%). 83% had AE on head or neck.

Exclusions: other skin conditions, pigmentation, or scarring, infected AE
Tacrolimus ointment 0.03% applied twice daily
vs
Tacrolimus ointment 0.1% applied twice daily
vs
Vehicle applied twice daily
Outcomes at 12 weeks:
Success (improvement of 90% or more on physician’s global assessment)
35.9% vs 40.7% vs 6.9%, p<0.001 both tacrolimus groups vs vehicle

EASI (mean score change)
−14 vs −15 vs −2, p<0.001 both tacrolimus groups vs vehicle (values estimated from graph)

Pruritus (mean score change)
−4 vs −4 vs −0.8, p<0.001 tacrolimus groups vs vehicle (values estimated from graphs)

Patient’s global assessment
No numerical data. Statistical significance reported for both tacrolimus groups vs vehicle, p<0.001

% BSA affected (mean change)
−26% vs −27% vs −6%, p<0.001 both tacrolimus groups vs vehicle (values estimated from graph)

Adverse effects
43% skin burning
41% pruritus
5% varicella
4% vesiculobullous rash
3% sinusitis vs
34% skin burning
32% pruritus
1% varicella
1% vesiculobullous rash
1% sinusitis

29% skin burning, p=0.04 vs tacrolimus 0.03%
27% pruritus, p=0.03 vs tacrolimus 0.03%
0% varicella, p=0.042 vs tacrolimus 0.03%
0% vesiculobullous rash, p=0.042 vs tacrolimus 0.03%
8% sinusitis, p=0.046 vs tacrolimus 0.1%

Tacrolimus blood concentrations
No measurable concentration in 90% of 148 samples. Mean and median levels below limit of quantification (2ng/ml) at all time points. Range of values 0–2.28ng/ml.
Source of Funding: Fujisawa Healthcare

Emollients permitted on unaffected areas.

Discontinuation rates due to adverse effects: 5% tacrolimus 0.03%, 2.5% tacrolimus 0.1%, 8% vehicle.

Incidence of herpes simplex reported for tacrolimus groups combined and vehicle (2.6% vs 0.9% respectively). Incidence of molluscum contagiosum also 2.6% vs 0.9%.

Median duration of treatment (days): 85 tacrolimus 0.03%, 85 tacrolimus 0.1%, 46 vehicle.

Mean quantities used per day: 4.6g, 4.1g, 7.4g.
Reitamo S;Van Leent EJ;Ho V;Harper J;Ruzicka T;Kalimo K;Cambazard F;Rustin M;Taieb A;Gratton D;Sauder D;Sharpe G;Smith C;Junger M;De PY; 2002266Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 560

Tacrolimus ointment 0.03%
N = 189

Tacrolimus ointment 0.1%
N = 186
Children aged 2–15 years (mean about 7 years) with moderate to severe AE affecting 5–60% BSA (mean 23–26%).

Exclusions: skin disorders other than AE, history of eczema herpeticum
Tacrolimus ointment 0.03% applied twice daily
vs
Tacrolimus ointment 0.1% applied twice daily
vs
Hydrocortisone acetate 1% applied twice daily
Outcomes at 3 Weeks:
Modified EASI (median score change)
−55.2% vs −60.2% vs −36.0%, p=0.006 both tacrolimus groups vs HC, p=0.006 between tacrolimus groups

Physician’s global evaluation (at least 90% improvement)
38.5% vs 48.4% vs 15.7%, p=0.001 both tacrolimus groups vs HC, p=0.055 between tacrolimus groups

Tacrolimus blood concentrations
23.4% levels below limit of quantification
75% <=1ng/ml
1.6% 1 to <5ng/ml vs
12.4% levels below limit of quantification
76.3% <=1ng/ml
11.3% 1to <5ng/ml

Adverse effects
18.5% skin burning
13.2% pruritus
5.8% folliculitis
3.2% skin infection
2.1% skin erythema vs
20.4%
11.3%
4.3%
2.2%
0.5% vs
7.0%, p<0.05 both tacrolimus groups vs HC
7.6%
2.7%
2.2%
1.6%
Source of Funding: Fujisawa GmbH, Munich

Double-blind.

Bath oils and non-medicated emollients were allowed.

Modified EASI includes assessment of itch.

