The ethical and regulatory oversight of any clinical activity related to human subjects is commonly determined based on its categorization as either clinical practice or research. Prominent bioethicists have criticized the traditional distinctions used to delineate these categories, calling them counterproductive and outmoded, and arguing that learning and clinical practice should be deliberately and appropriately integrated. Personalized trials represent a clinical activity with characteristics that overlap both categories, making ethical and regulatory oversight requirements less straightforward. When the primary intent of the personalized trial is to assist in the conduct of individualized patient care with an emphasis on protecting the clinical decision from the biases inherent in usual clinical practice, how should this activity be regulated? In this article, we will explore the ethical underpinnings of personalized trials and propose various approaches to meeting regulatory requirements. Instead of imposing standard research regulations on the conduct of all personalized trials, we recommend that personalized trialists and IRB panels should consider whether participation in a personalized trial results in any foreseeable incremental increase in risk to the participant compared with usual care. This approach may reduce regulatory barriers, which could promote more widespread uptake of personalized trials.

Personalized (N-of-1) trials offer a patient-centered research approach that can provide important clinical information for patients when selecting which treatment options best manage their chronic health concern. Researchers utilizing this approach should present trial results to patients in a clear and understandable manner in order for personalized research trials to be useful to participants. The current study provides participant feedback examples for personalized trial reports using lay summaries and multiple presentation styles from a series of 60 randomized personalized trials examining the effects of massage and yoga versus usual care on chronic lower back pain (CLBP). Researchers generated summary participant reports that describe individual participant results using multiple presentation modalities of data (e.g., visual, written, and auditory) to offer the most appealing style for various participants. The article discusses contents of the participant report as well as participant satisfaction with the personalized summary report, captured using a satisfaction survey administered after study completion. The results from the satisfaction survey in the current study show that participants were generally satisfied with their personalized summary report. Researchers will use feedback from the participants in the current study to refine personalized feedback reports for future studies.

The mainstay of evidence development in medicine is the parallel-group randomized controlled trial (RCT), which generates estimates of treatment efficacy or effectiveness for the average person in the trial. In contrast, personalized trials (sometimes referred to as \'single-person trials\' or \'N-of-1 trials\') assess the comparative effectiveness of two or more treatments in a single individual. These single-subject, randomized crossover trials have been used in a scattershot fashion in medicine for over 40 years but have not been widely adopted. An important barrier is the paucity of strong evidence that personalized trials improve outcomes. However, the principal impediment may have less to do with proof of efficacy than with practical aspects of design and implementation. These include decisions about treatment regimen flexibility, blinding, and washout periods as well as organizational, clinician, and patient-level challenges. After reviewing the essential elements of personalized trials, this article addresses these speed bumps and fundamentally asks, \'Why have personalized trials not been more widely adopted, and how can they be made more readily deployable and useful?\' The article concludes by suggesting ways in which emerging technologies and approaches promise to overcome existing barriers and open promising vistas for the next generation of personalized-trial researchers and practitioners.

Chronic lower back pain (CLBP) affects 25% of U.S. adults and is associated with high costs due to physician visits and reduced productivity. Research shows that massage and yoga can be effective nonpharmacological treatments for CLBP, but the feasibility, scalability, individual treatment, and adverse-event heterogeneity of these treatments are unknown. The current study evaluated the feasibility and acceptability of a series of personalized (N-of-1) interventions for virtual delivery of massage and yoga or usual-care treatment for CLBP in 57 participants. We hypothesized that this study would provide valuable information about implementing a virtual, personalized platform for randomized controlled trials of personalized (N-of-1) interventions among individuals with CLBP. The study will do so by determining participants\' ratings of usability and satisfaction with the virtual, personalized intervention delivery system and, in the long term, identifying ways to integrate these personalized trials into patient care. Of the 57 participants enrolled, two withdrew from the study and were not eligible to receive the primary outcome assessment. Thirty-seven of the remaining 55 participants (67.3%) completed satisfaction surveys comprising the System Usability Scale (SUS) and items assessing satisfaction with the components of the personalized trial. Participants rated the usability of the personalized trial as excellent (average SUS score = 85.8), 95% were satisfied with the personalized trial overall, and 100% stated they would recommend the trial to others. These results suggest that personalized trials of massage and yoga are highly feasible and acceptable to participants with CLBP.

