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.

BACKGROUND: Retinitis pigmentosa (RP) is an inherited disease characterized by a progressive loss of rod photoreceptors of the eye, leading to irreversible blindness. To date, to our knowledge, no clinical prospective studies have been undertaken that could document the effect of interventions that could reverse or reduce the progression of this disease. The application of microcurrent stimulation (ES) of the eye in the treatment of chronic eye diseases such as glaucoma and age-related macular degeneration has been used over several decades and has been reported to have beneficial effects to reduce the progression of these blinding diseases and has been supported by animal studies and smaller clinical studies, but to date, no large randomized clinical trials on the use of microcurrent therapy have been published. More recent clinical reports have also shown beneficial effects of ES on slowing the progression of RP but also lacks data from robust prospective clinical outcome studies. To our knowledge, this is the first prospective randomized study to evaluate the safety and clinical effectiveness of transpalpebral electrical stimulation (TpES) on the progression of RP.
METHODS: Randomized prospective study using N-of-1 trial 3 single-blind, crossover comparisons. The intervention period of each comparison is divided into treatment period and control period which are randomized arranged. Twelve participants will be strictly recruited in N-of-1 trial by the researcher in accordance with the inclusion and exclusion criteria. The main outcome of interest examined after each cycle of the 8-week intervention period is the assessment of the visual field (VF). Other variables of interest are best corrected visual acuity (BCVA), retinal function using electroretinogram (ERG), and visual function using NEI VFQ-25 questionnaire. Objective assessments of retinal changes will be undertaken using optical coherence tomography (OCT) and fundus autofluorescence (FAF).
CONCLUSIONS: The trial will evaluate the efficacy and safety of microcurrent stimulation on RP and provide high-quality evidence for clinical application through N-of-1 trial.
BACKGROUND: Chinese Clinical Trial Registry; ChiCTR2300067357; https://www.chictr.org.cn/showproj.html?proj=174635 . Registered on 5 January 2023.

BACKGROUND: The main aim of this paper is to present the feasibility of rigorously designed multiple N-of-1 design in prosthetics research. While research of adequate power and high quality is often lacking in rehabilitation, N-of-1 trials can offer a feasible alternative to randomized controlled group trials, both increasing design power at group level and allowing a rigorous, statistically confirmed evaluation of effectiveness at a single patient level. The paper presents a multiple N-of-1 trial protocol, which aim is to evaluate the effectiveness of Unity, a prosthetic add-on suspension system for amputees, on patient-reported comfort during daily activities (main outcome measure), prosthesis wearing time, perception of limb-prosthesis fitting and stump volume and functional walking parameters.
METHODS: Multicenter, randomized, prospective, double-blind multiple N-of-1 trial using an introduction/withdrawal design alternating Unity connected/disconnected phases of randomized length on twenty patients with unilateral transtibial amputation. The primary outcome measure is the Prosthetic Socket Comfort Score (SCS), a validated measure of comfort, administered daily by an phone app designed for the study. Secondary outcomes measures will be collected during the 50 days period of the N-of-1 trial: (1) by the same app, daily for patient-reported limb-prosthesis fitting, stump volume variation, and daily wearing time of the prosthesis; (2) by a pedometer for the number of steps per day; (3) by blind assessors in the rehabilitation center during adjustment visits for functional walking parameter (L-Test, 6-minute walk test), and by the patient for the QUEST, and ABC-S. Effectiveness of the Unity system regarding SCS and daily secondary outcome measures will be tested by randomization test. The secondary outcome measures assessed during visits in the rehabilitation center will be analyzed by Non Overlap of All pairs. An estimate of the effect on the amputee population will be generated by aggregating each individual clinical trial (N-of-1 trial) by Hierarchical Bayesian methods.
CONCLUSIONS: This study protocol was designed to answer the question \"which device is best for THIS patient\" and to conclude at a group level on the effectiveness of a new devic, using a Multiple N-of-1 trial, which is promising but underused in prosthetics research so far.
BACKGROUND: N° ID-RCB 2020-A01309-30 Clintrial.gov : NCT04804150 - Retrospectively registered March 20th 2021.

