Decentralized clinical trials and rare diseases: a Drug Information Association Innovative Design Scientific Working Group (DIA-IDSWG) perspective.

BACKGROUND: Traditional clinical trials require tests and procedures that are administered in centralized clinical research sites, which are beyond the standard of care that patients receive for their rare and chronic diseases. The limited number of rare disease patients scattered around the world makes it particularly challenging to recruit participants and conduct these traditional clinical trials. MAIN BODY: Participating in clinical research can be burdensome, especially for children, the elderly, physically and cognitively impaired individuals who require transportation and caregiver assistance, or patients who live in remote locations or cannot afford transportation. In recent years, there is an increasing need to consider Decentralized Clinical Trials (DCT) as a participant-centric approach that uses new technologies and innovative procedures for interaction with participants in the comfort of their home. CONCLUSION: This paper discusses the planning and conduct of DCTs, which can increase the quality of trials with a specific focus on rare diseases.

Does Daily Self-Weighing Contribute to Postpartum Weight Loss? A Secondary Analysis of Daily Postpartum Weights among Women with Hypertensive Disorders of Pregnancy.

OBJECTIVE: This study was aimed to examine the impact of daily self-weighing via remote monitoring on postpartum weight loss. STUDY DESIGN: This was a secondary analysis of a nonrandomized controlled trial comprised of postpartum women with diagnosed hypertensive-related disorders in pregnancy who received a tablet device linked to Bluetooth-enabled equipment including a scale and blood pressure cuff. In addition to blood pressure monitoring, participants were instructed to perform daily self-weighing. The primary outcome of this study was to determine whether postpartum women who performed daily self-weighing lost more weight than those who did not, with a 42-day endpoint based on a 6-week postpartum visit weight. RESULTS: Overall, 214 women participated in this program and 214 received usual care. Median weight loss for women participating in the remote blood pressure monitoring system was 23.0 (interquartile range [IQR]: 17-30) pounds versus 23.0 (IQR: 17-29) pounds among controls. Weight loss did not vary by prepregnancy obesity (median: 20 pounds [IQR: 17-28 pounds] for nonobese and 23 [IQR: 17-30] pounds for women with obesity, p = 0.16). Women who weighed themselves more than half of follow-up days lost a median of 24 pounds (IQR: 17-30 pounds) compared with 20.5 pounds (IQR: 14-29 pounds), p = 0.06. Women who weighed themselves more than half of follow-up days lost a mean of 11.4% (standard deviation [SD] = 0.41%) of body weight compared with 9.1% (SD = 0.74%; p = 0.01). The amount of weight loss in the telehealth group was correlated with the number of daily weights performed (Pearson's correlation coefficient 0.164, p = 0.025). Postpartum weight loss for daily self-weighing participants was most notable in the first 2 weeks with ongoing weight loss up to the 42-day (6-week) endpoint of this secondary analysis. CONCLUSION: Daily self-weighing alone may be insufficient to promote postpartum weight loss. However, there was a slight trend toward more weight loss with more frequent weighing. KEY POINTS: · Daily self-weighing is insufficient for postpartum weight loss.. · Women who weighed themselves more lost slightly more weight.. · Weight loss was the most notable in the first 2 weeks.. · Its use as one part of a program may be worth studying..

The Addition of a Defibrillator to Resynchronization Therapy Decreases Mortality in Patients With Nonischemic Cardiomyopathy.

OBJECTIVES: The aim of this study was to determine whether patients with heart failure with reduced ejection fraction (HFrEF) due to nonischemic etiology eligible for cardiac resynchronization therapy (CRT) benefit from an implantable cardioverter-defibrillator (ICD). BACKGROUND: It is uncertain whether CRT with an ICD (CRT-D) compared to without an ICD (CRT-P) is associated with a survival benefit in patients with nonischemic etiologies of HFrEF. METHODS: Analyses of the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial were performed, using Cox proportional hazards modeling stratified by HFrEF etiology of nonischemic cardiomyopathy (NICM) or ischemic cardiomyopathy (ICM). The primary outcome was all-cause mortality (ACM), and secondary outcomes were the combination of cardiovascular mortality or heart failure hospitalization and sudden cardiac death. RESULTS: Among patients randomized to CRT (n = 1,212), 236 (19.5%) died, 131 and 105 in the CRT-P and CRT-D arms, respectively. The unadjusted and adjusted hazard ratios (HRs) for CRT-D versus CRT-P were both 0.84 (95% confidence interval [CI]: 0.65 to 1.09) for ACM, with a significant device-etiology interaction (pinteraction = 0.015 adjusted; pinteraction = 0.040 unadjusted). In patients with NICM (n = 555), CRT-D versus CRT-P was associated with reduced ACM (adjusted HR: 0.54; 95% CI: 0.34 to 0.86), while patients with ICM (n = 657) did not exhibit a between-device reduction in ACM (adjusted HR: 1.05; 95% CI: 0.77 to 1.44). The effects of CRT-D versus CRT-P on sudden cardiac death (advantage CRT-D) and cardiovascular mortality or heart failure hospitalization (no difference between CRT-P and CRT-D) were similar between the 2 HFrEF etiologies. CONCLUSIONS: COMPANION patients with NICM exhibited a decrease in ACM associated with CRT-D but not CRT-P treatment, whereas patients with ICM did not.

