2. synopsis - europaart45-paediatric-studies-docs.ema.europa.eu/group l... · 2. synopsis name of...

2. SYNOPSIS

Name of Sponsor/Company: UCB Pharma SA Belgium

Individual Study Table Referring to Module 5.3.5.1

(For National Authority Use only)

Name of Finished Product: Xyzal®

Volume:

Name of Active Ingredient: Levocetirizine

Page:

Title of Study: The Early Prevention of Asthma in Atopic Children (EPAAC™) study A multi-country, double blind, placebo-controlled, randomized, parallel group trial: Evaluation of the efficacy and safety of levocetirizine (5 mg/mL oral drops - 0.125 mg/kg b.w. b.i.d.) administered for 18 months in preventing the onset of asthma in 12 to 24 months old children who suffer from atopic dermatitis (AD) and are sensitized to grass pollen and / or house dust mite allergens Investigator(s): 87 Investigators participated in this study Study Centers: 87 centers in 12 countries: Austria (1), Australia (4), Belgium (2), Czech Republic (9), France (9), Germany (12), Italy (12), the Netherlands (4), Poland (13), the Republic of South Africa (11), Spain (5), and the United Kingdom (5). Publication: Yes, abstract publication. See Appendix 16.1.11. Studied Period (years): Q1 2002 to Q1 2006

Phase of Development: Therapeutic confirmatory / Phase III

Objectives: The primary objective of this study was to compare the effect of levocetirizine (LCTZ) and placebo (PBO) on the time to onset of asthma after 18 months of treatment, in asthma-free young atopic children sensitized to grass pollen (GP) and / or house dust mite allergens (HDM). Secondary objectives were: • To compare the symptoms and the medications used for asthma during the treatment period; • To investigate the consistency of the treatment effect found overall on the time to onset of asthma

during the treatment period, with regard to sensitization of the children to GP and HDM at baseline (first analysis); sensitization to egg at baseline (second analysis), asthmatic status of the mother at baseline (third analysis) and region (fourth analysis);

• To compare the use of topical corticosteroids, topical tacrolimus and pimecrolimus, oral antihistamines and local antibiotics or antiseptics for atopic dermatitis (AD) during the treatment period, overall and according to the severity of AD at baseline;

• To assess the safety of the long-term use of LCTZ in a large population of children aged between 12 and 42 months;

• To compare the incidence of urticaria and the number of episodes of urticaria per subject during the treatment period, overall and in the following subgroups: subjects who had never shown symptoms of urticaria prior to inclusion in the study and subjects who suffered at least one episode of urticaria prior to inclusion in the study.

CSR: RRCE06L3017 Levocetirizine / A00309

Final / 07-Aug-2007 CONFIDENTIAL





Volume:


Page:

Exploratory objectives: • To describe the same parameters defined for the primary and secondary objectives in the LCTZ and

PBO groups after 24 months of study (i.e. 18 months of treatment and 6 months of follow-up); • To describe the time to onset of asthma in the LCTZ and PBO group considering an alternative

definition of asthma based on wheezing only and / or a new definition (should the latter be adopted by the scientific community during the course of the trial);

• To describe the symptoms and medications used for the treatment of AD. • To describe the status of sensitization to allergens; • To compare, between groups, direct medical cost parameters related to asthma over the 18 months of

treatment and during the 6 months post-treatment follow-up period; • To describe the psychomotor, verbal, cognitive and behavior development of the children during the

