CIGE025ADE03

Novartis Pharma AG

CH-4002, Basel, Switzerland,

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,

No

No

Yes

Final

05 Sep 2008

No

Yes

05 Sep 2008

No

The main objective of the study was to demonstrate that grass/rye pollen extract in combination with omalizumab has superior efficacy compared to grass/rye pollen extract monotherapy, for daily symptom load averaged over the pollen season in adult and adolescent subjects, sensitized against grass pollen allergens with seasonal allergic asthma and comorbidity with seasonal allergic rhinoconjunctivitis.

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. For symptoms of inter-current bronchospasm subjects were allowed to take short acting β-2 agonist (SABA) (salbutamol sulfate) as initial rescue medication. If the initial SABA did not result in symptom control , escalation co-medication was provided by the study physician. Escalation medication for treatment of seasonal asthma included low-dose inhaled corticosteroid (ICS) (budesonide) 200 microgram (mcg) once daily (o.d.) dose was provided, if no symptom control was achieved medium-dose inhaled corticosteroid (budesonide) 200 mcg twice daily (bid) dose was provided and if this dose was also insufficient to control asthma symptoms, oral corticosteroid (prednisone) 50 milligram (mg) was provided. If no symptom control was achieved after this step, patients had to be discontinued from the study. In this case, the responsible study physician needs to specifically optimize the patient’s individual treatment regimen, considering combination treatment with long acting beta agonists and inhaled corticosteroids. For symptoms of grass pollen allergic rhino-conjunctivitis subjects were allowed to take systemic antihistamine (levocetirizine dihydrochloride) 5 mg as initial rescue medication. If initial systemic antihistamine was insufficient , escalated co-medication was provided by the study physician. Escalation medication for treatment of seasonal rhino-conjunctivitis included a nasal steroid (mometasone) 50 mcg , if no symptom control was achieved , the next step was an oral corticosteroid (prednisone) 50 mg . The investigator provided follow-up medical care for all subjects who prematurely withdrew from study or referred them for appropriate ongoing care.

21 Feb 2006

No

No

Germany: 140

140

140

0

0

0

0

1

27

112

0

0

Period 1 (Core study)

Randomised - controlled

Randomization data were kept strictly confidential and the identity of treatments were concealed by the use of identical study drugs. Unblinding was allowed from time of randomization to database lock, except in the case of subject emergencies and at the conclusion of the study.

Yes

Grass/Rye pollen extract

Solution for injection

Subcutaneous use

Grass/rye pollen extract solution (0.5 ml) was administered weekly via s.c. route every 4 weeks. Grass/rye pollen extract solution consists depigmented and glutaraldehyde polymerised allergenic extract of 50% grass / 50% rye pollen adsorbed onto aluminum hydroxide.

Omalizumab

IGE025

Powder for solution for injection

Subcutaneous use

Omalizumab (75-375 mg) individualized dose was administered weekly via s.c. after reconstitution with 1.4 ml Sterile Water for Injection for 2-4 weeks.

Grass/Rye pollen extract

Solution for injection

Subcutaneous use

Pollen extract solution (0.5 ml) was administered weekly via s.c. route every 4 weeks. Pollen extract solution consists depigmented and glutaraldehyde polymerised allergenic extract of 50% grass / 50% rye pollen adsorbed onto aluminum hydroxide.

Placebo

Powder for solution for injection

Subcutaneous use

Placebo matched to omalizumab (75 - 375 mg) was administered weekly via s.c. route for 2-4 weeks.

Period 2 (Extension Period - 2007)

Not applicable

The extension period was open label, hence no blinding was performed.

Yes

Grass/Rye pollen extract

Solution for injection

Subcutaneous use

Grass/Rye pollen extract solution (0.5 ml) was administered weekly via s.c. route every 4 weeks. Grass/Rye pollen extract solution consisted of depigmented and glutaraldehyde polymerized allergenic extract of 50% grass / 50% rye pollen adsorbed onto aluminum hydroxide

Grass/rye pollen extract

Solution for injection

Subcutaneous use

Grass/rye pollen extract solution (0.5 ml) was administered weekly via s.c. route every 4 weeks. Grass/rye pollen extract solution consists depigmented and glutaraldehyde polymerised allergenic extract of 50% grass / 50% rye pollen adsorbed onto aluminum hydroxide.

Period 3 (Extension Period- 2008)

Not applicable

The extension period was open label, hence no blinding was performed.

