| 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| Interventions | Method of outcome assessment and timing of assessment | Number screened/eligible/enrolled | Number withdrawn/lost to follow- up/analyzed | Results |
|---|---|---|---|---|---|---|---|---|---|---|
| Active-control trials | ||||||||||
| Cetirizine | ||||||||||
| Tinkleman 1996 USA (Fair) | RCT, not blinded, parallel multicenter | SAR Children with a documented history of SAR during the grass pollen season and currently symptomatic; if they had concomitant mild-to-moderate asthma, they had to have a baseline forced expiratory flow of ≥75% of predicted value. Allergy to grass pollen had been verified by skin test (prick, intradermal, or radioallergosorbent) within 2 yrs before the start of the study. Entering pts were required to have a total score of ≥6 (on a range of 0–18) from the investigating MDs baseline assessment of 6 rhinitis symptoms, with a score of ≥2 for sneezing or nasal discharge and ≥1 other symptom. | Concomitant disease that could interfere with evaluation (e.g., acute sinusitis, nasal polyps), history of severe asthma during pollen season, significantly abnormal blood, renal, or hepatic function, hypersensitivity to study drugs or hydroxyzine, use of antihistamines, on immunotherapy, chronic medication use other than for asthma, asthma therapy in prior 2 months with beta-agonists or steroids | Allowed only these medications for chronic asthma: theophylline, inhaled cromolyn or inhaled bronchodilators; excluded beta-agonists or steroid therapy within 2 months prior to study | Mean age: 8.8y Range: 6–11 y 68.3% Male White: 82.3% Other races: 17.7% Mean weight: 74.5 lb; (% ≥ 25 kg: 86.5%) % who were asthmatic: 62.9% Mean duration of allergy: 5.6y Baseline TSS score: 5.8 | C1: Cetirizine 5mg for patients <25kg and 10mg for patients ≥ 25kg qd (n=63) C2: Cetirizine 2.25mg for patients <25kg and 5mg for patients ≥ 25kg bid (n=63) Ch: Chlorpheniramine 2 mg tid (n=62) | Diary cards were to be filled out each morning and evening Symptoms (sneezing, nasal discharge, itchy eyes, itchy nose/mouth/throat, conjunctivitis, and nasal congestion) were assessed by both patients and investigators as 0: “none”, 1: “mild”, 2: “moderate”, 3: “severe”. Those with concomitant asthma rated severity of asthma as: 1: “much worse’, 2: “slightly worse”, 3: “same”, 4: “slightly better”, 5: “much better than usual” TSS score; total symptoms severity score calculated from patient diary records; assessed at baseline, day 7, and day 14 Global investigator efficacy (scale 0–3): 0 - completely ineffective, 1 - slightly effective, 2 - quite effective, 3 - extremely effective | NR/NR/188 | 4/1/186 | Primary outcome: Mean change in patient-reported TSS score (except for nasal congestion): C1: −2.6 C2: −2.6 Ch: −2.6, NSD among groups Mean change in individual symptom score between day 0 and day 14 C1 vs C2 vs Ch (NSD for all 6 symptoms): (all values estimated from graphs) Sneezing: −0.5 vs −0.67 vs −0.5 Runny nose/post-nasal drip: −0.66 vs −1.0 vs −0.8 Itchy eyes: −0.6 vs −0.7 vs −0.4 Itchy nose, mouth or throat: −0.75 vs −0.75 vs −0.67 Teary or swollen eyes: −0.22 vs −0.21 vs −0.22 Stuffy nose: −0.75 vs −0.93 vs −0 Mean reduction in investigators’ mean TSS scores, C1 vs C2 vs Ch: −3.5 vs −3.6 vs −3.8, NSD for all comparisons |
| Loratadine | ||||||||||
