From: Evidence Tables
Copyright © 2010 by Oregon Health & Science University,
Portland, Oregon 97239. All rights reserved.
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Carson S, Lee N, Thakurta S. Drug Class Review: Newer Antihistamines: Final Report Update 2 [Internet]. Portland (OR): Oregon Health & Science University; 2010 May.
This publication is provided for historical reference only and the information may be out of date.
Evidence Table 9Perennial allergic rhinitis trials in children
| Author Year Country Quality score | Study design Setting | Population Eligibility criteria | Exclusion criteria | Allowed other medications/ interventions | Age Gender Ethnicity | Interventions | Method of outcome assessment and timing of assessment | Number screened/ eligible/ enrolled | Number withdrawn/ lost to fu/ analyzed | Results |
|---|---|---|---|---|---|---|---|---|---|---|
| Head-to-head trials | ||||||||||
| Sienra-Monge 1999 Mexico Fair | RCT, DB Single center | PAR Children age 2 to 6 years with PAR verified by the presence of a (+) radioallergosorbent test to house dust mites or plant pollens. Each patient had to have at least 3 of 5 major rhinitis symptoms (rhinorrhea, sneezing, nasal congestion, nasal pruritus, or ocular pruritis) and a combined symptoms severity score of 8 when each symptoms was rated by the investigator on a scale of 0 (none) to 3 (severe). | Excluded patients who were already receiving antihistamines, steroids, or immunotherapy. Also excluded were pts with major systemic disease, recent respiratory illness, or significant nasal anatomic abnormalities. | Mean age 4.4y (SD 1.2) 63% male Ethnicity NR | C: Cetirizine suspension 0.2 mg/kg qd L: Loratadine suspension 0.2 mg/kg qd Treatment duration 28d | Primary outcome was histamine skin test. Secondary outcomes: VAS; eosinophils in the nasal smear; investigator; parent and patient symptom assessments Symptom evaluations at baseline and after 28 days by the investigator; parents completed symptom assessments at baseline and on each day of the study in symptom diaries. The investigator provided a global assessment of therapy using a VAS with a 100-point scale. | NR/NR/80 | NR/NR/78 | Global Evaluation Score assessed by investigator (C vs L): −62.8% vs −64.6% (NSD) Histamine prick test (inhibition of wheal response): C>L (p<0.001) Eosinophil count: decreased in both groups, NSD between groups Investigator assessment of individual symptoms (sneezing, rhinorrhea, nasal obstruction, nasal pruritus, ocular pruritus): NSD between groups (both improved) Parent assessment of patient symptoms: both improved, C more effective in relieving rhinorrhea, sneezing, nasal obstruction, and nasal pruritis (p<0.001) | |
| Active-control trials | ||||||||||
| Cetirizine | ||||||||||
| Hsieh J-C 2004 Taiwan Fair | RCT, DB, placebo- controlled | PAR Children aged 6 to 12 years with a known history of moderate to severe PAR for ≥1 year. Any specific allergy to house dust mite was confirmed by a positive skin-prick test response to house dust mites and a mite- specific IgE response. | A positive response to any other allergen; nasal abnormality, concurrent purulent nasal infection, any other significant medical condition. | Any current medication affecting any allergy symptom was discontinued as appropriate | Mean age: (A) 8.05y, (B) 8.2y, (C) 8.05y % Female: (A) 40%, (B) 35%, (C) 45% Ethnicity NR | C: Cetirizine 20 mg qd M: Montelukast 5 mg qd P: Placebo qd Treatment duration 12 weeks | Patients recorded all symptoms in a diary card qd for 7d prior to study entry and a rhinitis symptom score was calculated. Pediatric rhino conjunctivitis Quality of Life Questionnaires, serum eosinophil cationic protein level, and nasal expiratory peak flow were measured