Of the tacrolimus blood concentrations, levels of 1ng/ml or more were seen in 1.6% of the tacrolimus 0.03% group, and 11.3% of the tacrolimus 0.1% group at some time point. No values exceeded 5ng/ml.
Lower limit of quantification was not reported.
Siegfried E;Korman N;Molina C;Kianifard F;Abrams K; 2006304Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 275

Pimecrolimus cream 1%
N = 183

Vehicle
N = 92
Children aged 3 months to 11 years (mean 39 months) with mild to severe AE (IGA score 2–4) involving 5% or more BSA (mean 29%). Mean IGA score 2.9 (scale 0–5 none- severe), mean pruritus severity score 1.9 (scale 0–3, none- severe).

Exclusions: immunocompromised children, concurrent skin disease, AE triggered by a known unavoidable allergen or irritant, active viral or bacterial infection.
Pimecrolimus cream 1% applied twice daily* vs vehicle applied twice daily*Outcomes at 6 Months:
% with no major flares
51.9% vs 34.1%, p=0.007

Mean duration of TCS use (days)
10.9 vs 17.3, p=0.002

Adverse effects
9.8% rhinorrhoea vs 2.2%, p=0.025
Source of Funding: Novartis Pharmaceuticals Corp

Double-blind study.

Emollients were applied to all areas of dry skin.

*used at the first sign or symptom of AE, plus a ‘major flare regimen’ was introduced if after 7 days pimecrolimus or vehicle plus emollient the condition had not improved, or worsened to a point where IGA 4 or more. A TCS (fluticasone propionate cream 0.05% or mometasone furoate 0.1% cream [the latter in children aged over 2 years]) was used at night during a flare, while pimecrolimus or vehicle continued to be used in the morning. The major flare regimen was used until all signs or symptoms of AE resolved or for a maximum of 3 weeks, after which twice daily use of pimecrolimus or vehicle resumed.

7% pimecrolimus vs 23% vehicle experienced more than 2 major flares.

Withdrawal rates 18% pimecrolimus vs 28% vehicle, due to unsatisfactory therapeutic effect in 3.8% vs 14.3%, p=0.003.
Rhinorrohoea was the only adverse effect occurring in significantly different proportions of children. Others were predominantly respiratory and gastrointestinal effects. Application-site reactions were the most common suspected drug-related adverse effects (2.2% in both groups).

Score change for EASI and pruritus were only reported for day 8; data not reproduced here.
Sikder M;Al MS;Khan RM;Chowdhury AH;Khan HM;Hoque MM;
2005267
Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 45

Clobetasone butyrate cream 0.05%
N = 15
Children aged 7–15 years with moderate- severe AE affecting 5–50% BSA (mean 25%).

Exclusions: other skin conditions, history of eczema herpeticum
Tacrolimus ointment 0.03% applied twice daily vs Clobetasone butyrate 0.05% applied twice daily vs Tacrolimus ointment 0.03% (evening) + clobetasone butyrate 0.05% (morning)Outcomes at 4 Weeks:
Modified EASI (median score change)
−81.9% vs −95.1% vs −98.7%, p=0.00 vs tacrolimus, p=0.018 clobetasone vs tacrolimus, p=NS clobetasone vs combination

% BSA affected (mean change)

−40% vs −66.7% vs −83.3%, p=0.00 vs tacrolimus, p=0.007 clobetasone vs tacrolimus, p=NS clobetasone vs combination

Investigator’s global evaluation (at least 90% improvement)
13.3% vs 66.7% vs 93.3%, p value not reported

Adverse effects
46% skin burning
20% itching vs 7%
13.3% vs 46%, p=0.010 tacrolimus vs clobetasone, p=0.042 clobetasone vs combination
6.7%, p=0.562
Breuer K;Braeutigam M;Kapp A;Werfel T;

2004300
Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 196

Pimecrolimus cream 1%
N = 130

Vehicle
N = 66
Children aged 3–23 months (mean 12 months) with AE affecting at least 5% of

BSA, and IGA score of 2 or more; 9.3% pimecrolimus vs 12.1% vehicle had mild AE, 58.1% vs 59.1% moderate, 26.4% vs 25.8% severe, 6.2% vs 3% very severe. Baseline EASI score 17 (mean).

