The dose was reduced from 25 mg to 5 mg for the cross-over trial (equal to part A, introduced in amendment 2), to change the approach for the first dosing in patients to a lower dose, which would be optimal for a first-in-patient study, avoiding exposure of patients to potentially unnecessary elevated concentrations of the active compound. The change was based on thorough analyses of older and recent pharmacology data collected in preclinical studies which suggested that a lower dose of FE 203799, such as 5 mg, could also show pharmacological activity.

The trial was extended from the initial part A (randomised, double-blind, 2-period cross-over) to also include the open label, dose ranging part B in order to enable dose exploration of FE 203799 beyond 5 mg once weekly. Due to the PK/PD profile of FE 203799 (with a half-life of 30 hours) early exploration of dose ranging was justified to adequately determine the risk/benefit of the future recommended dose and/or dose regimen (once weekly and/or every second week) and to guide the dose rationale for future pivotal clinical trials in the SBS population. The introduction of a part B enabled continued open label dose exploration of FE 203799 within the acceptable dose range defined by the no observed adverse effect level (NOAEL) derived from the toxicology studies (rats and minipigs exposed up to 13 weeks) and the phase 1 trials. It was defined that the sponsor’s decision on dose escalation to 10 mg or de-escalation to 2.5 mg in part B of the trial would be based on a recommendation from the DMC after review of safety data from a minimum of 4 patients from this trial or another trial actively recruiting patients with SBS (protocol GLY-321-2017). The title of the trial, the trial design figure, the schedule of procedures, and the text in relevant sections of the protocol were updated to describe a third treatment period to test a single dose of FE 203799, which was to be identical to treatment period 1 and 2 and to take place following a 6 to 10 week washout period after the last dose in treatment period 2. The statistical section was updated to include how to analyse data from part B. It was stated that parts A and B of the trial were to be analysed and reported separately.

The possibility to conduct interim analyses during the trial, if deemed necessary by the sponsor, was introduced. It was stated that any potential influence of interim analysis on the continued study conduct would be minimised by appropriate measures. The sponsor of the trial was changed from GLyPharma Therapeutic Inc. to GLyPharma Therapeutic Inc. (a wholly owned subsidiary of Therachon AG, Aeschenvorstadt 36, CH-4051 Basel Switzerland). Consequently, the sponsor medical officer and list of trial personnel were changed. An additional laboratory was included in order to analyse all exploratory biomarkers. It was clarified that safety case reports would be made accessible to specified, potentially unblinded sponsor personnel, who in case of being unblinded would not take any part in the operational activities. Clarifications related to the introduction of part B in protocol amendment 2 were made to the text. It was deleted that parts A and B of the trial were to be analysed separately.

Inclusion criterion number 9 was added, stating that male patients had to use barrier contraception during the trial and for 2 weeks after the end-of-trial visit. By error, an inclusion criterion for male contraception had not been included in the original protocol, although it had been included in the patient information sheet and male patients had been informed about thus requirement from the start. Exclusion criterion number 17 was changed so that only patients with changes in the listed treatments within 3 months of screening were to be excluded from the protocol. The original protocol stated that patients using systemic corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, infliximab, or other biologic therapy/immune modifiers within 30 days of screening were to be excluded from the protocol. A common cause of SBS is intestinal resection due to IBD, and consequently SBS patients may receive systemic immune modifiers as IBD treatment. Recent changes in these medications could indicate active disease, while patients that have been on stable treatment for at least 3 months were considered stable and could therefore be included in the protocol. Replacement of patients was changed so that patients not completing part B would also be replaced, so that 8 patients should complete part B. An inconsistency around the wording about FSH testing was addressed so that it was clear that the FSH test should only be used where there was doubt about the patient’s menopausal status.

A change in the company that owns the sponsor, GLyPharma Therapeutic Inc., from Therachon AG to VectivBio Holding AG. A change of company name of one of the analysis laboratories.