Study oversight
Alzheimer’s Disease, neutropenia
NEUTROPENIA, ADVERSE EVENTS, RECRUITMENT, MAY, EVENTS, SKIN TOXICITY
Study AB09004 (NCT01872598) was overseen by an Independent Data Monitoring Committee (IDMC). The trial protocol was approved by the appropriate Independent Ethics Committee/Institutional Review Board of all participating sites and all subjects provided informed consent. The sponsor (AB Science) participated in the design, conduct, management, and reporting of the study. Data was collected and analyzed in conjunction with independent steering committee members and authors, who contributed to manuscript draft revisions, provided critical comment, and approved submission for publication.Protocol amendments were implemented during the study following approval by the aforementioned committees. Briefly, study AB09004 initially planned to enroll patients into placebo or masitinib 6 mg/kg/day treatment-arms (1:1); however, a comprehensive, global safety analysis of all masitinib non-oncology clinical trials (not including the current AB09004 study) revealed that masitinib starting doses of 3 or 4.5 mg/kg/day had an incidence of severe adverse events similar to placebo, whereas a starting dose of 6 mg/kg/day showed increased frequency of certain events with respect to placebo (e.g., neutropenia and skin toxicity). Moreover, related analysis also revealed that starting doses of 3 or 4.5 mg/kg/day titrated to 6 mg/kg/day improved tolerability and minimized discontinuations during the first 3 months of treatment. Protocol amendments, with the objective to improve the benefit/risk balance, were therefore an unavoidable consequence of these developments. First, the 6 mg/kg/day (starting dose) treatment-arm was terminated (protocol version 5.0, May 2012, after recruitment of 12/718 (1.7%) patients) and replaced with a placebo versus masitinib at 4.5 or 3.0 mg/kg/day (1:1:1) design (administered orally as two daily intakes). The low-dose 3.0 mg/kg/day masitinib treatment-arm was later terminated (following recommendation from the IDMC for reasons not based on safety or futility), effectively collapsing this parallel group into a (1:1) comparison of masitinib 4.5 mg/kg/day versus placebo (protocol version 9.0, November 2015, after 25% (180/718) of randomized patients could have reached the 24-week timepoint) (Fig. Patient flow diagram, detailing patient disposition of the masitinib 4.5 mg/kg/day and titrated masitinib 6.0 mg/kg/day parallel groups. PBO, placebo; M4.5, masitinib 4.5 mg/kg/day; tPBO, placebo treatment-arm from the titrated dose parallel group; tM6.0, masitinib treatment-arm from the titrated dose parallel group; ITT, intention-to-treat population; SAF, safety population; FAS, full analysis database; GCP, Good Clinical Practice; ADAS-cog, Alzheimer’s Disease Assessment Scale - cognitive subscale; ADCS-ADL, Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale. * See eTable 1 of the Another notable amendment concerned the primary efficacy analysis, originally defined as co-primary endpoints of the Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) at week 24 (significance level of 5%), which was modified to multiple primary endpoints of ADAS-cog or ADCS-ADL at week 24 (based on fallback procedure with a significance level of 2.5%) (protocol version 10.0, December 2017, after 81% (580/718) of randomized patients could have reached the 24-week timepoint). This was done to give cognitive and functional outcomes equal importance, with autonomous assessment of each.