18 months of treatment and during the 6-month post-treatment follow-up period; • To describe potential risk factors for early sensitization (Immunoglobulin E ((IgE), AD severity, and

history of urticaria. Methodology: Double-blind, randomized, parallel group, placebo-controlled trial. After a screening visit (V1) and randomization visit (V2), subjects were to be treated for 18 months (up to V9), with a follow-up at 24 months (V10, 6 months after discontinuation of study drug). A new protocol (study number A00384) was introduced with Amendment 3 of the study protocol to assess whether the continuation of active treatment would maintain any benefit observed on prevention of asthma at the end of the 18-month treatment period. With this amendment, at V9 of the present study, subjects could choose to enter an extended 18-month, double-blind treatment period rather than continuing into the 6-month post-treatment follow-up period. The study was conducted under the auspices of an independent Scientific Advisory Board (SAB) and an independent Data Review Committee (DRC); members of the SAB were Prof JO Warner (Chairman, UK), Prof FER Simons (Canada), Prof U Wahn (Germany), Prof C Naspitz (Brazil), Prof T Diepgen (Germany), Prof de Benedictis (Italy) and Prof Neijens (Netherlands). The SAB was to supervise and advise the Sponsor during the preparation of the protocol, the follow-up of the trial, especially for the safety and ethical issues, and to provide its conclusions. Regularly during the trial, the SAB was to blindly review the safety data and advise the Sponsor accordingly. The DRC was established by the Sponsor to ensure central reviewing of the data related to asthma episodes to validate the primary endpoint before unblinding. The DRC developed its own operating procedures, which are part of the trial documentation (available in the Trial Master File). The results of the review were validated by the SAB before unblinding. The method of evaluation for the primary objective was the time to onset of asthma up to 18 months of the treatment period. The time to onset of asthma was defined as the period between the randomization visit (V2) and the date of onset of asthma. The symptoms of asthma (nocturnal cough and / or wheezing) were recorded by the caring person on diary cards and validated by the Investigator at the next visit.







Volume:


Page:

Number of Subjects: Planned: approximately 2500 to be screened; 500 to be randomized (250 per group) Participated: 2222 screened; 514 randomized (258 LCTZ; 256 PBO) Diagnosis and Main Criteria for Inclusion: Inclusion criteria that had to be verified during screening visit (V1): • Written informed consent signed and dated by parent(s) / legally acceptable representative(s)

according to local regulations; • Children of either sex aged between 12 and 24 months; • Subjects suffering from symptoms of AD lasting cumulatively for at least 2 months since birth. • Modified severity scoring of AD (Modified SCORAD) Index ≥ 10; • Subjects whose biological mother or father, or one sibling has a well-documented history of atopy

(AD, allergic rhinitis or asthma); • Caring person considered as reliable and capable of adhering to the protocol, according to the

judgment of the Investigator. Inclusion criteria that had to be verified during randomization (V2): • Results of the radio-allergosorbant test (RAST) test for GP and HDM were available and IgE level

against GP ≥ 0.35 kUA/L and / or IgE level against HDM ≥ 0.35 kUA/L; • Safety laboratory results were within the normal range of the central laboratory or considered as not

clinically significant or study disease related by the Investigator. Exclusion criteria to be verified at the screening visit (V1): To be excluded from the participation in the study, were those children who • Had height or weight below the 5th percentile; • Had experienced at least one episode of wheezing when aged 6 months or over; • Had suffered at age 6 months or over, from at least one nocturnal cough episode consisting of 3 (or

more) consecutive nights resulting in sleep disturbances in a clinical setting where asthma is likely and other conditions have been excluded;

• Had chronic pulmonary diseases of any type, such as, but not limited to, cystic fibrosis, or any cranio-facial abnormality, e.g., cleft palate;

• Had any chronic disease (other than AD) requiring therapy, such as, but not limited to, insulin dependent diabetes or epilepsy;

• Were suffering from any severe neurological or psychological disorder (i.e. requiring medical treatment and / or hospitalization);

• Had a caring person suffering from any severe neurological or psychological disorder (i.e. requiring psychiatric treatment), or known to be a drug or alcohol abuser;

• Had a history or showed evidence of any medical or surgical condition that might have made the diagnosis and the evaluation of newly occurring asthma difficult, e.g., gastro-esophageal reflux;







Volume:


Page:

