Methods

Study design and participant selection

A multicenter, prospective, observational study was conducted across nine Spanish hospitals in patients with locally advanced or MBC prescribed abemaciclib and registered in the PSP. PSP registration was voluntary, independent of the study and available to any patient treated with abemaciclib. The study inclusion criteria were: (i) age ≥ 18 years; (ii) diagnosis of locally advanced or MBC; (iii) prescription of abemaciclib; (iv) registration in the PSP before the first follow-up visit (15 days from treatment initiation, allowing a 7-day window); and (v) signed informed consent. Patients participating in clinical trials or other PSPs were excluded. The study had a 15-month recruitment period, from September 2022 to December 2023, and included a 6-month follow-up period, consisting of five visits that coincided with routine clinical visits at weeks 2, 4, 8, 12, and 24 (Supplementary Fig. 1).

The study was approved by the Hospital 12 de Octubre Ethics Committee (May 17, 2022) and local review boards and was registered with AEMPS (GESTO-REEC 0080-2022-OBS, No.: 22-0087). It complied with national regulations and the Declaration of Helsinki.

The primary objective was to evaluate the proportion of patients who reduced the dose or discontinued abemaciclib due to diarrhea during follow-up.

Additional objectives were to describe: (i) sociodemographic and clinical characteristics; (ii) temporary treatment interruptions due to diarrhea; (iii) management of diarrhea from both physician and patient perspectives; (iv) treatment adherence; (v) health-related quality of life (HRQoL); and (vi) persistence and satisfaction with the PSP.

Data collection and study variables

Data were collected using a paper Case Report Form (CRF) designed for the study. The CRF consisted of two modules. The physician-reported module captured sociodemographic and clinical data (age, weight, height, body mass index (BMI), carcinoma type, metastasis status, time since diagnosis, follow-up duration, and comorbidities). It also documented frequency and type of stool (according to the Bristol scale), diarrhea episodes, and their severity (graded using common terminology criteria for adverse events (CTCAE)), initial abemaciclib dose, any dose reductions, interruptions or discontinuations, including their reasons. Additionally, concomitant antidiarrheal treatments, instructions provided, PSP enrollment and withdrawal dates, and treatment adherence, were also collected during routine visits.

The patient-reported module included HRQoL, ad hoc questionnaires on self-care and diarrhea management, and a PSP satisfaction questionnaire.

At visit 1 (week 2), the data were collected covering the period before the initiation of abemaciclib and the first 15 days of treatment. Clinical, treatment-related, adherence, and patient-reported data were collected during all the follow-up visits, when available.

Patient-reported outcomes and related measures

Patients’ self-care and diarrhea management

This ad hoc questionnaire, completed by patients, consisted of two parts (Supplementary Table 1). The first included nine items on specific strategies used to manage diarrhea and identified whether these were recommended by an HCP, the PSP, or other sources. It also assessed the perceived effectiveness of each action. The second section included eight items assessing patients’ perceptions on their ability to manage diarrhea, rated on a 5-point Likert scale (from “Completely disagree” to “Completely agree”). At weeks 2 and 4, this questionnaire covered the period since the last study visit; at weeks 8, 12, and 24 it referred to the prior 2 weeks.

Treatment adherence (SMAQ)

Adherence to abemaciclib was assessed using the six-item Simplified Medication Adherence Questionnaire (SMAQ) [14], administered by physicians during study visits. The patients were classified as “non-adherent” if they responded with any non-adherent answer, missed more than two doses in the previous week or had not taken abemaciclib for more than two full days within the past three months, relative to the prescribed schedule; HCP-directed holds were excluded.

HRQoL assessment

HRQoL was assessed at all visits using the Functional Assessment of Chronic Illness Therapy-Diarrhea (FACIT-D) questionnaire, which evaluates four dimensions (physical, social/family, emotional, and functional) plus a diarrhea-specific subscale (DS) [15]. The responses were rated on a 0–4 Likert scale (“Not at all” to “Very Much”), with higher scores indicating a better HRQoL. The total FACIT-D score ranges from 0 to 152 and the DS from 0 to 44. The subscores were calculated when ≥ 50% of items were completed; 80% completion was required to calculate the total FACIT-D score.

Satisfaction with PSP

Patients completed an ad hoc questionnaire rating satisfaction on a 5-point Likert scale (from “Completely unsatisfied”, to “Completely satisfied”). The questionnaire also included the number of PSP consultations, and the topics discussed (nutritional or diarrhea management) (Supplementary Table 2).

Sample size calculation and statistical analysis

Sample size was based on an expected 18.8% rate of dose reduction or discontinuation due to diarrhea, as reported in clinical trials [11]. Assuming an expected registration in the PSP of 10 patients per month over 6 months, and applying a 95% bilateral confidence interval with a precision error of 8%, the minimum required sample size was 37 patients.

The categorical variables were presented as absolute and relative frequencies, with the number of patients indicated for each category. Quantitative data were reported using mean and standard deviation (SD) or median and interquartile range (IQR). As the main objective of the study was descriptive, no inferential statistical comparisons or calculation of confidence intervals or p values were performed.

Time-to-event variables were defined as the number of days from treatment initiation to the first occurrence of each outcome: dose reduction, temporary interruption, or permanent discontinuation.

Survival analyses were conducted using the Kaplan–Meier method to estimate the probability of each event over time. Patients who did not experience the event by the end of follow-up were censored. All analyses were performed using STATA version 14.