Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials

Background: Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown. Methods: Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models. Results: After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [OR adj ], 1.22 [95% CI, 1.16–1.28]; P <0.001) compared with men. Qualitatively consistent results were observed for women versus men in the placebo arms (OR adj , 1.20 [95% CI, 1.13–1.27]) and active therapy arms (OR adj , 1.23 [95% CI, 1.17–1.30)]; there was some evidence for regional heterogeneity ( P interaction <0.001). Of those who stopped study drug prematurely, a similar proportion of men and women in the active arm stopped because of an adverse event (36% for both; P =0.60). Women were also more likely to withdraw consent compared with men (OR adj , 1.26 [95% CI, 1.17–1.36]; P <0.001). Conclusions: Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.

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MMRM vs joint modeling of longitudinal responses and time to study drug discontinuation in clinical trials using a “de jure” estimand

Pharmaceutical Statistics ◽

10.1002/pst.2045 ◽

2020 ◽

Vol 19 (6) ◽

pp. 909-927

Author(s):

Alberto García‐Hernandez ◽

Teresa Pérez ◽

María del Carmen Pardo ◽

Dimitris Rizopoulos

Keyword(s):

Clinical Trials ◽

Study Drug ◽

Joint Modeling ◽

Drug Discontinuation ◽

Study Drug Discontinuation

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Therapeutic care in metastatic renal cell carcinoma during the follow-up phase of the RECORD-1 phase III trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e17531 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e17531-e17531

Author(s):

D. Wiederkehr ◽

R. Casciano ◽

L. Stern ◽

J. Zheng ◽

J. Baladi

Keyword(s):

Clinical Trial ◽

Mtor Inhibitor ◽

Kinase Inhibitors ◽

Study Drug ◽

Protein Kinase Inhibitors ◽

Phase Iii ◽

Drug Discontinuation ◽

Study Drug Discontinuation ◽

Trial Setting

e17531 Background: Following drug discontinuation for progression or adverse event in a clinical trial for relapsed or stage IV kidney cancer, supportive care including surgery, palliative radiotherapy, or bisphosphonates continue to be recommended by National Comprehensive Cancer Network (NCCN). However, published data on active therapeutic agents given to patients following study drug discontinuation in recent clinical trials is limited. Methods: World Health Organization Anatomical Therapeutic Chemical codes or therapeutic names, captured from the follow-up phase in a phase III clinical trial (RECORD-1) of patients with metastatic renal cell carcinoma (mRCC) patients, were used to describe antineoplastic therapies following discontinuation of study drug. Prior to trial, patients had progressed on at least one VEGFr-TKI therapy. Results: Of the 130 patients with follow-up after discontinuation of study drug, 78.5% received at least one of the following: corticosteroids, radiotherapy, protein kinase inhibitors, mTOR inhibitor, pyrimidine analogues, monoclonal antibodies, interferons, and investigational drugs. Among patients who received an active agent, nearly three-quarters (73.5%) utilized targeted therapy (protein kinase inhibitors, mTOR inhibitor, monoclonal antibodies). Conclusions: In a clinical trial setting with mRCC patients who have received several classes of systemic therapy, care delivered following study drug discontinuation often includes an active antineoplastic agent, despite the limited supportive evidence in this setting. While the placebo control with supportive care in a double-blind phase is acceptable to evaluate the efficacy and safety of a therapy for regulatory approval purposes, decision makers must also consider how these data may inform comparisons with the usual alternatives available to and used by physicians and patients in the non-trial setting. [Table: see text]

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Comparison of Time-to-First Event and Recurrent-Event Methods in Randomized Clinical Trials

Circulation ◽

10.1161/circulationaha.117.033065 ◽

2018 ◽

Vol 138 (6) ◽

pp. 570-577 ◽

Cited By ~ 22

Author(s):

Brian Claggett ◽

Stuart Pocock ◽

L.J. Wei ◽

Marc A. Pfeffer ◽

John J.V. McMurray ◽

...