Yes

Grass/rye pollen extract

Solution for injection

Subcutaneous use

Grass/rye pollen extract solution (0.5 ml) was administered weekly via s.c. route every 4 weeks. Grass/rye pollen extract solution consists depigmented and glutaraldehyde polymerised allergenic extract of 50% grass / 50% rye pollen adsorbed onto aluminum hydroxide.

Grass/rye pollen extract

Solution for injection

Subcutaneous use

Grass/rye pollen extract solution (0.5 ml) was administered weekly via s.c. route every 4 weeks. Grass/rye pollen extract solution consists depigmented and glutaraldehyde polymerised allergenic extract of 50% grass / 50% rye pollen adsorbed onto aluminum hydroxide.

Core: Grass/Rye Pollen extract + Omalizumab

Core: Grass/ Rye Pollen extract + Placebo

Core: Grass/Rye Pollen extract + Omalizumab

Core: Grass/ Rye Pollen extract + Placebo

Pollen extract (Core and Extension- 2007) + Omalizumab (Core)

Pollen extract (Core and Extension - 2007) + Placebo (Core)

Pollen extract (Core and Extension-2008) + Omalizumab (Core)

Pollen extract (Core and Extension - 2008) + Placebo (Core)

Symptom load is sum of mean daily symptom severity score plus mean daily rescue/escalation medication score combined for asthma and rhinoconjunctivitis. Overall symptom severity score was derived from subject diaries for various allergy symptoms. Subjects rated the symptoms on a 4-point scale: from 0 to 3 for “no”, “mild”, “moderate” and “severe” symptoms respectively. The rescue medication score is defined as mean of daily rescue medications scores during pollen season. Patients recorded daily usage of their rescue/escalation medication in patient diary. The point values assigned to usage of each individual medication on each day. A lower score indicated an improvement in the allergic condition. The analysis was on intent to treat (ITT) population defined as all subjects randomized receiving at least one dose of study drug and had at least one assessment of symptom load in their diaries. The missing values were imputed using last observation carried forward (LOCF).

Primary

Week 1 up to Week 18 (Core period), Week 4 up to Week 104 (Extension period)

Core: Grass/Rye Pollen extract + Omalizumab v Core: Grass/ Rye Pollen extract + Placebo

132

Pre-specified

-0.21

2-sided

Pollen extract (Core and Extension- 2007) + Omalizumab (Core) v Pollen extract (Core and Extension - 2007) + Placebo (Core)

128

Pre-specified

0.17

2-sided

Pollen extract (Core and Extension-2008) + Omalizumab (Core) v Pollen extract (Core and Extension - 2008) + Placebo (Core)

114

Pre-specified

0.24

2-sided

The overall symptom severity score of asthma/rhinoconjunctivits was derived from subject diaries for difficulty in breathing, difficulty in breathing on exercise, cough, tightness of chest, nocturnal awakening, sneezing, itchy nose, runny nose, stuffy nose, red eyes, watery eyes and itchy eyes. Subjects rated the symptoms on a 4-point scale: 0 – no symptoms, 1: mild symptoms, 2: moderate symptoms, 3: severe symptoms. A lower score indicated an improvement in the allergic condition. The analysis was performed in the ITT population. Here "Number of subjects analysed" signifies the subjects assessed for severity score during the study for each arm, respectively. The missing values were imputed using LOCF method.

Secondary

Week 1 up to Week 18 (Core period), Week 4 up to Week 104 (Extension period)

The rescue medication score was defined as mean score of daily rescue medication utilized for relief from asthma/ rhinoconjuctivitis during the pollen season. The improvement in symptoms post administration of any rescue medication were rated by subjects from 1 point to 6 point based on usage of medication, SABA: 1 point per accentuation, H1-blocking agent: 1 point per tablet, ICS (200 mcg): 3 points per capsule, Nasal steroid: 3 points per accentuation and Oral corticosteroids (50 mg): 6 points per tablet. The analysis was performed in the ITT population. Here "Number of subjects analysed" signifies the subjects assessed for rescue medication score during the study for each arm, respectively. The missing values were imputed using LOCF method.

Secondary

Week 1 up to Week 18 (Core period), Week 4 up to Week 104 (Extension period)

Asthma Control Questionnaire (ACQ), has 7 questions, each with a 7 point scale (0 – good control, 6 –poor control). The average score was calculated as the total of all 7 questions divided by 7 (or the number of questions that were answered at the time point as long as there are at least 4 questions answered). Lower score indicated improvement in symptoms. The analysis was performed in the ITT population. Here "Number of subjects analysed" signifies the subjects who had evaluable ACQ data in the corresponding time points during study for each arm, respectively. The missing values were not imputed.