• Were known to be allergic or intolerant to cetirizine, levocetirizine and other piperazines or parabens; • Had a personal history of sleep apnea or had siblings with a history of sleep apnea; • Had participated in another clinical trial within the three months prior to inclusion; • Showed any metabolic condition or disease that might have compromised the absorption,

distribution, elimination or metabolism of levocetirizine, such as, but not limited to, severe renal insufficiency;

• Were treated with any immuno-modulator medication, e.g., cyclosporin, cyclophosphamide or FK 506 (tacrolimus);

• Had received or were receiving allergen – specific immunotherapy; • Suffered from concomitant dermatological disease/condition other than AD, that might have

interfered with the evaluation of the clinical response for AD; • Had an insufficient wash-out period for the following medications:

• Intranasal or systemic antihistamines: 3 days; • Intranasal or systemic decongestants: 3 days; • Loratadine, desloratadine: 10 days; • Chromones: 2 weeks; • Oral corticosteroids: 1 month;

• Chronic use (i.e. cumulatively up to 2 weeks within the last 3 months) of • Inhaled / intranasal corticosteroids: 1 month; • Ketotifen: 1 month; • Astemizole: 6 weeks;

• Were children of an Investigator, co-Investigator or study collaborator; • Had been treated with any antihistamine, including ketotifen, with daily intake for more than

2 consecutive months in the last 6 months before screening; • Exclusion criteria to be verified at the randomization visit (V2):

• Intake of any prohibited medication listed above during the selection period. Test Product: Levocetirizine

Dose and Mode of Administration: Oral drops; 0.125 mg/kg body weight, twice daily

Batch Number / Expiry Date 11257 / Oct-2003 11800 / Jul-2005 13106 / Jan-2007

Duration of Treatment: 18 months







Volume:


Page:

Reference Therapy: Placebo

Dose and Mode of Administration: Formulation and dosing to match that of levocetirizine

Batch Number / Expiry Date 11258 / Oct-2003 11801 / Jul-2005 13107 / Jan-2007

Criteria for Evaluation: Efficacy: The primary efficacy variable was the time to onset of asthma during the treatment period (18 months). The time to onset of asthma was defined as the period elapsed between the randomization visit (V2) and the date of onset of asthma. The secondary efficacy variables evaluated during the treatment period were: • Symptoms and use of medications for asthma as measured by:

• Percentage of days with symptoms of either wheezing or nocturnal cough; • Percentage of days with symptoms of wheezing; • Percentage of days with symptoms of nocturnal cough; • Use and percentage of days of use of asthma medication; • Use and percentage of days of use of the following medications for AD: topical

corticosteroids; topical tacrolimus and pimecrolimus, oral H1 antihistamines; local antibiotics or antiseptics;

• Incidence of subjects with urticaria and the number of episodes of urticaria per subject. The primary and secondary variables evaluated after 24 months of study were to be considered as exploratory. In addition, the following variables were also considered as exploratory: • The time to onset of asthma based on an alternative definition of asthma based on wheezing only. • The symptoms of AD, as measured by:

• The SCORAD index, as assessed by the Investigator at each visit; • The severity of AD and pruritus scores, as assessed by the caring person each week; • The use and percentage of days of use of medications for AD;

• The status of sensitization to allergens; • The direct medical cost parameters related to asthma over the 18 months of treatment and during the

6-month post-treatment follow-up period (not reported here); • The risk factors for early sensitization (IgE), AD severity, history of urticaria.







