Following additional internal Novartis review, it was noted that any reference to “ligelizumab” as the generic name for QGE031 should be removed, as at the time of the protocol this INN has not yet been recommended. The protocol was therefore amended to remove this text from the cover page. An error in timing of ACQ and spirometry assessments was also noted. The ACQ-7 questionnaire requires entry of FEV1 data and therefore needed to align with scheduled spirometry; ACQ and spirometry assessments prior to randomization were not aligned in the original protocol. To ensure clarity, additional errors and inconsistencies had also been corrected following vendor and internal feedback received post protocol finalization.

During the set-up of study, it had become known that epinephrine auto-injectors may not be available or may not be able to be imported into all countries participating in the study. Therefore the protocol was amended to allow epinephrine use as per local standard of care for treatment of anaphylaxis. Also, following completion of reproductive toxicity studies, the requirement for contraception for female study participants had been limited to effective contraception instead of highly effective contraception. Also, following feedback from Ethics Committees, it was decided to add an exclusion criterion for patients with a history of generalized urticaria or with an acute urticarial episode at time of screening or during run-in. Further changes to the protocol were made to correct inconsistencies as follows: a) The Assessment Schedule was updated accordingly to be consistent with this timing of assessments. b) The use of permitted asthma medications was clarified. c) Similarly, the withdrawal criterion regarding use of prohibited medication had been updated. d) The instructions to the unblinded pharmacist preparing the syringes with study drug were updated. e) Guidance on the disposal of expired and unused rescue medication was added to the protocol. f) Also, when using the eDiary to monitor the occurrence of asthma worsening symptoms relative to a drop in PEF, it has been decided not to refer the patient’s predicted PEF but only to the patient’s personal best PEF measurements. The protocol was updated to this effect. g) minor changes and corrections of typographical errors were made.

In Europe, conditional approval only was received for Protocol Amendment 2 under the Voluntary Harmonisation Procedure (VHP) (Ref. VHP20125/SA1). The approval was conditioned to uphold the requirement of highly effective methods of contraception; this was changed to effective methods of contraception in Amendment 2, following completion of reproductive toxicity studies. The EMA therefore suggested keeping the original contraceptive language. A request was received from Central Ethics Committees that every patient with any two grade 3 unexpected hypersensitivity reactions (as defined by WAO) would immediately discontinue drug. This criterion had been added. Some of the in/exclusion criteria were furthered specified as follows: a) The requirement for historical asthma exacerbations had been reduced to 1 exacerbation in last 12 months instead of 2 exacerbations within last 2 years. b) The requirement for patients to be on maintenance LABA b.i.d. had been specified further to allow equivalent once daily LABA dosing. c) To better define what is meant with uncontrolled diabetes, the exclusion criterion on diabetes had been updated to exclude patients with uncontrolled diabetes if they have an HbA1C of 7% or more. d) The exclusion criterion for clinically significant laboratory abnormalities had been further specified to indicate these should only be excluded if they are not compatible with the natural history of atopic asthma. e) Finally, a couple of inconsistencies between the protocol synopsis and full text and between the informed consent and protocol text have been corrected to further improve the overall quality of the document.

The inclusion and exclusion criteria in this protocol were revised with the aim to reduce the screen failure rate, make the eligibility criteria more realistic and to prevent excluding suitable patients. The opportunity was taken to also make the following changes to the protocol: Following advice gathered during a recent expert advisory board, there was the desire to assess the impact of IgE suppression on mast cells and the opportunity was taken to collect urine samples for relevant biomarker assessments. Furthermore, an additional blood sample was collected for bio-banking to possibly assess currently non-specified biomarkers in future (a serum sample was already collected for this purpose, in addition, a plasma sample was collected and stored). Also, a non-allergen specific basophil activation assay (BAA) had recently become available and as part of this amendment additional serum samples were to be collected to assess the effect of QGE031 treatment on the sensitivity of basophils to stimulation. These samples were to be collected at selected sites only; at these sites also other additional samples for biomarker assessments, in particular for assessing FcR1 and CD23 receptor expression, their IgE occupancy levels and IgE levels on B cells, were to be collected at relevant time points. For all future studies with QGE031, the injection site was no longer be restricted to deltoid region in the arm or thigh if arm was not possible, but instead arms, thighs or abdomen were allowed. This change was also implemented in this study. Some updates had been made to the lists with prohibited and allowed medications to allow medications that were not expected to have any interactions with QGE031 or interpretation of the study. Finally, an extension to this study was being set up, CQGE031B2201E1, and a reference to this extension study was included in this protocol.

One inclusion criteria and one exclusion criteria in the protocol were, following recent feedback from participating study physicians and detailed internal discussions, respectively, updated with the aim to reduce the screen failure rate, make the eligibility criteria more realistic and to prevent excluding suitable patients.

This amendment included two additional Adjudication Committees (ACs); one for the assessment of neoplastic events and one for cardiovascular and cerebrovascular (CCV) events. While there is no known mechanism linking IgE suppression to CCV events or malignancy, statistically non-significant imbalances of these events have been identified in selected omalizumab data-sets and had been reflected in some Xolair country labeling. In order to closely monitor any potential relationship between IgE suppression and these events, and to strengthen patient safety in this trial and future trials, Novartis had decided to institute a CCV and a neoplastic adjudication committee. The other key change in this amendment was the removal of some exploratory biomarkers from the study protocol. The high number of biomarkers sampled and the required shipping conditions had frequently been reported as very cumbersome and too complex by the sites. In order to facilitate study conduct and to support protocol execution at the sites, Novartis decided to remove some of the exploratory biomarkers from the protocol.