| Boner 1989 Italy (Fair) | NR Single center | SAR Children with moderate and severe SAR, symptomatic at baseline, with their hypersensitivity confirmed by allergy history and a (+) response to skin prick test (allergen wheal diameter 3mm> histamine control) to seasonal allergen (grass pollen, parietaria. Children or parents had to be capable of recording the daily symptom score on a diary card, complying with the dose regimen, and able to maintain the study evaluation schedule. | Asthma; on immunotherapy; nasal polyps; abnormal laboratory test parameters; multiple drug allergies; history of reaction to antihistamines; antihistamine or decongestant use in last 24h prior to randomization; cromolyn sodium, terfenadine, or astemizole within last 2 weeks; or corticosteroids within last month | NR | Mean age: 7.7y Range: 4–12 y 65% Male Ethnicity: NR Mean weight: 28.6 kg Mean height: 123.7 cm | L: Loratidine 5 mL (5 mg) (1 mg/mL suspension) qam at same time for 14 days (range: 2.5–5 mg/d) (n=21) D: Dexchlorpheniramine 2.5 mL (1 mg) (1 mg/2.5 mL syrup) q8 h for 14 days (range: 1.5–3 mg/d) (n=19) Children <6y or weighing <20 kg received half dose | Clinical symptoms evaluated at baseline and day 3, 7, and 14; the severity of each symptom and the overall condition of rhinitis were rated and scored from 0 = none to 3 = severe. Overall therapeutic response was scored from 0: “treatment failure” to 4: “excellent, virtually all symptoms eliminated” | NR/NR/40 | 4/NR/unclear | Mean TSS, day 0 to 14, L vs D: −6.9 points vs −8.2 points, NSD (estimated from graph) Mean individual SS, day 0 to 14, L vs. D: −2.5 points vs −1.8 points, NSD (estimated from graph) TSS, as assessed by both investigator and patient/parent, decreased in both L and D, with NSD between groups (p=0.295 in favor of D) |
| Jordana 1996 Canada (Fair) | RCT, DB, parallel multicenter | SAR Patients 12–17y with a history of moderate to severe ragweed-induced SAR who had allergy confirmed with a ragweed skin-prick test (wheal and flare response with a wheal ≥ 3mm in diameter greater than buffer control). | Concurrent PAR; if they had taken long-acting H1 antagonists within the past 6w, inhaled intranasal or systemic corticosteroids, inhaled sodium cromoglycate within last 4w, loratadine or other OTC antihistamine within last week; received any other therapy for rhinitis (time frame unclear); clinical evidence of infection of sinuses or upper or lower respiratory tract.; nasal surgery in last year, structural abnormalities or nose; pregnant; lactating, not using reliable contraceptive measures | Terfenadine 60 mg, naphazoline and pheniramine combination eye drops, and bronchodilator salbutamol were the only rescue drugs allowed | Mean age: NR Range: 12–17y 56.25% male Ethnicity: NR Asthma: A 46/119, B 45/121 | L: Loratadine 10 mg syrup qam + placebo spray F: Fluticasone propionate 200 micrograms aqueous spray qam + placebo tablet 4-week treatment period | Patients visits at day 0, after 2 and 4 weeks of treatment, and 2 weeks after study completion Symptom-free days for nasal blockage was primary outcome (score of 0); patients given daily symptom diary cards, scale 0 (absent) to 3 (severe): nasal blockage on awakening, nasal blockage for rest of day, sneezing, nasal itch, eye watering or irritations recorded int he evening | NR/257/242 | 12/unclear/240; 2 withdrawn prior to randomization; 12 pts were discontinued from the study for AEs, and 5 for ineffective treatment | Symptom-free days (%): F> L for all nasal symptoms; NSD for eye-watering or eye-irritation SS F< L for all nasal symptoms; NSD for eye symptoms. Rescue-free days (%), L vs F: 96 days vs 93 days, NSD Patients receiving rescue antihistamines (% of patients), L vs F: 39% vs 21%, p<0.0025 NSD between groups for use of rescue eye drops or rescue bronchodilator Nasal peak inspiratory flow: F>L both in am (p=0.0051) and pm (p=0.0036) (n=56, chosen randomly from study population) |
| Placebo-controlled trials | ||||||||||