at baseline and follow-up. Rhinitis symptom score included: 4 nasal symptoms (rhinorrhea, nasal stuffiness/congestion, nasal itching, sneezing) and 4 non nasal symptoms (eye itching, eye tearing, eye redness, itching of ears or palate). Symptom score rated 0–3 (3, most severe). TSS was sum of both nasal and non nasal symptom scores. Average baseline TSS was mean of 7 daily scores at baseline. At follow-up, mean TSS and individual symptoms scores were based on prior 28 days at weeks 4, 8, and 12. | NR/NR/65 | 4/1/60 | TSS: C<M<P weeks 4,8,12 (p<0.05); Mean rhinorrhea score C and M<P weeks 4,8,12 (p<0.01), C<M weeks 8 and 12 (p<0.01); Nasal itching and sneezing C<P weeks 4,8,12, (p<0.05); Mean red-eyes scores C<P weeks 8 and 12 (p<0.01); NSD among groups itching throat and watery eyes NPEF: M>C>P weeks 4,8,12. C>P weeks 8 and 12 (p<0.05) QOL: Improved in C and M >P at 12 weeks (p<0.01) Eosinophil % of nasal smear: C and M<P at 12 weeks (p<0.01) |
| Lai 2002 Taiwan Fair | RCT, DB, parallel | PAR Children 6 to 12y with ≥1y history of moderate to severe PAR, with a (+) prick test response to house- dust mite and a (+) response to mite-specific IgE; no other significant medical condition or nasal abnormality | Significant other medical condition which may have affected allergy symptoms | No | Mean age: 8.07 y Range: 6–12 y 43.5% male Ethnicity; NR Mean weight: 29.4 kg | C: Cetirizine 10 mg qd (n=20) K: Ketotifen 1 mg/bid (n=20) O: Oxatomide 1 mg/kg bid (n=20) P: Placebo (n=20) Treatment duration 12 weeks | Nasal symptom scores in a diary card (which incorporated presence of a nocturnal cough) and a Pediatric Rhino conjunctivitis Quality of Life Questionnaire (PRQLQ) Total nasal symptom score (TSS): rhinorrhea, nasal stuffiness/congestion, nasal itching, sneezing, eye itching/burning, eye tearing/watering, eye redness, itching of ear or palate Patients reported scores for weeks 4, 8, and 12 | NR/ NR/ 80 | 11/ NR/ 69 | Mean TSS and individual symptom scores of diary card: Multiple posterior analyses of between-group comparisons reported: C, K, and O improved mean TSS from baseline compared to P at 4,8, and 12 w (p<0.01). Lower TSS for C than K and O for week 12 (p<0.05); C, K and O all demonstrated improved individual symptom scores compared to P and results were generally significant (p<0.05). Group C lower scores for mean rhinorrhea and nasal congestion than K, O and P and p-value generally <0.05 for these between-group comparisons Peak expiratory flow rate: higher for group C than for other treatment groups at 12 weeks (p<>0.05) Quality of life: higher for C and K at 12 weeks (p<0.05 vs P) |
| Lee 2009 Taiwan | RCT, DB, placebo- controlled Single center - Chung Shan Medical University Hospital | PAR 6 to 12 yr; moderate to severe perennial allergic rhinitis for at least 1 yr. All were allergic to the house dust mite, which was confirmed by skin prick-test response and a positive reaction to mite specific IgE | Positive, response to other allergens or deformities of the ear, nose, or throat or infection during the 2 wk preceding the initial visit, or having taken medicine which may have affected any allergy symptoms such as antihistamine, decongestant or any form of steroid within seven days; had a respiratory tract infection or took the above medicine during the study period | Not allowed H1-antagonist, decongestant or any form of steroid | Mean age 8.4 yrs 58% male Ethnicity NR | Cetirizine vs. levocetirizine vs.placebo for 12 weeks | Daily diary of nasal symptom score (TSS), follow up at 4, 8 and 12 weeks also Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) at baseline and 12 weeks; Nasal peak expiratory flow rate (nPEFR) and laboratory examinations. | NR/NR/80 | 6/0/74 | Cetirizine vs. levocetirizine