BACKGROUND: In the USA, the primary cause of death and morbidity continues to be cardiovascular disease (CVD). Numerous trials have shown that statin medication reduces the likelihood of CVD events; it is a cornerstone of CVD prevention. However, studies have also indicated that up to 60% of the estimated 26.8 million Americans prescribed primary prevention statin treatment are nonadherent during the first year. Multi-component behavioral change technique (BCT) therapies have shown moderate promise in improving medication adherence as well as other positive health behaviors (such as physical activity). However, no research has looked at the duration of multi-component BCT intervention needed to result in a clinically significant improvement in statin adherence behaviors. This study aims to determine the necessary dose of a multi-component BCT intervention (defined as duration in weeks) to promote adherence to statin medication among those on primary prevention statin treatment by utilizing the modified time-to-event continuous reassessment method (TiTE-CRM).
METHODS: The study will utilize the modified TiTE-CRM in 42 participants, recruited in 14 cohorts of 3 participants each. The goal of this analysis is to identify the minimum effective dose (MED) of a multi-behavior change technique (BCT) intervention required to increase adherence to statins by 20% between baseline and follow-up periods. Using the TiTE-CRM method, the dose of the behavior intervention in weeks will be assigned to each cohort based on the performance of the prior cohort. At the end of the study, the intervention dose that has been found to be associated with a 20% increase in statin adherence among 80% of participants assigned to that dose will be identified as the MED.
CONCLUSIONS: If successful, the current trial will provide additional guidance to researchers and clinicians seeking to increase statin medication adherence using a BCT intervention by identifying the dose (i.e., the duration) of an intervention required to meaningfully increase adherence.
BACKGROUND: ClinicalTrials.gov NCT05273736. Registered on March 10, 2022. https://www.
RESULTS: gov/ct2/show/NCT05273736.

BACKGROUND: Poor sleep, defined as short-duration or poor-quality sleep, is a frequently reported condition with many deleterious effects including poorer cognitive functioning, increased accidents, and poorer health. Melatonin has been shown to be an efficacious treatment to manage symptoms of poor sleep. However, the treatment effects of melatonin on sleep can vary greatly between participants. Personalized, or N-of-1, trial designs represent a method for identifying the best treatment for individual participants. Although using N-of-1 trials of melatonin to treat poor sleep is possible, the feasibility, acceptability, and effectiveness of N-of-1 trials using melatonin are unknown. Using the National Institutes of Health Stage Model for Behavioral Intervention Development, a stage IB (intervention refinement, modification, and adaptation and pilot testing) design appeared to be needed to address these feasibility questions.
OBJECTIVE: This trial series evaluates the feasibility, acceptability, and effectiveness of a series of personalized interventions for remote delivery of melatonin dose (3 and 0.5 mg) versus placebo supplements for self-reported poor sleep among 60 participants. The goal of this study is to provide valuable information about implementing remote N-of-1 randomized controlled trials to improve poor sleep.
METHODS: Participants will complete a 2-week baseline followed by six 2-week alternating intervention periods of 3 mg of melatonin, 0.5 mg of melatonin, and placebo. Participants will be randomly assigned to 2 intervention orders. The feasibility and acceptability of the personalized trial approach will be determined with participants\' ratings of usability and satisfaction with the remote, personalized intervention delivery system. The effectiveness of the intervention will be measured using participants\' self-reported sleep quality and duration and Fitbit tracker-measured sleep duration and efficiency. Additional measures will include ecological momentary assessment measures of fatigue, stress, pain, mood, concentration, and confidence as well as measures of participant adherence to the intervention, use of the Fitbit tracker, and survey data collection.
RESULTS: As of the submission of this protocol, recruitment for this National Institutes of Health stage IB personalized trial series is approximately 78.3% complete (47/60). We expect recruitment and data collection to be finalized by June 2023.
CONCLUSIONS: Evaluating the feasibility, acceptability, and effectiveness of a series of personalized interventions of melatonin will address the longer term aim of this program of research-is integrating N-of-1 trials useful patient care? The personalized trial series results will be published in a peer-reviewed journal and will follow the CONSORT (Consolidated Standards of Reporting Trials) extension for N-of-1 trials (CENT 2015) reporting guidelines. This trial series was approved by the Northwell Health institutional review board.
BACKGROUND: ClinicalTrials.gov NCT05349188; https://www.clinicaltrials.gov/study/NCT05349188.
UNASSIGNED: DERR1-10.2196/45313.

UNASSIGNED: Personalized interventions that can be delivered remotely are needed to increase physical activity (PA) in older adults to reduce risk of CV disease and mortality. Prior research indicates that Behavioral Change Techniques (BCTs) (e.g., goal setting, self-monitoring, behavioral repetition) can instill a habit for increasing daily walking. However, past interventions relied on between-subject randomized clinical trials, which can only only be informative about response of the hypothetical average person. Personalized trial designs can identify the benefits of an intervention for a specific individual although extended periods are required for collecting frequent measurements within-subject. Advances in remote, virtual technologies (e.g., text messaging, activity trackers), integrated with automatic platforms, can meet these requirements because they capacitate delivery of BCT interventions, and collection of data during daily life without personal contact. This Stage I-b trial is designed test whether a virtual, personalized intervention is feasible and acceptable to older adults, can elicit participant adherence and exhibit preliminary evidence for efficacy.
UNASSIGNED: A series of up to 60 single-arm, personalized trials, involving no personal contact, will recruit adults, 45-75 years of age, to wear an activity tracker during a 2-week baseline and a 10-week intervention. Five BCT prompts to execute a walking plan will be delivered on a daily basis during the intervention phase. Participants will rate satisfaction with personalized trial components and whether automaticity of the walking plan can be achieved. Step-counts, adherence to the walking plan and self-monitoring of step-count will also be recorded.