| Cetirizine | ||||||||||
| Allegra et al 1993 Europe (Fair) | PCT, DB, parallel multicenter | SAR Children between 2–6y with pollen-induced SAR, which was based on child’s history, one positive allergy test (prick test, RAST, or CLA) and the presence of at least 3 of the following 5 symptoms: sneezing, rhinorrhea, blocked nose, nasal pruritus, ocular pruritus, rated 0–3. A TSS of ≥6 was required for inclusion. | Vasomotor or infectious rhinitis, obstructive nasal polyposis, infection requiring antibiotic therapy, history of relevant drug allergy, clinically relevant systemic illness or unexplained laboratory test abnormalities. Patient could not use other antihistamines, sedatives, nasal decongestants, topical preparations for nose or eye, or corticosteroids (other than by oral inhalation for asthma) | Children with asthma could continue theophylline, beta2 sympathomimetics, inhaled cromoglycate, nedocromil, or inhaled corticosteroids (≤ 200 micrograms/day) | Mean age: 4.45y Range: 2–6y 69% male Ethnicity: NR | C: Cetirizine 5 mg qd (10 drops of a 10 mg/mL solution) P: Placebo solution of same color and taste 2-week treatment period | Parent completed daily diary cards assessing severity of symptoms (0=none, 3=severe) Investigators rated symptoms on same scale on each visit and at final visit. At final visit investigator made global assessment of efficacy using 5-point scale (0=worse, 5=excellent response, complete disappearance of symptoms) Disease Severity Score (DSS): maximum score of any one of the 5 symptoms evaluated (i.e., the score of the most troublesome symptom) computed each day per parent’s evaluations and at each visit per investigator evaluations. Cumulative frequency of the DSS from parents’ daily record was calculated fro each patients over the 2-week treatment period and expressed as a % of days with a maximum score of 0 (no symptoms), 1 (mild symptoms) and 2 (moderate). | NR/NR/107 | 0/0/107 | Results given as C vs P: Change in mean DSS (assessed by investigator) between baseline and last visit: −1.4 vs −1.1, p = 0.040 Group C associated with parent-assessed scores ≤ 1(ie, mild or absent symptoms) more often than P, p=0.002 Global evaluation of rhinitis by investigators: excellent or good: 63% vs 45.3%, p = 0.039 |
| Ciprandi et al 1997a Ciprandi 1997b (cough) Italy (Fair) | Randomized, double-blind, parallel group, single center | SAR Children ages 6 to 15 years with allergic rhino conjunctivitis; a history of allergic rhino conjunctivitis due to Parietaria Judaica and/or grass pollen for at least 2 previous seasons, without clinical asthma. Skin-prick test and RAST confirmed the diagnosis. | History of asthma or previous documented intolerance to the studied drug; any other ocular or nasal disease | Subjects did not receive topical and/or systemic drugs during the preceding 6 weeks, they had not received specific immunotherapy before and during the study. | Mean age: 8.5y Range 6–15 55% male Ethnicity: NR | C: Cetirizine 0.15 mg/kg qam P: Placebo qam | Rhinitis symptoms and possible adverse events were recorded in the evening on a diary card; signs and symptoms (ocular hyperaemia, itching, lacrimation, eyelid swelling, nasal itching, obstruction, rhinorrhea, sneezing) graded on a 4-point scale; cough was also reported on a 4 point scale. Patients underwent 2 clinical visits, at the beginning and end of the study (4 weeks). A nasal lavage was performed at each visit. | NR/NR/20 | 0/0/20 | Clinical signs and symptoms score: Improved in C vs P at week 1 (p=0.03), 2 (p=0.01), 3 (p=0.01), and 4 (p=0.01) Cough intensity: Improved in C vs baseline at week 2,3, and 4 (p<0.01). C < P at weeks 2 (p<0.02), 3 (p=0.01), and 4 (p=0.02) Cough frequency: C < P at weeks 1 (p=0.03), 2 (p=0.006), 3 (p=0.01) and 4 (p=0.02) PEF, FEV1: NSD Neutrophil (p=0.02) and eosinophil (p=0.01) counts, and intracellular adhesion molecule (ICAM-1) expression in nasal epithelial cells decreased in C compared to baseline; NSD in P |