Volume:


Page:

Safety: Safety assessments were as follows: physical examinations, adverse events (AEs), body mass parameters, safety laboratory variables (hematology and biochemistry), a psychomotor evaluation (the global psychomotor development [GPD] questionnaire), and evaluations of verbal, cognitive and behavior (see below). The GPD questionnaire was to be applied to all children in all countries at each visit. The verbal, cognitive and behavioral development of the child was evaluated by the caring person at randomization and then before each scheduled visit at centers in the United Kingdom and Australia, using three questionnaires: • MacArthur Communicative Development Inventory (MCDI); • Parent Report of Children’s Abilities (PARCA); • Behavior Checklist (BCL). Statistical Methods: Summary statistics consisted of frequency tables for binary or categorical variables. For continuous variables, descriptive statistics (number of available observations, mean, median, standard deviation [SD], minimum and maximum) were tabulated. All statistical tests were carried out using a two-tailed test at the 5% level of significance unless otherwise stated. Baseline characteristics for the intention-to-treat (ITT) population were summarized descriptively. Primary efficacy analysis: The primary efficacy variable was analyzed on the ITT population, using a Cox proportional hazard regression model including a term for treatment and a term for each of the factors used in the randomization process. The hazard ratio for the treatment effect between LCTZ and PBO and corresponding 95% confidence interval was estimated by fitting this model. Descriptive statistics consisted of the number and percentage of subjects with asthma during the treatment period and the cumulative incidence curves of asthma, estimated using the Kaplan-Meier approach. If applicable, the median time to onset of asthma was to be estimated with its 95% confidence interval (CI). The primary efficacy variable was also analyzed for the per-protocol (PP) population to assess the impact of any possible protocol violations on the study results. Secondary efficacy analyses: A sensitivity analysis of the primary efficacy variable was performed using randomization-based statistical tests. Secondary analyses on the primary efficacy variable aimed to investigate the consistency of the treatment effect found overall in relation to sensitization against GP and HDM at baseline (first analysis); sensitization to egg at baseline (second analysis); asthmatic status of the mother at baseline (third analysis); and region (fourth analysis). These four analyses were performed separately using the Cox proportional hazards regression model used for the primary analysis including an additional term for the interaction between treatment and factor. Descriptive statistics were presented for each subgroup.







Volume:


Page:

Secondary variables were analyzed descriptively on the ITT population using summary statistics by treatment group. Comparisons between the two treatment groups were performed by means of a chi-squared test or Fisher’s exact test or using a logistic model in case of binary variables, or analysis of variance or a Wilcoxon-rank-sum test in case of continuous variables. A comparison of the two treatment groups on the use and percentage of days of use of oral antihistamines, topical corticosteroids, topical tacrolimus and pimecrolimus and local antibiotics or antiseptics for AD was performed overall and according to the severity of AD at baseline, using a model including interactions. The analysis of the incidence of subjects with urticaria and the number of episodes of urticaria per subject was performed overall and considering the subgroups of subjects who had never experienced urticaria from birth to study inclusion and those who had experienced urticaria from birth to study inclusion. The consistency of the treatment effect between these two subgroups was investigated using a model including interactions. The exploratory variables were analyzed descriptively on the ITT population using summary statistics by treatment group. Safety: Safety analyses were performed on the ITT population. Safety variables were listed individually for detailed clinical review, when needed. Laboratory values, body mass parameters, and changes from baseline in laboratory values and body mass parameters were presented descriptively by treatment group. 95% CIs were calculated on the median of the difference between the on-treatment values and the baseline values. AEs were summarized descriptively by treatment group, system organ class (SOC), and preferred term. Additional tables summarized AEs by severity and relationship to study drug as well as separate tables for AEs leading to withdrawal from the study and serious AEs (SAEs). For the overall incidence and for the most frequent treatment - emergent adverse events (TEAEs), the relative risk was presented with its 95% CI. The psychomotor assessments as well as the verbal, cognitive, and behavioral assessment were analyzed descriptively by treatment group. SUMMARY – CONCLUSIONS In total, 2222 subjects were screened, 514 subjects were randomized, and 510 subjects were treated with study medication (255 LCTZ; 255 PBO). The majority of subjects in both groups completed the 18-month treatment phase: 219 (85.9%) LCTZ subjects; 215 (84.3%) PBO subjects. Of the 76 subjects who prematurely discontinued from study treatment, the majority of subjects withdrew consent (22 LCTZ subjects; 21 PBO subjects) or was lost to follow-up (4 LCTZ subjects; 8 PBO subjects). Nine subjects withdrew due to AEs (6 LCTZ subjects; 3 PBO subjects). Approximately half of the subjects who completed the 18-month treatment phase continued into the 6-month untreated follow-up phase (n = 219) and approximately half continued their randomized study medication in the prolongation study (A00384) (n = 207).