A roadmap to using historical controls in clinical trials - by Drug Information Association Adaptive Design Scientific Working Group (DIA-ADSWG).

Historical controls (HCs) can be used for model parameter estimation at the study design phase, adaptation within a study, or supplementation or replacement of a control arm. Currently on the latter, there is no practical roadmap from design to analysis of a clinical trial to address selection and inclusion of HCs, while maintaining scientific validity. This paper provides a comprehensive roadmap for planning, conducting, analyzing and reporting of studies using HCs, mainly when a randomized clinical trial is not possible. We review recent applications of HC in clinical trials, in which either predominantly a large treatment effect overcame concerns about bias, or the trial targeted a life-threatening disease with no treatment options. In contrast, we address how the evidentiary standard of a trial can be strengthened with optimized study designs and analysis strategies, emphasizing rare and pediatric indications. We highlight the importance of simulation and sensitivity analyses for estimating the range of uncertainties in the estimation of treatment effect when traditional randomization is not possible. Overall, the paper provides a roadmap for using HCs.

Impact of Degree of Left Ventricular Remodeling on Clinical Outcomes From Cardiac Resynchronization Therapy.

OBJECTIVES: This study tested the hypothesis that the extent of left ventricular (LV) eccentric structural remodeling in heart failure with reduced ejection fraction (HFrEF) is directly associated with clinical event responses to cardiac resynchronization therapy (CRT). BACKGROUND: Whether the severity of LV structural remodeling influences CRT treatment effects is unknown. METHODS: COMPANION (Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure) trial data were analyzed retrospectively. Left ventricular internal dimensions at end diastole indexed by body surface area (LVEDDI) were measured pre-randomization by 2-dimensional echocardiography. LVEDDI values were stratified around the median value of 35 mm/m2, and CRT (including CRT-P [CRT with only pacing capability] and/or CRT-D [CRT with an implantable defibrillator]) treatment effects were assessed and compared by LVEDDI group. Patients assigned to these treatments were compared to those undergoing optimal pharmacologic therapy (OPT) for the outcomes of all-cause mortality (ACM) or ACM and heart-failure hospitalization (ACM/HFH). RESULTS: In the LVEDDI ≥35 mm/m2 group (n = 614), CRT vs. OPT was associated with a lower ACM/HFH hazard ratio (HR) (HR: 0.53; 95% confidence interval [CI]: 0.40 to 0.70; p <0.001), whereas in the LVEDDI <35 mm/m2 group, the CRT vs. OPT ACM/HFH hazard ratio was not statistically significant (HR: 0.80; 95% CI: 0.59 to 1.08; p = 0.15). For ACM alone, in the LVEDDI ≥35 mm/m2 group, the hazard ratio for CRT-P was 0.59 (95% CI: 0.39 to 0.90; p = 0.012) and for CRT-D 0.50 (95% CI: 0.32 to 0.77; p = 0.002). Neither of the CRT groups showed a statistically significant reduction in ACM in the LVEDDI <35 mm/m2 group. CONCLUSIONS: Larger versus smaller LVEDDIs are associated with a reduction in ACM with CRT-P or CRT-D treatment, and with a more effective reduction in ACM/HFH for the combined CRT treatment groups.

Prospective crossover clinical trial comparing transdermal with oral phenobarbital administration in epileptic cats.

OBJECTIVES: The aim of this study was to compare serum phenobarbital concentrations, adverse events and client satisfaction during 14 weeks of transdermal vs oral phenobarbital administration to epileptic cats. METHODS: This was a prospective, fixed-order, crossover pilot study. Nine client-owned cats with presumptive or diagnosed idiopathic epilepsy were enrolled. Oral phenobarbital (PO-PB) was administered for weeks 1-14 (median starting dosage of 3.8 mg/kg [2.0-5.4 mg/kg/day] q12h); transdermal phenobarbital (TD-PB) was administered for weeks 14-28 (median starting dosage 18.8 mg/kg/day [17.6-24.0 mg/kg/day] q12h). Serum phenobarbital concentrations (S-PB) were measured at weeks 2, 14, 16 and 28. Client satisfaction questionnaires and biochemistry were evaluated at 14 and 28 weeks. RESULTS: Median S-PB concentrations during oral administration were 21 µg/ml (observed range 11-40 µg/ml) at week 2 and 22 µg/ml (8-35 µg/ml) at week 14, and at the higher TD dosage were 18 µg/ml (0-42 µg/ml) at week 16 and 17 µg/ml (7-50 µg/ml) at week 28. Phenobarbital concentrations were significantly correlated with PO dosage at week 2 (r = 0.75, P = 0.03) but not at weeks 16 and 28. Significantly more dose adjustments were needed during the TD phase (P = 0.03), but 6/9 owners (67%) still preferred TD to PO administration. Adverse effects were mild and comparable in both groups. CONCLUSIONS AND RELEVANCE: Therapeutic S-PB concentrations were achievable in some cats using TD-PB at 18 mg/kg/day q12h. Poor correlation between TD dosage and S-PB concentrations was observed and more dosage adjustments were required during TD administration. These findings necessitate close therapeutic drug monitoring if TD-PB is prescribed.