Statin therapy is a mainstay of cardiovascular disease (CVD) prevention, but research shows that statin therapy alone is insufficient for preventing incident CVD and mortality. Combining statin medication with increased physical activity (PA) can lower mortality risk more than either statin or PA alone. However, PA levels often remain the same and may even decline following statin prescription. Additional information is needed to identify how to increase PA among statin users and determine the minimal length of an intervention (i.e., intervention dose) necessary to increase PA.
The study aims to identify the required dose of a behavior change technique (BCT) intervention to increase PA among individuals on primary prevention statin therapy who have an elevated risk for cardiovascular disease (CVD).
The study will utilize the modified time-to-event continual reassessment method (TiTE-CRM) in 42 participants. We expect insights relating to dose-efficacy models and BCTs (Behavior Change Techniques) to improve PA in adults at risk for CVD. This trial will also examine potential mechanisms of action (MoAs) for interventions to increase PA, identify any effect a PA intervention may have on medication adherence, and determine whether participants respond uniformly to their respective behavioral interventions.
This trial was approved by the Northwell Health Institutional Review Board (IRB) and all participants will complete informed consent. The trial results will be published in a peer-reviewed journal. All publications resulting from this series of personalized trials will follow the CONSORT reporting guidelines.
This trial is registered on www.
gov (Number NCT05273723).

Blood pressure (BP) is often inadequately controlled in children treated for hypertension, and personalized (n-of-1) trials show promise for tailoring treatment choices. We assessed whether patients whose treatment choices are informed by an n-of-1 trial have improved BP control compared to usual care.
A randomized clinical trial was conducted in a pediatric hypertension clinic in Houston from April 2018 to September 2020. Hypertensive adolescents and young adults 10-22 years old were randomized 1:1 to a strategy of n-of-1 trial using ambulatory BP monitoring to inform treatment choice or usual care, with treatment selected by physician preference. The primary outcome was the proportion of patients with ambulatory BP control at 6 months in a Bayesian analysis.
Among 49 participants (23 randomized to n-of-1 trials and 26 to usual care), mean age was 15.6 years. Using skeptical priors, we found a 69% probability that n-of-1 trials increased BP control at 6 months (Bayesian odds ratio (OR) 1.24 (95% credible interval (CrI) 0.51, 2.97), and 74% probability using neutral informed priors (OR 1.45 (95% CrI 0.48, 4.53)). Systolic BP was reduced in both groups, with a 93% probability of greater reduction in the n-of-1 trial group (mean difference between groups = -3.6 mm Hg (95% CrI -8.3, 1.28). There was no significant difference in side effect experience or caregiver satisfaction.
Among hypertensive adolescents and young adults, n-of-1 trials with ambulatory BP monitoring likely increased the probability of BP control. A large trial is needed to assess their use in clinical practice.
NCT03461003.
ClinicalTrials.gov; NCT03461003.

OBJECTIVE: To examine pain treatment preferences before and after participation in an N-of-1 trial.
METHODS: In this observational study nested within a randomized trial, we examined chronic pain patients\' preferences before and after treatment in relation to N-of-1 trial results; assessed the influence of different schemes for defining comparative \"superiority\" on potential conclusions; and generated classification trees illustrating the relationship between pre-treatment preferences, N-of-1 trial results, and post-treatment preferences.
RESULTS: Treatment preferences differed pre- and post-trial for 40% of participants. The proportion of patients whose N-of-1 trials demonstrated \"superiority\" of one treatment regimen over the other varied depending on how superiority was defined and ranged from 24% (using criteria that required statistically significant differences between regimens) to 62% (when relying only on differences in point estimates). Regardless of criteria for declaring treatment superiority, nearly three-fourths of patients with equivocal N-of-1 trial results nevertheless expressed definite preferences post-trial.
CONCLUSIONS: A large segment of patients undergoing N-of-1 trials for chronic pain altered their treatment preferences. However, the direction of preference change did not necessarily correspond to the N-of-1 results. More research is needed to understand how patients use N-of-1 trial results, why preferences are \"sticky\" even in the face of personalized data, and how patients and clinicians might be educated to use N-of-1 trial results more informatively.