vs.placebo Change at 12 weeks TSS −5.54(2.58)* ** vs. −3.30 (3.90) vs. −0.18 (1.77) Rhinorrhea −0.92 (0.54)* vs. −0.62 (0.95)* vs. −0.14 (0.28) Nasal decongestion −1.00 (0.39)* ** vs. −0.50 (0.65)* vs. −0.05 (0.32) Nasal itching −0.73 (0.81)* vs. −0.60 (0.95) vs. −0.11 (0.47) Sneezing −0.71 (0.53)* vs. −0.49 (0.74)* vs. −0.12 (0.28) Conjuctiva itching −1.06 (0.95)* vs. −0.82 (1.13)* vs. 0.01 (0.34) Tearing −0.22 (0.42)* **vs. −0.01 (0.33) vs. 0.00 (0.28) Conjunctiva hyperemia −0.79 (0.51)* ** vs. −0.42 (0.53)* vs. −0.02 (0.13) PRQLQ −19.73 (11.04)* vs. −24.09 (16.82)* vs. −1.63 (5.13) *Significant change compared with placebo (P < 0.05). **Cetirizine compared with levocetirizine (P < 0.05). |
| Placebo-controlled trials | ||||||||||
| Cetirizine | ||||||||||
| Baelde 1992 Belgium (Fair) | Randomized, DB, parallel group, multicenter | PAR Children ages 2 to 14 years who had suffered from well- documented PAR for ≥2y; (+) skin tests and/or radioallergosorbent tests for allergens other than pollen and at least 2/ 5 principal symptoms of PAR (nasal obstruction, rhinorrhoea, nasal pruritis, sneezing, and pharyngeal drip) | Children with co-existing allergic disorders were eligible for inclusion if they were not on any treatment other than the study drug. Patients with asthma were permitted to take sodium cromoglycate, inhaled beta- 2 sympathomimetics or inhaled corticosteroids to a maximum dose of 400 mcg per day. Patients could not take other antihistamines, corticosteroids, anticholinergics, sedatives, adrenergic agens, antiinflammatory agents or aspirin during the study period. | Mean age 8.6 y (sd 2.2) 67% male Ethnicity: NR | C1: Cetirizine 5.0 mg bid C2: Cetirizine 2.5 mg bid P: Placebo bid | Investigators evaluated every symptom at each clinical visit and rated them on a scale of 0 (absent) to 4 (severe enough to require treatment with drugs other than or in addition to an antihistamine). In addition, investigators made a global assessment of efficacy at the end of treatment using a scale of 0 (aggravation) to 4 (disappearance of all symptoms). Parents completed daily record cards in which they entered the severity of symptoms assessed on a scale of 0 (none) to 3 (severe), side effects, and any additional treatment. Clinical visits at baseline, 1 and 2 weeks. | NR/NR/138 | 13/NR/125 | Mean percent change from baseline, assessed by investigator (C1 vs C2 vs P) Nasal obstruction: −47.9% vs −33.2% vs 28.7% (C1 vs P, p=0.03) Rhinorrhea: 59.4% vs 47.3% vs 37.9% (C1 vs P, p=0.03) Sneezy: 68.2% vs 47.3% vs 37.9% (C2 vs P, p=0.04) Pharyngeal drip: 77.2% vs 53.2% vs 54.9% (C1 vs C2, p=0.03) Nasal pruritis: NSD, data not reported Overall average score for all symptoms: C1 vs P p=0.01 Global evaluation by investigators: C1>C2 (p=0.04) and C1>P (p=0.006) Evaluation by parents: NSD C1 vs P or C2 vs PC | |
| Ciprandi 2001 Italy (Fair) | Randomized, DB, parallel group, single center | PAR Children ages 3 to 10 years who showed isolated sensitization to house dust mite (evaluated by skin testing and RAST), and suffered from perennial rhino conjunctivitis and/or mild intermittent asthma. | Anatomical alterations of the upper airways, immunologic deficiencies, or major systemic diseases (diabetes, anemia, cystic fibrosis, inherited metabolic disorders); history of cardiac disease and/or arrhythmia. | Specialists could prescribe some drugs as needed. Patients were allowed to use rescue or symptomatic drugs when needed. Investigators suggested cetirizine (5 mg qd), inhaled albuterol, inhaled fluticasone in case of asthma exacerbations, or short courses of systemic corticosteroids. Any other drug considered appropriate was also allowed. | Mean age: 6.5y Range: 3–10y 75% male Ethnicity: NR | C: Cetirizine 5 mg qhs for 24w