Exclusions: ‘insufficient washout’ from other treatments for AE, concomitant disease that might interfere with the study, severe concurrent skin disease, active viral or bacterial infections
Pimecrolimus cream 1% applied twice daily vs vehicle applied twice dailyOutcomes at 16 Weeks*:
No numerical data for efficacy outcomes; but reported to be sustained. Adverse effects believed to be related to treatment:

6 children (2 cases of impetigo, 1 herpes simplex dermatitis, 1 varicella, 1 asthma, 1 aggravated atopic eczema, 1 exacerbated eczema).

Outcomes at 4 Weeks:
EASI (mean score change)
−71.5% vs +19.4%, p<0.001

EASI (mean score change in components)
−61.5% infiltration
−60.3% excoriation
−54% erythema
−37.1% lichenification vs
−4.3% infiltration
+24.1% excoriation
+7.4% erythema
+10.5% lichenification (all p<0.001 vs pimecrolimus)

IGA (mean score change) −50.7% vs −5.5%, p<0.001

IGA (score of 0 or 1) 53.5% vs 10.6%, p<0.001

SCORAD (mean score change) −55.2% vs +1.1%, p=0.002

Pruritus severity (mean score change) −59% vs +16%, p<0.001

Sleep loss (mean score change) −57% vs +5%, p<0.001

Dry skin (mean change in % with) −27.1% vs −5.3%, p<0.1

Adverse effects
63.8% reported at least one
2.3% treatment-related (1 application-site burning, 1 impaired healing, 1 burning sensation) vs 60.6% reported at least one
3.0% treatment-related (1 application-site burning, 1 erythema)
Source of Funding: Novartis Pharma AG

Double-blind.

Emollients were only permitted on areas not treated with study medication.

Correlations between changes in EASI, IGA and SCORAD scores were also reported - data not reproduced here.

Adverse effects were reported in a related publication (Kaufmann 2004301).

Drop-out rates: 10% pimecrolimus, 38% vehicle.

*after 12 weeks open-label, uncontrolled use.
Schachner LA;Lamerson C;Sheehan MP;Boguniewic z M;Mosser J;Raimer S;Shull T;Jaracz E;US Tacrolimus Ointment Study Group.;

2005307
Study Type: Randomised Control Trial

Evidence Level: 1+
Total number of patients = 317

Tacrolimus ointment 0.03%
N = 158

Vehicle
N = 159
Children aged 2–15 years (mean about 7 years) with mild to moderate AE affecting 2–30% of BSA (mean 12%).

Baseline EASI score 6, itch score 5 (on scale 0–10).

Exclusions: other skin conditions, previous use of tacrolimus ointment
Tacrolimus ointment 0.03% applied twice daily vs vehicle applied twice dailyOutcomes at 6 Weeks: IGA (% with score of 0 or 1) 50.6% vs 25.8%, p<0.0001

EASI (mean score change)
−54.8% vs −20.8%, p=0.0004

% BSA affected (change)
−50.5% vs −16.4%, p<0.0001
Itch (mean score change)
−2.8 (57%) vs −1.2 (24%), p<0.0001

Adverse effects
19% burning/stinging
23.4% itching
7.6% erythema
2.5% withdrew due to application-site reactions
1.3% folliculitis
2.5% skin infections
1.3% acne
0 eczema herpeticum vs 17%
33.3%, p=0.05
18.9%, p=0.003
7.5%, p=0.04
3.8%
3.1%
0%
0.6% eczema herpeticum
Source of Funding: Astellas Pharma US

Double-blind study.

Nonmedicated emollients were allowed on non-affected areas.

Tacrolimus was used on the head and neck (areas affected in 54% and 59% of children respectively).

Withdrawal rates were 18.4% tacrolimus vs 38.4% vehicle, p<0.0001; 2.5% vs 12.6% due to lack of efficacy, p=0.0007.
Bibliographic informationStudy type and evidence levelAim of studyNo. of patientsPatient characteristicsOutcomesComments
Hanifin JM;Paller AS;Eichenfield L;Clark RA;Korman N;Weinstein G;Caro I;Jaracz E;Rico MJ;

2005312
Study Type: Case series

Evidence Level: 3
To evaluate the long-term safety and efficacy of tacrolimus ointment.Total No. of Patients = 799
Tacrolimus ointment 0.1% (185 aged 2–6 years, 206 aged 7–15 years)
Children 2–15 years and adults who participated in a previous clinical trial of tacrolimus ointment 0.1% for mild to severe AE. Tacrolimus was applied twice daily to affected areas, continuing for a week after clearance of these areas. 30–35% of children’s BSA was affected.