| Masi 1993 Italy (Fair) | Randomized, DB, parallel group, multicenter | SAR Children 6–12 y with pollen-associated allergic rhino-conjunctivitis, diagnosed on the basis of a reliable history, a positive allergy test for prevailing pollen (skin test or RAST) within the previous year and the presence of ≥3 of these symptoms: rhinorrhea, sneezing, blocked nose or pruritus involving nose or eyes (scaled 0–3). TSS had to be ≥8 as assessed by investigator at first visit. | Infectious or vasomotor rhinitis, recent URTI, sinusitis, otitis media, obstructive nasal polyposis, any infection requiring antibiotic therapy, history of sensitivity to study drugs, any illness that might interfere with the assessment of therapeutic response or laboratory tests | Children with asthma could continue theophylline, beta2 sympathomimetic drugs, inhaled cromoglycate, nedocromil or inhaled corticosteroids (<200 mcg/d) provided dose unchanged throughout study. Sedative and topical preparation for nasal or ocular use were prohibited. | Mean age: 10.15y 61.3% male Ethnicity: NR | C: Cetirizine 5 mg bid P: Placebo 2 week treatment period | Patients kept daily symptom diary Disease Severity Score: the maximum score (i.e. most troubling symptom) of any of the 5 symptoms (rhinorrhea, sneezing, blocked nose, pruritis involving nose or eyes), each assessed on a 0–3 scale (0= no symptoms, 3=severe) Cumulative frequency of the DSS: calculated as a % of study days when DSS was 0 (no symptoms, ≤1 (symptoms mild to moderate, and ≤2 (symptoms absent to moderate). % days when DSS ≤1: primary outcome | NR/NR/124 | 10/2/unclear | All data given as C vs P Patient-assessed DSS: % patients ≤2 A: 90.0 B: 75.8 (p=0.0004) Differences in investigator-assessed DSS between baseline and: Week 1: −1.22 vs −0.87, p=0.007 Week 2: −1.75 vs −1.22, p<0.001 Investigator global evaluation of rhino conjunctivitis: 79% vs 50% patients considered “excellent” or “good” at end of 2 weeks, p<0.001 |
| Pearlman et al 1997, Winder et al 1996 (safety) US (Fair) | Randomized, double-blind, parallel group, multicenter | SAR Children ages 6 to 11 years with documented histories of SAR during the fall pollen season; allergy to pollen confirmed by an intradermal or skin prick test or a RAST within 2 years prior to the start of the study. Entering patients were required to achieve a minimum TSS score of 6 (range, 0 to 18) with the investigator’s baseline assessment of 6 rhinitis symptoms. TSS included at least 2 symptoms of moderate severity (score 2 or higher), one of which had to be sneezing or nasal discharge. | Patients were excluded if they had diseases that might interfere with the evaluation of the therapeutic response (e.g., recent URI, acute sinusitis, nasal polyposis); history of severe exacerbations of asthma during the pollen season, significantly abnormal hematologic, renal, or hepatic function; hypersensitivity to cetirizine or hydroxyzine; escalating course of immunotherapy or on maintenance therapy for <6m. | Administration of oral steroids or astemizole within 2 months prior to the study was not permitted. Nasal decongestants were discontinued 24h prior, antihistamines for 48h, and cromolyn sodium or intranasal steroids for 2w prior. | Mean age: NR Range 6–11 67% male Ethnicity: 88% white, 11% other | C1: Cetirizine 5 mg qd C2: Cetirizine 10 mg qd P: Placebo qd | Patient