P: Placebo qhs for 24w | Parents recorded symptoms on diary cards: sneezing, nasal itching, and obstruction, rhinorrhea, lacrimation, conjunctival itching and hyperemia, cough, wheezing, and chest tightness. Symptoms graded with 4-point scale: 0=absent, 1=mild, 2=moderate, and 3=severe. Participants also recorded the number of nights their sleep was disturbed and all treatments taken. | NR/NR/20 | 0/0/20 | (Data presented graphically only) Weekly mean rhinitis scores: C<P for 24/24 weeks; for 11/24 weeks, between-group difference significant (p<0.05) Weekly mean asthma symptom scores: C<P for 6/24 weeks (p<0.05); for 10/24 weeks P<C (NSD); for 8/24 weeks C=P Drug intake: C<P for 24/24 weeks (p<0.05 for 16/24 weeks); C consumed less cetirizine (p<0.001), inhaled fluticasone (p<0.01), systemic steroid (p<0.05), and antibiotics (p<0.05) than B |
| Chen 2006 Taiwan | DB RCT, single center | Documented clinical history of perennial allergic rhinitis (PAR) of at least half a year, a positive prick-test for house dust-mite and a positive mite-specific IgE, aged from 2 to 6 yr old | Corticosteroids or sodium cromoglycate within the past 4 wk, or H1-antagonist and/or decongestant within the past 7 days. | see exclusions | Mean age 4.5 yrs 53% male Ethnicity NR | Cetirizine vs. Montelukast vs. Placebo For 12 weeks | Patient diaries which included The Total Symptom Score (TSS) was the mean of eight symptoms, ranged from 0 to 3 on the scores for the previous 28 days at 4, 8, and 12 wk after treatment; the item of night sleep quality in the diary, in which symptoms were scored as follows: 0, slept well and did not wake up; 1, did not sleep too well or woke up once; 2, slept poorly or woke up two to three times; 3, slept very poorly or woke up more than three times and the PRQLQ | 102/NR/60 | 0/0/60 | Cetirizine vs. Montelukast vs. Placebo (SD) Change from baseline at week 12 TSS −0.60 (0.25)** vs −0.43 (0.23)** vs. −0.11 (0.12)- Nasal itching −1.07 (0.74)** vs. −0.48 (0.60) vs. −0.20 (0.17) Sneezing −0.72 (0.57)** vs. −0.56 (0.59)* vs. −0.08 (0.36) Rhinorrhea −0.56 (0.40)* vs. −0.49 (0.58)* vs. −0.10 (0.35) Nasal congestion −0.63 (0.40)** vs. −0.57 (0.43)* vs. −0.17 (0.24) Throat itching −0.26 (0.45) vs. −0.20 (0.47) vs. −0.05 (0.19) Conjuctiva itching −0.76 (0.49)** vs. −0.47 (0.57)* vs. −0.08 (0.29) Conjuctiva hyperemia −0.53 (0.41)* vs. −0.45 (0.54)* vs. −0.11 (0.26) Tearing −0.26 (0.28) vs. −0.22 (0.29) vs. −0.10 (0.14) Night sleeping quality −0.32 (0.15)** vs. −0.45 (0.17)** vs. −0.08 (0.0) PRQLQ −31.15 (23.36)** vs. −19.15 (20.71)* vs. −3.85 (5.56) |
| Jobst 1994 Germany, The Netherlands (Fair) | Randomized, DB, parallel group, multicenter | PAR Children ages 6 to 12 years with a documented history of PAR for ≥ 1y with a (+) skin test or RAST for nonseasonal respiratory allergens (e.g., house-dust mite, molds, and cat and dog dander) within the year preceding entry to the study, and symptoms of PAR within the preceding 24 hours. | Presence of pollen- or its predicted appearance with 4 week- to which the patient was allergic; presence of any conditions requiring systemic corticosteroids, such as bronchial asthma (unchanged treatment with the equivalent of 200 mcg betamethasone daily by inhaleation was allowed) and atopic dermatitis; vasomotor or infectious rhinitis; URI within the previous 3 weeks; obstructive nasal polyps or signnificant septal deviation; hypersensitivity to piperazines (e.g., cetirizine, hydroxyzine); clinically relevant renal, hepatic, cardiovascular, or related problems; clinically relevant biochemical abnormalities not linked to PAR; insufficient washout periods; administraion of an escalating course of desensitization therapy; participation in another drug trial within the previous 3 