Volume:


Page:

The numbers of subjects in the ITT, PP and V10 populations were as follows: Data set PBO LCTZ Overall ITT 255 255 510 PP 244 238 482 V10 109 110 219 Demographic characteristics: Demographic characteristics at baseline were similar in both groups:

Characteristics Descriptive statistics

PBO N = 255

LCTZ N = 255

Overall N = 510

Age (months) Mean (SD) 19.42 (3.86) 19.28 (3.94) 19.35 (3.90) Min − Max 12.2−26.3 12.1−26.4 12.1−26.4 Gender

Male n (%) 164 (64.3) 155 (60.8) 319 (62.5) Female n (%) 91 (35.7) 100 (39.2) 191 (37.5)

Race Caucasian n (%) 217 (85.1) 225 (88.2) 442 (86.7) African n (%) 7 (2.7) 5 (2.0) 12 (2.4) Asian / Pacific Islander n (%) 10 (3.9) 9 (3.5) 19 (3.7) Other / mixed race n (%) 21 (8.2) 16 (6.3) 37 (7.3)

Weight (kg) Mean (SD) 11.58 (1.59) 11.41 (1.53) 11.50 (1.56) Min − Max 8.0 − 17.0 7.7 − 16.0 7.7 − 17.0 Height (cm) Mean (SD)

Min − Max 82.64 (5.12) 68.0 − 96.0

82.55 (5.13) 71.0 − 95.0

82.59 (5.12) 68.0 − 96.0

Baseline characteristics: The AD characteristics at screening were similar in both groups: Characteristics Descriptive

statistics PBO

N = 255 LCTZ

N = 255

n 99 116 Duration of atopic dermatitis (months)

Mean (SD) 15.53 (5.44) 15.37 (5.20) Min - Max 3.0 – 24.9 3.3 – 24.9 Modified SCORAD index n 255 255 Mean (SD) 30.02 (13.38) 29.84 (13.24) Min - Max 10.0 – 79.0 10.9 – 74.0







Volume:


Page:

EFFICACY RESULTS: Over the total treatment period, treatment compliance data were missing for approximately 40% of subjects. For subjects with compliance data, compliance was generally good with a mean intake of 97.4% (± 23.24). The results of the primary analysis of efficacy for the ITT population are tabulated below and illustrated in the Kaplan-Meier plot. Over the first 6 months of treatment the onset of asthma was slightly lower in the LCTZ group than in the PBO group in the ITT population. Thereafter, the Kaplan-Meier curves for time to onset of asthma were increasingly similar and from 8 to 18 months were almost superimposable. Kaplan-Meier estimates at 18 months were 39.8% (95% CI 33.2, 46.2) for LCTZ and 40.2% (95%CI 33.8, 46.5) for PBO. The hazard ratio over the 18-month treatment period was 1.002 (p = 0.991; 95% CI: 0.750, 1.338). The criteria for a positive study were not met. Primary Analysis of Efficacy: Comparison of Time to Onset of Asthma During the 18-Month Treatment Period – ITT Population PBO

(N = 255) LCTZ

(N = 255) Number of subjects at risk, n 252 252

Subjects censored, n (%) 158 (62.7) 160 (63.5) Subjects with asthma, n (%) 94 (37.3) 92 (36.5)

Probability of asthma at 18 months Kaplan-Meier estimate (95% CI), % 40.2 (33.8; 46.5) 39.8 (33.4; 46.2) First quartile (95% CI), months 9.5 (7.9; 13.4) 10.3 (8.3; 13.3)

Comparison LCTZ vs. PBO(a) Hazard ratio (95% CI) 1.002 (0.750; 1.338) p-value 0.991

(a) p-value corresponding to the likelihood ratio test statistic, using the Cox regression model, adjusted for region, mother status of asthma, sensitization to GP, HDM and egg at baseline with and without the term for treatment effect.







