Study characteristics

Methods

Double‐blind randomized parallel assignment placebo‐controlled study.

Multicentre: Belgium, Germany, Italy, Netherlands, and United Kingdom.

Participants

Inclusion Criteria:

• diagnosis of CF complicated by ABPA;

• oral corticosteroid use for ABPA flare;

• age ≥ 12 years (except for Italy; ≥ 18 years), both male and female;

• total serum IgE levels ≥ 500 IU/mL;

• their FEV₁ at baseline was no lower than 90% of their previous best FEV₁ as measured at screening and their FEV₁ was >40% of predicted or >30% of predicted;

• Females could only be included if they were using adequate methods of contraception, were proven to be surgically sterilized or post‐menopausal;

• All participants (or parents for minors) had to be able to communicate well with the investigator and to have understood and signed the written informed consent prior to inclusion.

Exclusion Criteria:

• history of cancer in the last 10 years;

• history of severe allergic reactions;

• pregnant and lactating women;

• prior use of omalizumab (Xolair®);

• lung or other transplant;

• participation in any clinical trial within 4 weeks prior to initial dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations;

• haemoglobin levels below 10.0 g/dl at screening;

• history of immunodeficiency diseases;

• significant illness other than CF with ABPA within 2 weeks prior to initial dosing;

• a past medical history of clinically significant ECG abnormalities.

• known to be positive for chronic atypical Mycobacteria and Burkholderia cepacia including subspecies;

• history of elevated liver enzymes (3x ULN) or active liver disease, or those who have experienced liver toxicity with other drugs;

• elevated liver enzymes (3x ULN) at screening;

• individuals treated with contraindicated drugs as listed in the Itraconazole SPC, ie cisapride, pimozide, quinidine or dofetilide;

• history or active condition of congestive heart failure or evidence of ventricular dysfunction;

• history of hypersensitivity to itraconazole and/or oral corticosteroid tablets (or any excipients).

Intervention group: 9 participants (5 females); mean (SD) age was 21 (4.1) years.

Placebo group: 5 participants (4 females); mean (SD) age was 28 (9.5) years.

Interventions

Experimental arm:

omalizumab (Xolair®) subcutaneous injections into the upper arm in the area of the deltoid or to the thigh of 600 mg daily for 6 months in the double‐blind phase of the study along with itraconazole 2x daily, while receiving oral corticosteroids, with a maximum daily dose of 400 mg.

Placebo arm:

placebo subcutaneous injections into the upper arm in the area of the deltoid or to the thigh blinded to match experimental arm dosing regimen daily for 6 months in the double‐blind phase of the study along with itraconazole 2xe daily, while receiving oral corticosteroids, with a maximum daily dose of 400 mg.

Outcomes

Primary outcome measures:

• change from baseline in the percentage of participants requiring rescue with corticosteroids (Time frame: 6 months of blinded treatment);

• time to deviation from the protocol prescribed steroid tapering regimen (Time frame: 6 months of blinded treatment).

Secondary outcome measures:

• change in ABPA exacerbation rates during double‐blind treatment period and open‐label treatment period (Time frame: 6 months, 12 months);

• change in FEV₁ from baseline (Time frame: 3 months, 6 months);

• time to steroid‐free state (Time frame: 12 months);

• change from baseline in average oral corticosteroid use (Time frame: 6 months, 12 months);

• percentage of participants responding to omalizumab, as defined by a reduction in oral corticosteroid dose use of 50% or more as compared to baseline (Time frame: 6 months, 12 months).

• number of steps needed to reduce the steroid dose to zero (or to 5 mg or less) following 6 months of treatment

• immunogenicity (anti‐omalizumab antibodies)

• PK/PD: total omalizumab levels, free & total IgE

Notes

Study was started in Novermber 2008 and was terminated in July 2010 after enrolling just 14 participants. Reason for premature termination was not available.

Participants who completed the double‐blinded phase of the study, entered an open‐label treatment period of 6 months and continued the same regimen of omalizumab as in the double‐blinded phase. No placebo was used in the open‐label period.

Sponsors and Collaborators: Novartis Pharmaceuticals.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information available.

Allocation concealment (selection bias)

Unclear risk

No information available.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Study was double blind where participant, caregiver, investigator, and outcome assessor were masked to treatment assignment.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Of the 9 participants enrolled in the intervention group only 4 completed the double‐blind phase of the study (5 dropped out: 1 due to adverse events; 1 due to lack of efficacy; and 3 due to administrative problems); of the 5 participants in the placebo group only 3 completed this phase (2 dropped out: both due to administrative problems).

Selective reporting (reporting bias)

High risk

Data related to all outcome measures were not reported on the website, not even for those participants who completed study before its termination.

Other bias

High risk

Early termination of study.