months; recent or foreseeable changes in lifestyle (e.g., changing one’s residence, holidays, etc); and assessed risk of noncompliance. | Yes; concomitant medications were taken by 26–31% of patients (mainly antiasthmatics, B-agonists, Theophyllin, inhaled corticosteroids) and nasal preparations (sodium cromoglycate [not allowed by protocol but used by 8–9 patients during study ]) | Mean age group (A) 8.6y, (B) 9.2, (C) 9.3, (D) 8.9 % Male: (A) 54.8, (B) 70.6, (C) 57.9, (D) 57 Race/ethnicity: (D) Caucasian 97.6% | C1: Cetirizine 2.5 mg qd for 2w C2: Cetirizine 5 mg qd for 2w C3: Cetirizine 10 mg qd for 2w P: Placebo qd | Symptoms were scored every day by the patient and recorded on a diary card according to a 4-point scale of main rhinitis symptoms (sneezing, nasal discharge, and nasal obstruction), and of accessory rhinitis symptoms (nasal pruritus and ocular pruritus): 0=not present at all, 1=mild, 2=moderate, 3=severe. At each visit (baseline, 1 week, 2 weeks) assessments were conducted by the investigator (5 point scale, 0= worsening, 4=excellent improvement) and diary cards were collected. | NR/NR/330 | 17/0/311; reasons for withdrawal: incomplete information (1), lack of efficacy (4), AE (8), development of an exclusion criteria (1), use of unauthorized medication (1), unrelated to study (2) | Active vs. placebo *P ≤ 0.05, **P ≤ 0.001 Compliance: Considering patient’s severest symptom: % days asymptomatic: C3>P (p=0.008), NSD C1 vs P and C2 vs P % days when symptoms were absent or mild: C3>D (p=0.016), NSD C1 vs P and C2 vs P % days when no severe symptoms: C1>P (p=0.012), B>P (p=0.006), C3>P (p=0.002) Over time patient’s severest symptom score decreased in all groups, most marked for C3, least marked for P Investigator assigned severest symptom scores: among-group differences week 1 (p=0.022), week 2 (p=0.052), P had highest score; NSD among C1, C2 and C3 at end week 2 Investigator global assessment score (end week 2): differences among groups (p<0.0001), little difference between C2 and C3 |
| Loratadine | ||||||||||
| Potter 2005 South Africa | DB RCT, multicenter (24) | 6 to 12 years who had PAR of at least 1 year’s duration were included in the study, provided they were confirmed to be sensitive to house dust mite by a positive skin prick test result (wheal 3 mm larger than the diluent control for prick testing) or a positive Immunocap radioallergosorbent test result (class 3 or greater or 3.5 IU/mL) in the preceding 12 months. | Seasonal allergic rhinitis, with an ear, nose, or throat infection during the 2 weeks preceding the initial visit, or those with asthma that required corticosteroid treatment or a dermatologic condition that required antihistamine or topical corticosteroid treatment; vasomotor rhinitis, obstructive nasal polyposis, or obstructive deviation of the nasal septum and asthma that required corticosteroid treatment | No rescue meds allowed | Mean age 9.9 yrs 60.8% male Ethnicity NR | Placebo vs. Levocetirizine, 5 mg | The rhinitis symptoms were measured using a 4-grade scale, with scores ranging from 0 to 3 (0 indicates absent; and 3, severe) for each symptom. Symptoms were evaluated daily for each preceding 24 hours and recorded by the child or guardian on a daily record card. The mean T4SS was computed (sum of each individual symptoms score) for the initial 2 weeks of treatment and for the total treatment duration. PRQLQ at baseline and at each of the 3 subsequent clinic visits. Investigators also recorded their global evaluation of disease evolution for each patient at the end of the treatment period. | 371/NR/306 | 9/NR/306 | Placebo vs. Levocetirizine Total 4 Symptoms Scores-mean (SD) baseline/2 weeks/4 weeks 7.51 (1.85)/6.75 (2.21)/6.19 (0.16) vs. 7.53 (1.85)/6.07 (0.15)/5.59 (0.16) Difference (95% CI) vs placebo at 2 weeks 0.69 (0.27–1.12) P= 0.001 and 4 weeks 0.61 (0.16–1.06) P = 0.008 50% Response Rates- mean (SD) 2 weeks/4 weeks 3.9%/11.2% vs. 12.3%/17.5% OR (95% CI) Two weeks 3.42 (1.33–8.83) P = 0.01, Four weeks 1.69 (0.88–3.24) P = 0.12 |
