Clarify that CCX114643 is not positioned as a pivotal study, but is a feeder study for the pivotal maintenance trial, CCX114157 as this study was not designed to provide pivotal evidence of induction efficacy to support a registration package. This study was included as a component of the Phase III clinical program, positioned as a feeder study to qualify subjects for the maintenance study, CCX114157, and additional clarity was provided in the modified wording. Amend description of eligible patients to clarify that subjects must have had Crohn’s disease for at least 4 months duration, rather than a diagnosis for greater than 4 months as the protocol was designed to include patients who have had Crohn’s disease for greater than 4 months duration. Clarify that the management of the approximate 50% limitation of inclusion of subjects who received prior treatment with an anti-TNF agent and discontinued due to loss or lack of efficacy was implemented by the GSK study team to ensure that all eligible subjects who enter screening were able to be randomised. Amend duration of subject participation from a minimum of 15 weeks and a maximum of 19 weeks to a minimum duration of approximately 14 weeks and a maximum duration of 21 weeks to reflect the shortening of the screening period to approximately 2 weeks, consistent with the most common period of time for subjects to complete the screening assessments. The maximum duration reflects the duration of participation required if both a 5-week screening period and a 4-week follow up post completion of treatment were required. Clarify that fistula remission is being assessed as closure of all fistula that were open at baseline , as fistula that are draining are open and the wording was modified for consistency with the approach for data collection and the wording in the eCRF. Clarify that treatment allocation will only be grouped by subjects who have ever received anti-TNF therapy or not and not by current use of corticosteroids.

Include confirmation of active disease by ileocolonoscopy within 3 months prior to screening with documentation confirming the presence of a minimum of 3 nonanastomotic ulcerations (each >5 mm in diameter) consistent with Crohn’s disease, as patients may have active Crohn’s disease in the absence of elevations in the inflammatory biomarkers, CRP or faecal calprotectin. Clarify that the determination of inadequate response and/or intolerance/adverse event for discontinuation of corticosteroids or immunosuppressants will be based on investigator judgment, as this determination is most appropriately based on the expert opinion of the investigator. Amend requirement for subjects to complete at least 8 consecutive days of Crohn’s disease symptom recording using the IVRS prior to the Randomisation Visit, as the CDAI score is based on 7 days of patient symptoms and the IVRS did not require 8 days of patient-recorded information to confirm the CDAI score and eligibility for randomization. Clarify acceptable methods for confirmation of male partner sterilisation prior to the female subject's entry into the study, as male partner sterilisation prior to the female subject's entry into the study could be confirmed by interview with the subject or substantiated by other methods as deemed necessary by the investigator. Clarify that only fistula with abscesses and fistula likely to require surgery are exclusionary. Clarify that short bowel syndrome or chronic diarrhoea related to malabsorption and/or multiple bowel re-sections for Crohn’s disease are exclusionary. Updated prohibited medications: Use of any biologic for the treatment of Crohn’s disease, including investigational agents is prohibited, with natalizumab, vedolizumab, ustekinumab specifically named; use of intravenous antibiotics for the treatment of Crohn’s disease is no longer prohibited; stable use of enteral feeding or short term enteral or parenteral nutritional supplementation is no longer prohibited.

The start of long-term enteral feeding within 4 weeks prior to screening is not allowed based on the following rationale: Use of all biologics, including investigational agents, was exclusionary due to their potential to impact the ability to more fully characterize the efficacy and safety profile of GSK1605786A. Immunosuppressants considered to be investigational agents may have received approval during the conduct of this study. Additional wording was included to clarify that use of any immunosuppressant not specifically designated as a permitted medication is prohibited. Intravenous antibiotics are not commonly used to treat Crohn’s disease symptoms but may be used to treat certain gastrointestinal complications such as abscesses. Due to the limited potential to impact the efficacy profile of GSK1605786A and the potential need for treatment of Crohn’s disease-related abscesses or other complications, it was appropriate to allow the use of these medications. The stable use of enteral feeding is consistent with allowance of other Crohn’s disease medications at stable doses, with minimal potential to impact the safety and efficacy profile of GSK1605786A. Clarify re-screening of subjects who test positive for C difficile and receive antibiotic treatment to specify that subjects may be re-screened when they have completed treatment for C difficile and the investigator has determined that the infection has resolved. Clarify that confirmation of positive hepatitis B and hepatitis C test results and confirmation of positive QuantiFERON TB Gold test results was allowed. Clarify description of the study hypotheses in a manner consistent with the study objectives. Identify additional populations for analysis (biomarker, quality of life, and PK), and refine the definition of the Safety population. Include additional language clarifying the interpretation, significance, and multiplicity adjustment for presentation of p-values.

Include description of the interim analysis for the IDMC. Include definition of the term baseline for analysis purposes. Include the Week 12 timepoint for the analysis endpoints. Correct the description of the response and remission endpoints, describe the logistic regression model in more detail, refine the definition of clinical response and remission, remove the Fisher’s Exact test analysis. Add the analysis of CDAI 70-point decrease and clarify the description of the analysis of fistula remission. Correct and clarify the algorithm used to assign exposure in the case of missing data. Describe subgroup analyses of safety to be performed. Denote the separate analyses of machine and manually collected ECG data. Correct description of SF36 v2 raw item and summary scores. Include analysis of a log transformation of the biomarker data and clarify the description of the timepoint.