CURATE.AI-assisted dose titration for anti-hypertensive personalized therapy: study protocol for a multi-arm, randomized, pilot feasibility trial using CURATE.AI (CURATE.AI ADAPT trial).

Aims: Artificial intelligence-driven small data platforms such as CURATE.AI hold potential for personalized hypertension care by assisting physicians in identifying personalized anti-hypertensive doses for titration. This trial aims to assess the feasibility of a larger randomized controlled trial (RCT), evaluating the efficacy of CURATE.AI-assisted dose titration intervention. We will also collect preliminary efficacy and safety data and explore stakeholder feedback in the early design process. Methods and results: In this open-label, randomized, pilot feasibility trial, we aim to recruit 45 participants with primary hypertension. Participants will be randomized in 1:1:1 ratio into control (no intervention), home blood pressure monitoring (active control; HBPM), or CURATE.AI arms (intervention; HBPM and CURATE.AI-assisted dose titration). The home treatments include 1 month of two-drug anti-hypertensive regimens. Primary endpoints assess the logistical (e.g. dose adherence) and scientific (e.g. percentage of participants for which CURATE.AI profiles can be generated) feasibility, and define the progression criteria for the RCT in a 'traffic light system'. Secondary endpoints assess preliminary efficacy [e.g. mean change in office blood pressures (BPs)] and safety (e.g. hospitalization events) associated with each treatment protocol. Participants with both baseline and post-treatment BP measurements will form the intent-to-treat analysis. Following their involvement with the CURATE.AI intervention, feedback from CURATE.AI participants and healthcare providers will be collected via exit survey and interviews. Conclusion: Findings from this study will inform about potential refinements of the current treatment protocols before proceeding with a larger RCT, or potential expansion to collect additional information. Positive results may suggest the potential efficacy of CURATE.AI to improve BP control. Trial registration number: NCT05376683.

A review and additional post-hoc analyses of the incidence and impact of constipation observed in darifenacin clinical trials.

BACKGROUND: Constipation is a common side effect of antimuscarinic treatment for overactive bladder (OAB). This review evaluates the incidence and impact of constipation on the lives of patients with OAB being treated with darifenacin. METHODS: Constipation data from published Phase III and Phase IIIb/IV darifenacin studies were reviewed and analyzed. Over 4000 patients with OAB (aged 18-89 years; ≥80% female) enrolled in nine studies (three Phase III [data from these fixed-dose studies were pooled and provide the primary focus for this review], three Phase IIIb, and three Phase IV). The impact of constipation was assessed by discontinuations, use of concomitant laxatives, patient-reported perception of treatment, and a bowel habit questionnaire. RESULTS: In the pooled Phase III trials, 14.8% (50/337) of patients on darifenacin 7.5 mg/day and 21.3% (71/334) on 15 mg/day experienced constipation compared with 12.6% (28/223) and 6.2% (24/388) with tolterodine and placebo, respectively. In addition, a few patients discontinued treatment due to constipation (0.6% [2/337], 1.2% [4/334], 1.8% [4/223], and 0.3% [1/388] in the darifenacin 7.5 mg/day or 15 mg/day, tolterodine, and placebo groups, respectively), or required concomitant laxatives (3.3% [11/337], 6.6% [22/334], 7.2% [16/223], and 1.5% [6/388] in the darifenacin 7.5 mg/day or 15 mg/day, tolterodine, and placebo groups, respectively). Patient-reported perception of treatment quality was observed to be similar between patients who experienced constipation and those who did not. During the long-term extension study, a bowel habit questionnaire showed only small numerical changes over time in frequency of bowel movements, straining to empty bowels, or number of days with hard stools. CONCLUSION: While constipation associated with darifenacin was reported in ≤21% of the patient population, it only led to concomitant laxative use in approximately one-third of these patients and a low incidence of treatment discontinuation. These data suggest that constipation did not impact patient perception of treatment quality.

Time-to-effect with darifenacin in overactive bladder: a pooled analysis.