Exclusions: other skin conditions.
Outcomes at 49 Months:
Adverse effects in children 2–15 years
20% pruritus
13% pustular rash
19% skin burning
8% skin erythema
23% skin infection:
5.3% herpes simplex
7% warts
5.4% varicella zoster
8% molluscum contagiosum
0.3% eczema herpeticum
Koo JYM;Fleischer Jr AB;Abramovits W;Pariser DM;McCall CO;Horn TD;Gottlieb AB;Jaracz E;Rico MJ;
2005310
Study Type: Case series

Evidence Level: 3
To evaluate the safety and efficacy of tacrolimus ointment in children and adults.Total No. of Patients = 7923
Children (2–15 years)
N = 3959

Adults N = 3964
Children aged 2–15 years and adults with mild to severe AE treated with tacrolimus ointment 0.03% or 0.1% twice daily to affected areas, and continued for one week after clearance of affected area. BSA affected 36%.

Exclusions: other skin conditions
Outcomes at 6 Months:
Adverse effects
17% pruritus
19% skin burning
15% skin infection
6.5% skin erythema
Source of Funding: Astellas
Comments:
Emollients permitted on non-treatment areas.

Median study duration 210 days (1–687), mean 239 days (135 for tacrolimus 0.03% and 247 for tacrolimus 0.1%). 26% discontinued treatment.

Efficacy data (% BSA affected) not reproduced here. <4% were prescribed TCS for AE at some time point, and 7% for any reason.

Adverse effects occurring in more than 5% were allergic reaction (e.g. conjunctivitis, seasonal allergy, food allergy), asthma, cough, fever, flu-like symptoms, headache, infection, otitis media, pharyngitis, sinusitis.

Data on infections reported for overall group (children and adults): 1.3% varicella zoster, 2.3% herpes simplex, 1.3% warts, 0.9% molluscum contagiosum, 0.3% eczema herpeticum
Kaufmann R;Folster- Holst R;Hoger P;Thaci D;Loffler H;Staab D;Brautigam M;-Study Group.;
2004301
Study Type: Case series

Evidence Level: 3
To assess the efficacy and safety of longer-term use of pimecrolimus.Total No. of Patients = 188
Pimecrolimus cream 1%
N = 188
Children included in Breuer 2004,300 who were offered 12 weeks’ open-label use of pimecrolimus cream 1% after the 4-week DB randomised phaseOutcomes at 12 Weeks:
EASI (mean score change) no numerical data; ‘significant improvements sustained’

Adverse effects
73% reported one, 4% of these treatment-related:
4 infections
1 asthma
1 aggravated AE*
1 exacerbated eczema*
Source of Funding: Novartis Pharma AG

Comments:

This extension study provides little data on safety or efficacy of 12-weeks’ pimecrolimus use.

*terms not defined
Lakhanpaul M;Davies T;Allen BR;Schneider D;
2006318
Study Type: Case series

Evidence Level: 3
To measure the systemic absorption of pimecrolimus after 1 years’ use.Total No. of Patients = 5
Pimecrolimus cream 1%
N = 5
Children aged 6–12 months, included in the Allen 2003317 study who were followed up for 1 year in total.Outcomes at 12 Months:
Mean blood pimecrolimus concentration 0.68 (SD 0.76) ng/ml

Outcomes at 6 Months:
Mean blood pimecrolimus concentration 0.32 (SD 0.35) ng/ml
Source of Funding: None declared

Comments:
pimecrolimus was used as required: mean duration of use (days) was 332 (range 168–365). Two children were also treated with TCS during the study.

Lower limit of quantification of blood pimecrolimus concentrations was 0.1ng/ml.
Lubbe J;Friedlander SF;Cribier B;Morren M;Garcia-Diez A;Gelmetti C;Hofmann H;Houwing RH;Kownacki S;Langley RGB;Virtanen M;Wolff K;Wisseh S;McGeown C;Abrams B;Schneider D;
2006315
Study Type: Case series

Evidence Level: 3
To assess safety and efficacy of pimecrolimus used in everyday practice.Total No. of Patients = 947
Pimecrolimus cream 1%
N = 947
Children and adults aged 3 months to 81 years with AE of any severity. Median age 8 years; 62% were aged up to 12 years.