Volume:


Page:

Kaplan-Meier Curve: Time to Onset of Asthma During the 18-Month Treatment Period – ITT Population

No statistically significant differences were found between groups regarding the percentages of days with wheezing, nocturnal cough, and wheezing or nocturnal cough. Fewer subjects treated with LCTZ required treatment for asthma with inhaled or systemic corticoids (15.3% and 12.5%, respectively) than in the PBO group (18.8% and 18.4%, respectively) during the 18-month treatment phase; the difference was not statistically significant. The usage of other asthma medications was similar in both groups. Statistically significantly fewer LCTZ subjects (27.5%) had episodes of urticaria during the 18-month treatment period than PBO subjects (41.6%), p < 0.001. In total, 69 (33.0%) PBO subjects and 41 (20.8%) LCTZ subjects who had not previously had urticaria had episodes during the study. The mean number of episodes of urticaria and the mean number of days with urticaria were also less for LCTZ subjects (0.71 episodes ± 1.83 and 4.4 days ± 25.00, respectively) (p<0.001) than for PBO (1.71 episodes ± 4.05 and 5.4 days ± 20.21, respectively) (p<0.001). The difference between groups was more marked for subjects who had urticaria prior to inclusion in the study than in those who had never had urticaria before entering the study. As in the ETAC™ study, during the 6-month follow-up period of the EPAAC™ study, when subjects were untreated, there was no difference between groups in the incidence, number of episodes, or number of days with urticaria for all subjects, those who had urticaria from birth, and those who had never experienced urticaria before study inclusion.







Volume:


Page:

The results of the analysis of the primary efficacy variable (time to onset of asthma) over the 24-month study period for the ITT population showed the Kaplan-Meier curves of time to onset of asthma from 8 to 24 months were almost superimposable. The Kaplan-Meier estimates at 24 months were 49.9% (95% CI: 42.2, 57.5) for LCTZ and 47.0% (95% CI: 39.7, 54.2) for PBO. Over the 18-month treatment period, based on episodes of wheezing only, the onset of asthma was similar in both groups up to 3 months after the start of study medication; thereafter, the onset of asthma was consistently lower for the LCTZ group than for the PBO group (see below). The Kaplan-Meier estimates at 18 months were 17.8% (95% CI: 12.9, 22.8) for LCTZ and 22.1% (95% CI: 16.7, 27.5) for PBO. Kaplan-Meier Curve for Time to Onset of Asthma Based on Wheezing Only During the 18-Month Treatment Period – ITT Population

Severity of AD: At baseline, the mean SCORAD index was similar for subjects in the both groups. The SCORAD index reduced during the treatment phase in both groups and at V9, mean scores were 14.93 (± 15.62) and 16.52 (± 17.22) for the LCTZ and PBO groups, respectively. The severity of AD based on the weekly scoring by caring persons was similarly reduced during the 18-month treatment phase in both the LCTZ and PBO groups. Likewise, the pruritus scores were reduced during the 18-month treatment phase in both the LCTZ and PBO groups.