INTRODUCTION AND HYPOTHESIS: This study was conducted to assess time-to-effect with darifenacin in patients with overactive bladder (OAB). METHODS: Efficacy and safety data were pooled from 1,059 patients (19-88 years, 85% women) randomized to darifenacin 7.5 or 15 mg once daily or matched placebo in three double-blind 12-week studies. Patients completed electronic bladder symptom diaries (number of micturitions/day; incontinence episodes/day; urgency episodes/day). A post hoc efficacy analysis was performed on the earliest recorded timepoints. RESULTS: The full analysis population comprised 1,053 patients. Statistically significant improvements were observed in all OAB symptoms (except nocturnal awakenings) for both darifenacin doses versus placebo at week 2, with further improvements over 6 and 12 weeks. Both darifenacin doses significantly improved all OAB symptoms from as early as days 6-8 versus placebo. CONCLUSIONS: Darifenacin 7.5 and 15 mg significantly reduced OAB symptoms throughout the study. The rapid onset-of-effect is desirable to patients with OAB and useful for their clinical management.

Patient satisfaction with the benefits of overactive bladder treatment: exploration of influencing factors and development of a satisfaction assessment instrument.

INTRODUCTION: Patient-reported outcome (PRO) instruments are useful for assessing treatment success in patients with overactive bladder (OAB). PROs such as the OAB Questionnaire (OAB-q) and Patient Perception of Bladder Condition (PPBC) focus more on OAB symptoms than satisfaction. We describe the development of the Patient Satisfaction with Treatment Benefit (PSTB) questionnaire, and examine the face, content and criterion validity of this tool in a study of darifenacin treatment in OAB patients who expressed dissatisfaction with prior antimuscarinic therapy. METHODS: The PSTB questionnaire was created based on treatment-related items identified as relevant to OAB patients in exploratory interviews, then refined to comprise an Overall Satisfaction question and 23 items addressing specific treatment benefits using a 5-point Likert scale. The PSTB questionnaire was completed at last visit by 473 patients participating in an open-label, 12-week study of darifenacin treatment. Factors driving Overall Satisfaction were explored by investigating its relationship to PPBC, bladder symptom diaries and specific benefits assessed by the PSTB. RESULTS: At study end, mean Overall Satisfaction score was 3.1, corresponding to "satisfied." Overall Satisfaction correlated strongly with each specific benefit in the PSTB, and with PPBC and OAB symptoms at last visit, but more weakly with change from baseline PPBC/symptoms. Satisfaction at last visit was higher for patients with mild/moderate versus severe problems on baseline PPBC. CONCLUSIONS: Patients' reported satisfaction appears to reflect their current status rather than improvement over time. The PSTB tool may have a place alongside other symptom-based instruments. Further testing is required to validate these findings.

Differential pharmacological effects of antimuscarinic drugs on heart rate: a randomized, placebo-controlled, double-blind, crossover study with tolterodine and darifenacin in healthy participants > or = 50 years.

Antimuscarinics, used commonly to treat overactive bladder, may differ in their potential to increase heart rate via effects on cardiac muscarinic M2 receptors. This prospective, 3-way crossover, randomized, double-blind study assessed the heart rate effects of 7 days' exposure to a nonselective M2/M3 receptor blocker (tolterodine; 4 mg/d), a highly selective M3 receptor blocker (darifenacin; 15 mg/d), and placebo in 162 healthy participants > or = 50 years. Heart rate was measured by 24-hour Holter monitoring. Tolterodine significantly increased heart rate versus darifenacin and heart rate versus placebo, while darifenacin did not affect heart rate versus placebo. The proportion of participants with an increase in mean heart rate per 24 hours of > or =5 beats per minute was higher with tolterodine than with darifenacin (P = .0004) or with placebo (P = .0114) but did not differ between darifenacin and placebo. The results show that antimuscarinics exert differential effects on heart rate depending on their muscarinic receptor profile. This should be considered when selecting a treatment.