Exclusions: active viral infections at treatment site, other skin conditions, treatment with immunosuppressive therapy or phototherapy.
Outcomes at 6 Months:
IGA (% with reduction in whole-body score)
66% aged <2 years
71% aged 2–12 years

IGA (% with reduction in facial score)
78% aged <2 years
79% aged 2–12 years

IGA (% with whole-body score of 0 or 1)
54% aged <2 years
48% aged 2–12 years
76% aged <2 years
80% aged 2–12 years
Duration and quantity of pimecrolimus use 135.6 mean days use (75%) mean quantity used 4.2g per day daily use in 55%

Adverse effects*
15.7% nasopharyngitis
14.6% URTI
10.5% cough
10.2% pyrexia
5.2% application site burning
3.7% pruritus
3.0% impetigo
2.0% worsening AE
1.7% molluscum contagiosum
0.8% herpes simplex infections
0.3% skin papilloma
Source of Funding: Novartis

Comments:
Pimecrolimus was used in addition to standard care (emollients, treatment for infections as per physician’s usual practice, TCS used to treat flares at the physician’s discretion).
85% received concomitant treatment for AE (no details other than for TCS, which were used at least once by 53%). 88% were using emollients at baseline, 80% after bathing/showering, which fell to 53% at 6 months.

Pimecrolimus was applied twice daily to affected areas at the first signs or symptoms of AE and continued as long as signs or symptoms of the disease persisted; the aim of treatment was to prevent progression to flare).

Data for children aged up to and including 12 years extracted here.

16% discontinued early, 10% due to loss of follow-up or unsatisfactory therapeutic effect, and 2.3% due to adverse effects.

*Those occurring in more than 10%, and those related to skin or skin infections listed here
Papp KA;Werfel T;Folster-Holst R;Ortonne JP;Potter PC;De PY;Davidson MJ;Barbier N;Goertz HP;Paul C;
2005303
Study Type: Case series

Evidence Level: 3
Assess long-term efficacy and safety of pimecrolimus (up to 2 years).Total No. of Patients = 91

Pimecrolimus cream 1%
N = 91
Children from the study Kapp 2002303 who were offered continued treatment with pimecrolimus cream 1% for a further year.
Mean age 28 months (range 18–41 months). IGA scores: 14.3% =0, 22% =1, 24.2%=2, 36.2%=3, 3.3%=severe, 0 = very severe.
Of the 91 enrolled, 76 had been treated with pimecrolimus in the RCT, and 15 with vehicle.
Outcomes at 2 Years:
% with no flares
76.9%

% using TCS
27.5% (mean duration of use 7.5 days)

IGA score of 0 or 1 71.4%

EASI (mean score change from year 1 to 2) −50%

Total BSA affected (mean change year 1 to 2) −42%
Source of Funding: Novartis Pharma AG

Comments:
Pimecrolimus was applied to affected areas at the first sign or symptoms of disease flare. The use of moderately potent TCS was also permitted for flares uncontrolled by pimecrolimus.

2 years’ use refers to the 1-year DB RCT and this 1 year follow-up phase. 16% had previously been treated with vehicle rather than pimecrolimus.

Over the 2 years, 57.9% of those treated with pimecrolimus had not used TCS.

Median duration of pimecrolimus use = 99 days (range not quoted).
Staab D;Pariser D;Gottlieb AB;Kaufmann R;Eichenfield LF;Langley RG;Scott G;Ebelin ME;Barilla D;Schmidli H;Burtin P; 2005316Study Type: Case series

Evidence Level: 3
To evaluate systemic exposure to pimecrolimus.Total No. of Patients = 21
Pimecrolimus cream 1%
N = 21
Children 3–23 months (mean 12 months) with AE affecting 50% BSA (range 10–92%).Outcomes at 3 Weeks:
% blood samples within given concentration
31% <0.1ng/ml
40% 0.1 to <0.5ng/ml
15% 0.5–1.0ng/ml
10% >1.0–2.0ng/ml
2% >2.0–2.26ng/ml

96% of the 100 blood samples were below 2ng/ml.
Source of Funding: none declared
Comments:
Pimecrolimus was applied to all skin areas, including face and neck.