| Yang 2001 Taiwan (Fair) | Randomized, DB, parallel group, single center | PAR Children ages 3 to 12y, with a history of allergic rhinitis due to house dust mites. All children had at least 3 of the following 5 symptoms at enrollment: sneezing, rhinorrhea, nasal congestion, nasal itching and ocular symptoms. Symptoms were graded on a 4-point scale (0=absent, 3=severe). Patients had to be symptomatic with a total symptom score ≥ 7. Sensitivity to dust mites was confirmed by a positive skin prick test and/or a positive CAP result to Dermatophagoides pteronyssinus or Dermatophagoides farinae. | Diseases that might interfere with the study outcome or require specific treatment (such as severe asthma, severe atopic dermatitis, heart failure, renal or hepatic dysfunction); known idiosyncratic reaction to antihistamines, history of multiple drug allergies; patients who received drugs before the enrollment, including ketotifen within 2 weeks, second generation antihistamines within 4 weeks, short acting antihistamines within 4 days, systemic corticosteroids within 2 months, intranasal or eye drops containing a corticosteroid within 2 weeks, anticholinergics within 2 days, topical cromoglycate within one week, and nasal decongestants within 2 days. | No | Mean age group (A) 6.0y, (B) 6.6y % Male: 57 Ethnicity: NR | L: Loratadine syrup 1 mg/mL; doses adjusted according to body weight (5 mg if body weight < 30 kg, 10 mg if weight >30 kg) P: Placebo, not described | Evaluations at baseline, day 7, and day 21 during which investigators reevaluated the 5 cardinal symptoms of allergic rhinitis. Parents were given diary cards for daily recording of the 5 symptoms. All symptoms were graded on a 4-point scale: 0=absent, 3=severe. | NR/NR/46 | Investigator rated markedly or moderately improved 44.7% vs. 57.1% P = NS Mean percentage change from baseline (L vs P; p-values are for the between-group comparison at each time point) Investigator-assessed TSS: Day 7 (visit II): 48.9% vs 14.8% (p=0.003) Day 21 (visit III): 42.2% vs 22.7% (p=0.063) Patient-assessed TSS: Week 2: 4.6% vs 2.8% (p=0.029) Week 3: 13.2% vs 5.6% (p=0.014) Individual symptoms: Rhinorrhea (p=.009) and sneezing (p=004) improved in L vs P; other symptoms NSD | |
| Azelastine | ||||||||||
| Herman 1997 France | DB RCT, multicenter (18) | PAR 5 and 12 years and were skin prick positive to either house dust mites and/or cat or dog dander | Severe total nasal blockage | Concomitant anti-allergic treatment was not permitted during the study; in addition, any concurrent medication which could interfere with the parameters evaluated in the study was not permitted. | Median age 8.71 yrs 60% male Ethnicity NR | Azelastine vs. placebo 6 weeks | Patient diaries assessed before and after a 2 week placebo washout phase and also following 2, 4 and 6 weeks of study medication. Symptoms evaluated were: Sneezing, nasal itch, rhinorrhea and nasal blockage | NR/NR/125 | 8/NR/125 | Results shown in graphs - Compared to the baseline, for each of the six study weeks, the reduction in the VAS scores for all four symptoms (sneezing, nasal blockage, nasal itch and rhinorrhea) was statistically greater (P = 0.0001) for the azelastine group compared to the placebo group |
- Evidence Table 9, Perennial allergic rhinitis trials in children - Drug Class Re...Evidence Table 9, Perennial allergic rhinitis trials in children - Drug Class Review: Newer Antihistamines
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