Volume:


Page:

SAFETY RESULTS: The mean exposure to LCTZ was 17.33 months (± 3.50) at a dose of 0.125 mg/kg mg/kg b.w. b.i.d. The TEAEs reported during the study are summarized as follows: PBO

(N = 255) n (%)

LCTZ (N = 255)

n (%) Total number of AEs 2422 2471 Subjects with at least one AE 244 (95.7) 247 (96.9) Subjects with AEs that lead to permanent study drug discontinuation

3 (1.2) 5 (2.0)

Subjects with drug-related AEs 16 (6.3) 13 (5.1) Subjects with SAEs 37 (14.5) 31 (12.2) Subjects with drug-related SAEs 1 (0.4) 0 Numbers of deaths 0 0 There was no clinically meaningful difference between groups in the incidence of AEs and SAEs or in the profile of AEs and SAEs reported. Most TEAEs could be attributed to intercurrent respiratory or gastrointestinal infections, exacerbation of allergic disorders, or age-related concerns and the age-related common childhood conditions in the treated target-population, rather than to medication-related AEs. There were no deaths during the study. AEs occurred in most subjects in the study during the 18-month treatment phase; they were generally mild or moderate in intensity, and occurred with similar frequency in both treatment groups. The AEs reported most frequently were upper respiratory tract infections and similar or related events, which were described verbatim by the Investigators as nasopharyngitis, rhinitis, pharyngitis, otitis media, ear infection, tonsillitis, viral infection, rhinorrhea, laryngitis, viral URTI, and acute tonsillitis. Pyrexia, gastroenteritis, vomiting and diarrhea were also common. In addition, cough, bronchitis, allergic rhinitis, conjunctivitis, worsening AD, and seasonal allergies were frequently reported, as were varicella and teething. AEs relating to the central nervous system were infrequent. Febrile convulsions were reported in 5 subjects in the LCTZ and one in the PBO group. Behavioral issues were more frequently reported in the PBO subjects. Few AEs were assessed by the Investigators as being treatment-related (6.3%of PBO subjects and 5.1% of LCTZ subjects). Moreover, permanent discontinuation of study medications due to AEs was infrequent, occurring in 2.0% of LCTZ subjects and 1.2% of PBO subjects. Only one SAE was considered related to study medication (PBO group; hepatic enzyme increased). The incidence of post-treatment AEs during the 6-month post-treatment follow-up phase (between V9 and V10) was lower for subjects who had previously been treated with LCTZ (70.9%) than for those had had received PBO (81.7%). The profile of post-treatment AEs was similar in both groups and similar to the TEAE profile.







Volume:


Page:

Compared with the PBO controls, there was no clinically meaningful effect of LCTZ on hematology or biochemistry values, physical examination, use of concomitant medications, or incidence of concurrent medical procedures. Compared with the PBO controls, there was no clinically meaningful effect of LCTZ on psychomotor, verbal, cognitive, or behavioral development as assessed using the GPD questionnaire, MCDI, PARCA, and BCL, respectively. CONCLUSIONS: Time to onset of asthma with Levocetirizine was similar when compared with Placebo administered for 18-months in 12- to 24-month children suffering from atopic dermatitis and sensitized to grass pollen and / or house dust mite allergens and with a history of atopy in the family. Statistically significantly fewer Levocetirizine subjects than Placebo subjects had urticaria during the 18-month treatment period. The mean number of episodes of urticaria and the mean number of days with urticaria were also less for Levocetirizine subjects. The difference was more marked for subjects who had urticaria from birth than in those who had never had urticaria before entering the study. Levocetirizine was generally safe and well tolerated. Most reported adverse events were mild or moderate in intensity and could be attributed to intercurrent respiratory or gastrointestinal infections, exacerbation of allergic disorders, or age-related concerns and the age-related common childhood conditions in the treated target-population, rather than to medication-related adverse events. There were no statistically or clinically relevant differences between the groups for growth, developmental assessments, and laboratory safety results. The safety profile of LCTZ (0.125 mg/kg bid), given during 18 months was consistent with the findings of the ETAC ™study with cetirizine and provides robust and compelling evidence of the excellent safety profile of LCTZ in this pediatric patient population. Report Date: 07-Aug-2007



2. synopsis - europaart45-paediatric-studies-docs.ema.europa.eu/group l... · 2. synopsis name of...

Documents