Emollients were used to treat dry skin areas and affected areas after pimecrolimus had been ‘visibly absorbed’.

Mean quantity of pimecrolimus used per application ranged from 1g to 8.5g.

Blood samples taken on days 1 and 10, collected 1 and 2 hours, or 2 and 3 hours after application of study medication.

Limit of quantification = 0.1ng/ml.

The relationship between BSA and pimecrolimus blood concentrations were also considered (data shown graphically) - the difference in mean concentrations of pimecrolimus between children with 10% and 90% BSA affected was 0.4ng/ml.
Allen BR;Lakhanpaul M;Morris A;Lateo S;Davies T;Scott G;Cardno M;Ebelin ME;Burtin P;Stephenson TJ;
2003317
Study Type: Case series

Evidence Level: 3
To measure pimecrolimus blood concentrations and report efficacy and tolerability of pimecrolimus.Total No. of Patients = 26
Pimecrolimus cream 1%
N = 26
Children aged 4 months to 14 years with 21–80% BSA affected by atopic eczema.Outcomes at 3 Weeks:
% blood samples within given concentration
44% 0–0.5ng/ml
33% 0.5–1.0ng/ml
21% 1.0 to <2.0ng/ml
2% 2.0–2.6ng/ml

Blood pimecrolimus concentrations in relation to BSA
Mean difference between concentrations for where 10% or 90% BSA affected: 0.7ng/ml
On linear regression analysis, blood concentration increased with increased BSA affected, p=0.028
Source of Funding: none declared

Comments:
Use of bland emollients was encouraged (applied 1 hour after pimecrolimus).

Blood concentrations measured on days 4 and 22. The lower limit of quantification was 0.5ng/ml.

It was reported that there was ‘no evidence of accumulation’ between days 4 and 22 (results were in a similar range on graph).
Tan J;Langley R;
2004311
Study Type: Case series

Evidence Level: 3
To evaluate the safety and efficacy of tacrolimus used for 6 monthsTotal No. of Patients = 236
Tacrolimus ointment 0.1% in children
N = 83
Children or adults aged 2 years or older who had used tacrolimus ointment 0.1% twice daily for mild to severe AE.

Exclusions: other skin conditions.
Outcomes at 6 Months:
Adverse effects in children 2–15 years
32% skin infections:
6.1% folliculitis
13.4% impetigo

6.1% ‘other’ application site
2.4% herpes simplex
2.4% molluscum contagiosum
1.2% fungal infection
1.2% nail infection
Application-site effects:
38.1% burning
33.9% pruritus
19.9% infection
9.3% paraesthesia
5.1% warmth
Source of Funding: Fujisawa Canada

Comments:
Itch and BSA affected were also reported - data not reproduced here.
Bibliographic informationStudy type and evidence levelAim of studyNumber of patients and patient characteristicsPopulation characteristicsOutcome measuresResults and commentsStudy summaryReviewer comment
Bieber T; Vick K; Folster-Holst R; Belloni- Fortina A; Stadler G; Worm M; Arcangeli F;

2007308
Study Type: Randomised comparative trial

Evidence Level: 1−
Intervention: Patients applied 0.03% tacrolimus ointment twice daily or 0.1% methylprednisolone aceponate (MPA) ointment in the evening over all affected areas for a minimum of 2 weeks and maximum of 3 weeks and cleared areas were treated for an additional 7 days post clearance.

Comparison: comparison between 0.03% tacrolimus and 1% MPA
n=265 children and adolescents of which n=129 were randomised to MPA or n=136 to tacrolimus

MPA group n=96 (74%) were age 11 years or less

Tacrolimus n=102 were age 11 years or less

n=257 of children and adolescents completed the study
Children and adolescents with severe and very severe atopic eczema three age groups:2–6, 7–1 and 12–15 years

mean ages MPA = 7.8 ±4.2 years tacrolimus = 7.5 ±4.2 years
IGA score

EASI

Modified EASI (mEASI) for patients

BSA

Patients’ assessment of itch (VAS), quality of sleep (VAS), cost effectiveness of treatment and assessment of change of disease from baseline.