Machine Learning Algorithm Predicts Cardiac Resynchronization Therapy Outcomes: Lessons From the COMPANION Trial.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure patients with reduced left ventricular function and intraventricular conduction delay. However, individual outcomes vary significantly. This study sought to use a machine learning algorithm to develop a model to predict outcomes after CRT. METHODS AND RESULTS: Models were developed with machine learning algorithms to predict all-cause mortality or heart failure hospitalization at 12 months post-CRT in the COMPANION trial (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure). The best performing model was developed with the random forest algorithm. The ability of this model to predict all-cause mortality or heart failure hospitalization and all-cause mortality alone was compared with discrimination obtained using a combination of bundle branch block morphology and QRS duration. In the 595 patients with CRT-defibrillator in the COMPANION trial, 105 deaths occurred (median follow-up, 15.7 months). The survival difference across subgroups differentiated by bundle branch block morphology and QRS duration did not reach significance (P=0.08). The random forest model produced quartiles of patients with an 8-fold difference in survival between those with the highest and lowest predicted probability for events (hazard ratio, 7.96; P<0.0001). The model also discriminated the risk of the composite end point of all-cause mortality or heart failure hospitalization better than subgroups based on bundle branch block morphology and QRS duration. CONCLUSIONS: In the COMPANION trial, a machine learning algorithm produced a model that predicted clinical outcomes after CRT. Applied before device implant, this model may better differentiate outcomes over current clinical discriminators and improve shared decision-making with patients.

Outcomes of cardiac resynchronization therapy in patients with intermittent atrial fibrillation or atrial flutter in the COMPANION trial.

BACKGROUND: Controlled clinical trial data are lacking for cardiac resynchronization therapy (CRT) outcomes in patients with advanced heart failure (HF) from reduced left ventricular ejection fraction (HFrEF) and intermittent atrial fibrillation or flutter (IAF/AFL). OBJECTIVE: The purpose of this study was to describe CRT outcomes in patients with IAF/AFL and advanced HF. METHODS: HF outcomes in patients in the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial with New York Heart Association class III or IV HFrEF, left ventricular ejection fraction ≤0.35, sinus rhythm at randomization, and no history of baseline arrhythmia were compared with those with a history of IAF/AFL. RESULTS: In those with no history of baseline arrhythmia (n = 887), compared with optimal pharmacological therapy (OPT) with no CRT, the CRT + OPT arms exhibited a significant reduction in the end points of death or any hospitalization (hazard ratio [HR] 0.73 [95% Confidence Interval (CI): 0.60 to 0.89]; P = .002) and death or HF hospitalization (HR 0.53 [95% CI: 0.41 to 0.68]; P < .001). In contrast, in the IAF/AFL subgroup (n = 293), CRT did not result in improved outcomes compared with OPT (death or any hospitalization: HR 1.16 [95% CI: 0.83 to 1.63]; P = .38; death or HF hospitalization: HR 0.97 [95% CI: 0.64 to 1.46]; P = .88). The interaction between history of AF/AFL and CRT was statistically significant for both outcomes (P < .05). CONCLUSION: In the COMPANION trial, patients with moderate to severe HFrEF and a history of IAF/AFL had no benefit from CRT.

Lessons Learned and Insights Gained in the Design, Analysis, and Outcomes of the COMPANION Trial.

COMPANION (Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure), the first cardiac resynchronization therapy (CRT)-heart failure mortality and morbidity controlled clinical trial planned, conducted, and reported, was a randomized, 3-arm study that compared CRT delivered by a biventricular pacemaker (CRT-P) or a CRT defibrillator device (CRT-D) with optimal pharmacological therapy alone. The patient population had advanced chronic heart failure with QRS interval prolongation ≥120 ms and reduced left ventricular ejection fraction (heart failure with reduced ejection fraction). COMPANION had a composite hospitalization and mortality endpoint as the primary outcome measure but was also powered for mortality as the first secondary endpoint. The conduct of COMPANION was challenged by important issues that arose during the trial, the most important of which was U.S. Food and Drug Administration approval of CRT devices. Along with other challenges, this issue was appropriately dealt with by the Steering Committee and the Data and Safety Monitoring Committee and did not negatively affect trial results or conclusions. The authors report here updated analyses from the study, which are consistent with previously published results indicating that CRT-P or CRT-D has favorable effects on heart failure morbidity and mortality in a patient population "precision" selected by the surrogate marker of increased QRS interval duration. New analyses indicate that increasing the number of classes of neurohormonal inhibitor concurrent therapy has a positive effect on CRT mortality reduction. Hypothesis-generating new findings are that in patients receiving beta-blocker therapy, the mortality reduction advantage of CRT-D versus CRT-P may be minimized or eliminated and that there may be adverse effects of CRT-D defibrillator shocks on pump failure-related outcomes.