diary and physical examination at weeks 1, 2, 3, and 4; each symptom evaluated on a 4-point scale by investigator each week, and by parent/child each day. | NR/NR/209 | For efficacy: 4/0/205 For safety: 4/16/189 for ECG analysis: NR/88/121 | Group C2 vs P: Patient-assessed change in mean TSS from baseline (4-point scale; baseline scores not reported) −3.19 vs −2.09 (p<0.05) Individual symptoms Ocular itching: −0.73 vs −0.10 (p<0.05) Oral/nasal itching: −0.74 vs −0.53 (p<0.05) Group C1 vs P: Patient-assessed change in mean TSS from baseline −2.41 vs −2.09 (NSD) Other outcomes not reported for C1 vs P Group C1 vs C2: C2>C1 for relief of ocular itching at week 3 (p<0.05) and relief of oral/nasal itching at weeks 2 and 3 (p<0.05) Investigator-assessed TSS: NSD among treatment groups (data not reported) |
| Fexofenadine | ||||||||||
| Wahn et al 2003 15 countries: Argentina, Austria, Chile, Finland, France, Germany, Israel, Italy, Poland, Portugal, South Africa, Spain, Uruguay, US (Fair) | Randomized, double-blind, parallel group, multicenter | SAR Children ages 6 to 11 years with spring or fall SAR and an approximate 1- year history of SAR. A positive skin prick test result (wheal diameter 3 mm or greater compared with diluent within 15 minutes of the skin prick) to at least 1 allergen indigenous to the study site area or, when relevant, to a child's site of residence, which must have been positive in serum allergen-specific IgE testing, was required. In addition, the appropriate sensitizing allergen was required to be present at visit 1 and likely to be present for 3 weeks from visit 1. Children also needed to satisfactorily demonstrate that they could swallow the study medication. | Upper respiratory tract infection within 30 days of the study; purulent conjunctivitis or rhinitis of any type other than SAR; obstructive deviated nasal septum or obstructive nasal polyposis; active perennial allergic rhinitis; cystic fibrosis; immunotherapy to treat SAR; and clinically significant cardiovascular, hepatic, neurologic, psychiatric, endocrine, or other major systemic disease; Excluded drugs: corticosteroids: oral (30d loratadine, fexofenadine, and cetirizine; prior), nasal (14d), inhaled (30d); cromolyn sodium inhaled or oral (14d) | Drugs that were excluded included oral, nasal, and inhaled corticosteroids for 30, 14, and 30 days, respectively, before visit 1, and inhaled or oral cromolyn sodium for 14 days before the visit. Between visits 1 and 2, the following drugs were excluded: the H1- receptor antagonists astemizole, and leukotriene modifiers, such as montelukast and zafirlukast. | Mean age: 9.0y, range 5–12 % male: NR 80% White 7.0% Black 1% Asian, 11% Multiracial | F: Fexofenadine 30 mg bid P: Placebo bid 2-week treatment period | Symptoms assessed by the child and caregiver immediately before dosing. Diary cards were collected at visits 2, 3, and 4 (though visit 3 was not mandatory). Primary efficacy variable was mean change from baseline in the average PM-reflective TSS. Secondary efficacy variables were AM- reflective TSS, PM and AM reflective individual SAR symptom scores, and the daily PM-reflective TSS. | 1961/NR/935 | 3/NR/932 7 (withdrew for treatment failure), 32 did not complete entire study but had at least one follow-up measure and were analyzed | Mean change from baseline on pm-reflective TSS, F vs P (4-point scale): −1.94 vs −1.21 (p≤0.0001) TSS in am: −1.67 vs −0.93 (p<0.0001) Individual symptom scores in pm (sneezing; rhinorrhea; itchy nose, mouth, throat; itchy watery eyes; nasal congestion) all decreased in F vs P (p<0.05) |
From: Evidence Tables
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