CDLQI

Safety assessment by physical examination, record of other medications, pregnancy tests, medical history and monitoring of AEs throughout study.
Results were reported as a whole for all age groups.

IGA:
IGA score was ‘clear’ or ‘ almost clear’ by the end of treatment in 86/129 (67%) in the MPA group and 91/136 (67%) in the tacrolimus group p=0.9314

EASI:
By end of treatment the mean % change was 90% in the MPA group compared with 85% in the tacrolimus group p=0.0667

mEASI:
Data were reported to reflect the EASI score but was not given.

BSA:
%BSA was ~29% at baseline and dropped to 6.8% in the MPA group and 7.7% in the tacrolimus group.

Patients’ assessment of itch was 68.0mm to 6.3 mm in the MPA group and 63.6mm to 13.8mm with tacrolimus at the end of the study p=0.0004

Patients’ assessment of sleep was 54.6mm to 5.3mm in the MPA group and 51.5mm to 11.0mm in the tacrolimus group from baseline to end of treatment. P=0.0094.

Medication costs:
Mean cost for MPA treatment was 14.59 Euros and 100.99 Euros for tacrolimus treatment during the study. P=0.0001
CDLQI data was reported in favour of
MPA over tacrolimus in terms of ‘symptoms and feelings ‘and ‘sleep’ but no data was shown.

n=0 of the MPA and n=2 in the tacrolimus group reported a worsening of their atopic eczema during the study.
The authors concluded that both treatments had a similar efficacy in the treatment of severe atopic eczema but suggested that the severity index (EASI), sleep and itch data shown increased benefit of MPA over tacrolimus which made it a more favorable treatment as it is also significantly cheaper.Comparative study which showed both treatments were of benefit to children with severe atopic eczema [EL=1−] Presentation of data was selective. The comparative cost of the two treatments was significant.

This study was sponsored by Intendis GmbH Berlin.
Arkwright PD; Gillespie MC; Ewing CI; David TJ;

2006309
Study Type: Cohort within patient left-right side (arms and legs) comparison Evidence Level: 2−Intervention: One set of arms and legs were treated with their usual topical corticosteroid (hydrocortisone 1%, flucinolone acetonide 0.00625%, clobetasone butyrate 0.05%, betamethasone valerate 0.025% or 0.1%, hydrocortisone butyrate 0.1% or mometasone furoate 0.1% for 7 days. The opposite side of the body was treated with 0.03% tacrolimus ointment twice a day for 7 days. If the 0.03% tacrolimus ointment had no effect after 7 days, it was stepped up to 0.1% tacrolimus for a further week

Comparison: Side to side body comparison
n=96 childrenChildren aged 6 months to 18 years were recruited (no mean available but data suggests all children participating were 12 years or below) with moderately severe atopic eczema. This was defined as incomplete control of atopic eczema from emollients and topical corticosteroids.Severity of atopic eczema as determined by clinical examination regarding erythema and lichenification (visual and by touch)
Classifications: less severe, no difference and more severe between sides.
After 7 days 48/93 children had a greater improvement with 0.03% tacrolimus compared with their usual topical corticosteroid.

The remaining 45 children for whom 0.03% tacrolimus was no more effective than their usual treatment were given a further weeks treatment of 0.1% tacrolimus. After the second week with 0.1% tacrolimus 24/45 (53%) showed a more marked improvement compared with their usual treatment. Overall tacrolimus ointment (0.03% and 0.1%) was more effective than usual topical corticosteroid treatment in 72/93 children (77%).
Topical tacrolimus (0.03% or 0.1%) was found to be more effective than topical corticosteroid treatment in 77% of children who completed a side to side body comparison study.This study lacked detail on demographic data, diagnosis and outcome measures. [EL=2−] There were also no safety data.

The funding of this study was undeclared.
Remitz A; Harper J; Rustin M; Goldschmidt WFM; Palatsi R; van der Valk PGM; Sharpe G; Smith CH; Dobozy A; Turjanmaa K. 2007313Study Type: Longitudinal case series

Evidence Level: 3
Intervention: 0.03% topical tacrolimus ointment twice daily to affected areas of body. If improvement did not occur within 2 weeks, children in the verum group were provided with 0.1% tacrolimus. If this failed to work at 2 weeks, children were excluded at investigator’s discretion.