UNASSIGNED: Blood pressure [BP] should be measured using a bare upper arm with an appropriately sized cuff. In practice, it is more convenient to measure BP on a bare arm below a rolled-up sleeve or on a sleeved arm.
UNASSIGNED: A n-of-1 randomized controlled trial was performed to assess the difference between BP measurements over a sleeve or below a rolled-up sleeve.
UNASSIGNED: The study subject was male, white, 72 years old, BMI 26 kg/m2, arm circumference 29 cm, and under stable antihypertensive treatment. The mean of three BP measurements over a thin sleeve was compared with measurements below a rolled-up sleeve. Additional measurements on a completely bare arm, with thicker sleeves and up to three layers were performed. The order of measurements was determined by chance and two oscillometric devices were used. Descriptive statistics, Bland-Altman test and 2-side T test were used for comparisons.
UNASSIGNED: 504 measurements were performed: 50 % over the sleeve and 50 % below the rolled-up sleeve. The mean systolic blood pressure (SBP) was respectively 116.9 ± 9. 2 [95% CI 115.7-118.0, range 96-135] and 122.8 ± 9.2 [95% CI 121.7-124.0, range 103-139, p = 0.001] mm Hg. The mean diastolic blood pressure [DBP] was respectively 67.6 ± 6.8 [95% CI 66.8-68.4, range 52-84] and 71.8 ± 6.8 [95% CI 71.0-72.7, range 55-85, p = 0.001] mm Hg. There was no significant difference between the measurements over the sleeve and on the completely bare arm [n = 94, p = 0.97]. Sleeve thickness with 2 layers up to 3 mm thick did not affect the results.
UNASSIGNED: Blood pressure measurements over a thin sleeve were significantly lower than measurements below a rolled-up sleeve and match measurements on a completely bare arm.

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.

UNASSIGNED: Evidence-based management of neuropathic pain is commonly ineffective due to the large variability in response between cases. Patients often have to trial several drugs before finding one that provides adequate relief, leading to increased costs and worsened outcomes. There is thus a need for tools to guide and streamline prescribing decisions in neuropathic pain. N-of-1 trials provide a potentially precise and economical method of selecting between multiple interventions in an individual patient, and merit a feasibility assessment for use in clinical pain practice.
UNASSIGNED: We aim to evaluate the feasibility of N-of-1 trials to compare pregabalin and gabapentin for individual presentations of neuropathic pain.
UNASSIGNED: This is a double-blinded multiple crossover study, with recruitment from existing patients at an outpatient pain clinic in New South Wales, Australia. Participants will undergo three 4-week treatment pairs, comprising 2 weeks of pregabalin (150-600 mg/day) and 2 weeks of gabapentin (900-3600 mg/day), in an individually randomised order. Intervention doses will be derived from participants\' existing treatment dose. Medications will be taken orally three times daily. The primary outcome will be pain intensity; measures will be self-reported daily in patient diaries. After completing all three cycles, participants and their physicians will be presented with the results of the trial to form an informed decision about their treatment.
UNASSIGNED: As a stable yet debilitating condition, neuropathic pain is especially amenable to an N-of-1 study design. A successful trial would represent a significant quality of life improvement for the patient, possibly extending over the course of their lifetime.

Background: Both anxiety and depression in family caregivers (FCs) of advanced cancer patients are common, and they have a negative influence on both the FCs and the patients. Some studies suggested that a variety of interventions could alleviate the psychological symptoms of FCs. However, there is no consensus on much more effective methods for intervention, and relatively high-quality research is blank in psychological problems of these population in China. The validity of mindfulness-based stress reduction (MBSR) and psychological consultation guided by the needs assessment tool (NST) in the psychological status of caregivers will be compared in this study to select a more suitable intervention for the FCs of advanced cancer patients in China. Methods and Analysis: A randomized N-of-1 trial would be conducted at the Cancer Hospital, Chinese Academy of Medical Sciences. Fifty eligible FCs of advanced cancer patients will be recruited, and all will receive three cycles of psychological intervention treatment, with each cycle including both of MBSR and psychological consultation guided by the NST. MBSR and psychological consultation guided by the NST will be compared with each other in each cycle, and the intervention sequence will be based on the random number table generated after the informed consent has been completed. Each treatment period is 2 weeks, and the interval between different treatment cycles or treatment periods is 1 week. The self-reported scales are measured at the beginning and end of each treatment period, including the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), Distress Thermometer (DT), Zarit Burden Interview (ZBI), Chinese version of the Medical Outcomes Study 12-item Short Form (C-SF-12), and Family Carer Satisfaction with Palliative Care scale (FAMCARE-2). Dissemination: The protocol of the study was approved by the Institutional Review Board of the Ethical Committee of the Cancer Hospital, Chinese Academic of Medical Science. The results will be published in a peer-reviewed medical journal. The study is registered at Chinese Clinical Trials Registry with the trial registration number chiCTR2000033707. This study employs an innovative methodological approach on the effectiveness of MBSR and psychological consultation guided by the NST for psychological status of FCs of advanced cancer patients. The findings of the study will be helpful to provide high-quality evidence-based medical data for psychological intervention of FCs of advanced cancer patients, and guide clinicians on best quality treatment recommendations.