Secondary

Week 18 (End of core period), Week 52 after core period (End of extension - 2007), Week 104 after core period (End of extension - 2008)

Asthma Quality of Life Questionnaire (AQLQ) was 32 item questionnaire defined in 4 domains (symptoms, activity limitation, emotional function and environmental exposure). Each question was answered on a 7 point scale (1–totally limited/problems all the time to 7–not at all limited/no problems). The overall AQLQ score was the mean of all 32 responses (overall score of 1 = severely impaired, overall score of 7 = not impaired at all). Higher score indicated improvement. The analysis was performed in the ITT population. Here "Number of subjects analysed" signifies the subjects who had evaluable AQLQ data in the corresponding time points during study for each arm, respectively. The missing values were not imputed.

Secondary

Week 18 (End of core period), Week 52 after core period (End of extension- 2007), Week 104 after core period (End of extension - 2008)

Rhinoconjunctivitis quality of life questionnaire (RQLQ) was 28-item disease-specific questionnaire defined in 7 domains (activities, sleep, common complaints, practical problems, nasal symptoms, ocular symptoms, and emotions). Each question was answered on a 7 point scale. The overall RQLQ score was the mean of all 28 responses (1–low to 7–high). Higher values represented worse quality of life. The analysis was performed in ITT population. Here "Number of subjects analysed" signifies the subjects with evaluable data for RQLQ during the study for each arm, respectively. The missing values were not imputed.

Secondary

Week 18 (End of core period), Week 52 after core period (End of extension - 2007), Week 104 after core period (End of extension - 2008)

The AQLQ and RQLQ clinical differences were categorized as important, moderate, or meaningful improvement; no clinical change; meaningful, moderate, or important impairment. Clinically important differences was scored between any two assessments determined by the authors of the AQLQ and RQLQ. Changes in scores of 0.5 to 1.0 were considered clinically meaningful; 1.0 to 1.5 as moderate and > 1.5 as marked clinically important differences for any individual domain or for the overall summary score. Baseline = Core Screening period i.e. Day -14 to Day -1. The analysis was performed in ITT population. Here "Number of subjects analysed" signifies the subjects who had evaluable data in AQLQ and RQLQ for the core study for each arm, respectively.The missing values were not imputed.

Secondary

Baseline to Week 18 (End of core period)

The AQLQ and RQLQ clinical differences were categorized as important, moderate, or meaningful improvement; no clinical change; meaningful, moderate, or important impairment. Clinically important differences was scored between any two assessments determined by the authors of the AQLQ and RQLQ. Changes in scores of 0.5 to 1.0 were considered clinically meaningful; 1.0 to 1.5 as moderate and > 1.5 as marked clinically important differences for any individual domain or for the overall summary score. Baseline = Core Screening period i.e. Day -14 to Day -1. The analysis was performed in ITT population. Here "Number of subjects analysed" signifies the subjects who had evaluable data in AQLQ and RQLQ for the extension study for each arm, respectively. The missing values were not imputed.

Secondary

Baseline to Week 52 after core period (End of extension- 2007), Week 104 after core period (End of extension-2008)

Subjects were assessed by investigator based on GETE, a five point scale that evaluated change in asthma control/symptoms (1: excellent for complete control of asthma, 2: good for marked improvement of asthma, 3: moderate for discernible, but limited improvement of asthma, 4: poor for no appreciable change, and 5: worsening for asthma). The analysis was performed in the ITT population. Here "Number of subjects analysed" signifies the subjects with evaluable data for GETE assessment during the study for each arm, respectively. The missing values were not imputed.

Secondary

Week 18 (End of core period), Week 52 after core period (End of extension - 2007), Week 104 after core period (End of extension - 2008)

Subjects were assessed by subject/caregiver based on GETE, a five point scale that evaluated change in asthma control/symptoms (1: excellent for complete control of asthma, 2: good for marked improvement of asthma, 3: moderate for discernible, but limited improvement of asthma, 4: poor for no appreciable change, and 5: worsening for asthma). The analysis was performed in the ITT population. Here "Number of subjects analysed" signifies the subjects with evaluable data for GETE assessment during the study for each arm, respectively. The missing values were not imputed.