Comparison: None
n=466 of which n=328 completed the study.Children aged 2–15 years (no details but split into two age groups 2–6 and 7–15 years) with moderate and severe atopic eczema (50/50) as defined by Hanifin and Rajka.Safety assessments of adverse events and laboratory tests (haematology, renal and hepatic function) at day 1, 6 and 12 months and at the end of study.

Children’s weight and height.

EASI

IDQOL

CDLQI
Mean study duration was 16.3 SD 6.4months
On average children used tacrolimus on 64% of the study days.

Safety
Most common AE was pruritus and skin burning. Other AEs assessed as causally related were skin infection, lack of drug effect, skin erythema, folliculitis, herpes simplex, application site reaction, rash, skin neoplasm benign, flu syndrome and pustular rash.

33 children (7.1%) experienced a serious AE, this lead to discontinuation of treatment in 15 patients (3.2%).
One 6 year old boy had leukopaenia with no accompanying symptoms and was withdrawn from study.

Eosinophil levels were greater in 40% of the study population

No other abnormalities were seen in the biochemical tests.

No growth retardation was seen during the study.

Efficacy:
Both age groups improved (EASI), with notable effect by 2 weeks and was maintained throughout study (data in graph form only)

Physician’s assessment of therapeutic response was 73–77% of patients experiencing at least a satisfactory response to treatment by the end of the study. This was reflected in the QoL scores (IDQOL, CDLQI) (also presented in graph form only)
There was a significant improvement in the children’s atopic eczema within 2 weeks of use of the tacrolimus ointment and this was maintained throughout the study. Adverse events do occur with tacrolimus treatment with local irritation being the most prevalent however all adverse events were transient.This is a large and longer term uncontrolled case series and shows that the efficacy is maintained over time and the safety profile is similar to that of shorter studies. [EL=3]

This study was funded by a grant from Fujisawa GmbH
Singalavanija S; Noppakin N; Limpongsanuru k W; Wisuthsarewong W;Aunhachoke K; Chunharas A; Wananukul S; Akaraphanth R. 2006314Study Type: Case series

Evidence Level: 3
Intervention: 0.03% tacrolimus (Protopic®) twice daily for 4 weeks on affected areas or until one week after the affected areas had cleared. Minimum length of treatment 2 weeks.

Comparison: None
n=61 of which n=58 completed the studyChildren (mean age 6.98 ±2.81 years) with moderate (n=29) or severe (32) atopic eczema as defined by Hanifin and Rajka criteria.Physician’s Global Evaluation of Clinical Response (PhGECR) EASI

Patient’s Global Evaluation of Clinical Response (PaGECR)

CDLQI (Thai version)

Safety assessment of adverse events
PhGECR significantly increased from week 1 to week 4 (2.28,3.07 respectively, p<0.001)

PhGECR at week 4 rated 7% clear, 26% excellent, 40% marked, 21% moderate and 4% slightly improved.

EASI significantly decreased 6.09 at baseline, 2.09 at week 4 (p<0.001).

PaGECR significantly increased between week 1 and week 4 (1.91, 2.31 respectively, p=0.018).

PaGECR at week 4 rated 57% much better, 26% better, and 12% slightly better, 3% the same, 2% worse.

Mean CDQoL scores significantly decreased from 1.19 to 0.68 at end of study (p<0.01).

Adverse events reported application site burning (n=14), erythema (n=2), itching (n=10), folliculitis (n=1) and infection (n=2).
Topical 0.03% tacrolimus is effective in treating moderate to severe eczema over a 4 week period. Most adverse events (burning sensation, erythema, and pruritus and itching) were resolved after 1 week.Uncontrolled case series of short duration. Safety issues of longer or repeated application of treatments not addressed.[EL=3]

The funding of the study was undeclared

From: Evidence tables

Cover of Atopic Eczema in Children
Atopic Eczema in Children: Management of Atopic Eczema in Children from Birth up to the Age of 12 Years.
NICE Clinical Guidelines, No. 57.
National Collaborating Centre for Women's and Children's Health (UK).
London: RCOG Press; 2007 Dec.
Copyright © 2007, National Collaborating Centre for Women’s and Children’s Health.

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