BACKGROUND: Modified Sijunzi decoction (SJZD) has been used to treat ulcerative colitis (UC) in remission. However, more rigorous clinical trials are necessary to evaluate its effectiveness. Therefore, a series of single-case randomised controlled trials (N-of-1 trials) is proposed to compare the efficacy of modified SJZD with mesalazine for treating UC in remission.
METHODS: This is a single-site, hospital-based, double-blind N-of-1 trial for 10 single subjects. Three cycles of N-of-1 trials are planned. There are two treatment periods in each cycle. Modified SJZD combined with mesalazine placebo or mesalazine combined with modified SJZD placebo will be randomised during each 8-week treatment period. There is no washout period in the study. Subjects will be selected by the researcher strictly in accordance with the inclusion and exclusion criteria.
CONCLUSIONS: Paired t tests and mixed-effect models will be used to analyse the visual analogue scale (VAS) for clinical symptoms and the quality of life questionnaire responses. The findings will be interpreted with caution. We anticipate that the results will show that modified SJZD is effective for patients with UC in remission.
BACKGROUND: Chinese Clinical Trial Register, ID: ChiCTR1900024086. Registered on 24 June 2019.

Abstract: Sleep deprivation is a prevalent and rising health concern, one with known effects on blood glucose (BG) levels, mood, and calorie consumption. However, the mechanisms by which sleep deprivation affects calorie consumption (e.g., measured via self-reported types craved food) are unclear, and may be highly idiographic (i.e., individual specific). Single-case or \"n-of-1\" randomized trials (N1RT) are useful in exploring such effects by exposing each subject to both sleep deprivation and baseline conditions, thereby characterizing effects specific to that individual. We had two objectives: (1) To test and generate individual-specific N1RT hypotheses of the effects of sleep deprivation on next-day BG level, mood, and food cravings in two non-diabetic individuals; (2) To refine and guide a future n-of-1 study design for testing and generating such idiographic hypotheses for personalized management of sleep behavior in particular, and for chronic health conditions more broadly. We initially did not find evidence for an idiographic effect of sleep deprivation, but better-refined post hoc findings indicate that sleep deprivation may have increased BG fluctuations, cravings, and negative emotions. We also introduce an application of mixed-effects models and pancit plots to assess idiographic effects over time.

BACKGROUND: Whiplash associated disorder (WAD), a common and disabling condition, incurs huge burden and costs to Australia. Yet, current treatments for whiplash are not very effective; improved outcomes are urgently needed. Clinical guidelines recommend simple analgesia (paracetamol and non-steroidal anti-inflammatory drugs) but there have been no trials of guideline-recommended drugs. This study will investigate the effectiveness of evidence-based advice (EBA), paracetamol, naproxen, and both paracetamol and naproxen, in reducing daily neck pain and preventing chronic neck pain after whiplash injury.
METHODS: This study is a pilot series of multi-cycle, double-blinded, randomised N-of-1 trials, nested in a multiple baseline design. The design will comprise three baselines of 5, 8 or 11 days duration. Post enrolment, participants will be randomly assigned to one of the baselines. Fifteen participants with acute (<2 weeks) Grade II WAD, experiencing at least moderate pain (NRS: ≥ 5/10), and at risk of poor recovery will be recruited from hospitals in Queensland, Australia, and through local physiotherapists. Patients will receive EBA plus a randomised sequence of three cycles of ten day treatment triplets (paracetamol designated as a C phase, naproxen, designated as a D phase, and both paracetamol and naproxen, designated as an E phase).
CONCLUSIONS: We will test the effects of different treatments on the primary outcome of average neck pain intensity collected daily and at 4 and 7 months post-injury. Secondary outcomes, including disability, depression, post-traumatic stress symptoms, pain catastrophizing, and feasibility of study procedures, will also be evaluated. The results of this study will inform a larger trial aiming to strengthen the evidence on EBA and simple analgesics for WAD.
BACKGROUND: Clinical Trials Primary Registry: Australian and New Zealand Clinical Trials Registry.
BACKGROUND: ACTRN12618001291279.
UNASSIGNED: 31/07/2018.
UNASSIGNED: The University of Queensland, Brisbane QLD 4072 Australia.
BACKGROUND: The University of Queensland.