Secondary

Week 18 (End of core period), Week 52 after core period (End of extension - 2007), Week 104 after core period (End of extension - 2008)

Work Productivity and Activity Impairment-Allergic Asthma (WPAI-AA) questionnaire, covers 6 questions relating to hours missed from work and work productivity in the previous 7 days. The 6 items and 5 additional derived scores was summarized for each time point. The scale ranged from minimum value as 0 to the maximum value of 1. A negative change indicated improvement. The analysis was performed in the ITT population. Here "Number of subjects analysed" signifies the subjects assessed for WPAI-AA during the study for each arm, respectively. The 'n' in each category signifies those subjects evaluable for this measure at specified time points for each group respectively. The missing values were not imputed.

Secondary

Week 18 (End of core period), Week 52 after core period (End of extension - 2007), Week 104 after core period (End of extension - 2008)

Forced Expiratory Volume in One Second (FEV1) was defined as the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, was measured during grass pollen season before each injection of pollen extract. FEV 1 more than or equal to (≥) 70% was ensured prior to administration of pollen extract. Percentage of Forced Expiratory Volume in One Second (FEV1 %) is calculated for each patietn as FEV1(%) = [FEV (best test) * 100]/ Predicted FEV1 At least three maneuvers are performed at each sampling time point. The FEV1 "best test" curve is defined as the spirogram that gives the largest FEV1. The analysis was performed in ITT population. Here "Number of subjects analysed" signifies the subjects assessed for FEV1 during the study for each arm, respectively. The missing values were not imputed.

Secondary

Week 18 (End of core period), Week 52 (End of extension - 2007), Week 104 (End of extension - 2008)

The Peak Expiratory Flow (PEF) was measured during grass pollen season before each injection of pollen extract, through spirometry testing. The PEF was assessed using a Mini Peak Flow Meter provided to subjects within 15 minutes of awakening in the morning, prior to any rescue medication use. The analysis was performed in ITT population. Here "Number of subjects analysed" signifies the subjects with evaluable data for PEF during the study for each arm, respectively. The missing values were not imputed.

Secondary

7 days after Week 16 (Day 113) (Core period), 7 days after Week 48 after core period (Extension - 2007), 7 days after Week 100 after core period (Extension - 2007)

Local reactions defined according to the size, itching and pain, for size of swelling the largest diameter was evaluated. Local reactions were graded as, mild (< 5 cm), moderate (> 5–10 cm) and severe (> 10 cm). The analysis was performed in Safety (SAF) population, defined as all subjects who received at least one dose of study drug. Here, "Number of subjects analysed" signifies subjects with evaluable data for local reactions for each arm, respectively.

Secondary

Day 1 (Start of treatment), Week 18 (End of core period)

Patients were evaluated for allergic symptoms and unwanted effects in terms of adverse events, and the intensity based on the grades as per German Society for Allergology and Immunology (DGAI) criteria: Grade 1 Mild: General skin redness, urticaria, pruritus (palmar and plantar), rhino-conjunctivitis, unspecific symptoms like headache, restlessness ; Grade 2 Moderate: Circulation disturbances like changes in blood pressure or heart rate, mild dyspnea or mild bronchial obstruction, tenesmus, anxiety; Grade 3 Severe: Shock (severe hypotension, paleness), severe bronchial obstruction, unconsciousness, urge incontinence; Grade 4 Anaphylaxis; Heart or circulatory failure. The severity was judged using visual analogue scale (VAS) from 0 = none to 10 = very severe. The analysis was performed in the SAF population. Here, "Number of subjects analysed" signifies subjects with evaluable data for systemic reactions for each arm, respectively.

Secondary

Day 1 (Start of treatment), Week 18 (End of core period)

Airway inflammation was assessed by bronchial hyperreactivity (PC20) test defined as a provocative concentration of omalizumab producing a 20 % fall in FEV1 from baseline. Baseline = Core Screening period i.e. Day -14 to Day -1. The analysis was performed in the SAF population. Here "Number of subjects analysed" signifies the subjects assessed for bronchial hyperreactivity during core study for each arm, respectively. The 'n' signifies those subjects evaluable data for this measure for each group respectively.

Secondary

Baseline, Week 12 (Day 85), Week 18 (Day 127) of core period

Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.

AE additional description

11.0

Core: Grass/Rye Pollen extract + Omalizumab

Core: Grass/ Rye Pollen extract + Placebo

Pollen extract (Core and Extension- 2007) + Omalizumab

Pollen extract (Core and Extension - 2007) + Placebo (Core)

Pollen extract (Core and Extension-2008) + Omalizumab

Pollen extract (Core and Extension - 2008) + Placebo (Core)