Keyword(s):

Clinical Trials ◽

Statistical Power ◽

Recurrent Events ◽

Randomized Clinical Trials ◽

Cox Model ◽

Study Drug ◽

Recurrent Event ◽

Drug Discontinuation ◽

Patient Heterogeneity ◽

Study Drug Discontinuation

Background: Most phase-3 trials feature time-to-first event end points for their primary and secondary analyses. In chronic diseases, where a clinical event can occur >1 time, recurrent-event methods have been proposed to more fully capture disease burden and have been assumed to improve statistical precision and power compared with conventional time-to-first methods. Methods: To better characterize factors that influence statistical properties of recurrent-event and time-to-first methods in the evaluation of randomized therapy, we repeatedly simulated trials with 1:1 randomization of 4000 patients to active versus control therapy, with true patient-level risk reduction of 20% (ie, relative risk=0.80). For patients who discontinued active therapy after a first event, we assumed their risk reverted subsequently to their original placebo-level risk. Through simulation, we varied the degree of between-patient heterogeneity of risk and the extent of treatment discontinuation. Findings were compared with those from actual randomized clinical trials. Results: As the degree of between-patient heterogeneity of risk increased, both time-to-first and recurrent-event methods lost statistical power to detect a true risk reduction and confidence intervals widened. The recurrent-event analyses continued to estimate the true relative risk (0.80) as heterogeneity increased, whereas the Cox model produced attenuated estimates. The power of recurrent-event methods declined as the rate of study drug discontinuation postevent increased. Recurrent-event methods provided greater power than time-to-first methods in scenarios where drug discontinuation was ≤30% after a first event, lesser power with drug discontinuation rates of ≥60%, and comparable power otherwise. We confirmed in several actual trials of chronic heart failure that treatment effect estimates were attenuated when estimated via the Cox model and that increased statistical power from recurrent-event methods was most pronounced in trials with lower treatment discontinuation rates. Conclusions: We find that the statistical power of both recurrent-events and time-to-first methods are reduced by increasing heterogeneity of patient risk, a parameter not included in conventional power and sample size formulas. Data from real clinical trials are consistent with simulation studies, confirming that the greatest statistical gains from use of recurrent-events methods occur in the presence of high patient heterogeneity and low rates of study drug discontinuation.

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Are survival and mortality rates associated with recruitment to clinical trials in teenage and young adult patients with acute lymphoblastic leukaemia? A retrospective observational analysis in England

BMJ Open ◽

10.1136/bmjopen-2017-017052 ◽

2017 ◽

Vol 7 (10) ◽

pp. e017052 ◽

Cited By ~ 7

Author(s):

Rachael Hough ◽

Sabrina Sandhu ◽

Maria Khan ◽

Anthony Moran ◽

Richard Feltbower ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Clinical Trials ◽

Acute Lymphoblastic Leukaemia ◽

Lymphoblastic Leukaemia ◽

Relative Survival ◽

Data Repository ◽

Trial Participation ◽

Patient Benefit ◽

Cancer Data

ObjectiveParticipation rates in clinical trials are low in teenagers and young adults (TYA) with cancer. Whilst the importance of clinical trials in informing best practice is well established, data regarding individual patient benefit are scarce. We have investigated the association between overall survival and trial recruitment in TYA patients with acute lymphoblastic leukaemia (ALL).DesignRetrospective.SettingNational (England) TYA patients treated for ALL.Participants511 patients aged 15–24 years diagnosed with ALL between 2004 and 2010 inclusive, of whom 239 (46.7%) participated in the UKALL2003 trial.Outcome measuresPatients were identified using National Clinical Trial (UKALL2003) and Cancer Registry (National Cancer Data Repository, English National Cancer Online Registration Environment) Databases. Relative survival rates were calculated for trial and non-trial patients and observed differences were modelled using a multiple regression approach. The numbers and percentages of deaths in those patients included in the survival analysis were determined for each 3-month period, p values were calculated using the two-tailed z-test for difference between proportions and 95% CIs for percentage deaths were derived using the binomial distribution based on the Wilson Score method.ResultsPatients treated on the trial had a 17.9% better 2-year survival (85.4% vs 67.5%, p<0.001) and 8.9% better 1-year survival (90.8% vs 81.9%, p=0.004) than those not on the trial. 35 (14.6%) patients recruited to the trial died in the 2 years following diagnosis compared with 86 (32.6%) of those not recruited (p<0.001).ConclusionsTYA patients recruited to the clinical trial UKALL 2003 in England had a lower risk of mortality and a higher overall survival than contemporaneous non-trial patients. These data underline the potential for individual patient benefit in participating in a clinical trial and the importance of international efforts to increase trial participation in the TYA age group.Trial registration numberISRCTN07355119.

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Disparities in clinical trials participation in a vertically integrated care delivery system.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.128 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 128-128

Author(s):

Ahmed Megahed ◽

Gary L Buchschacher ◽

Ngoc J. Ho ◽

Reina Haque ◽

Robert Michael Cooper

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Healthcare System ◽

Care Delivery ◽

Trial Participation ◽

Cancer Type ◽

Clinical Trial Participation ◽

Integrated Healthcare ◽

Clinical Trial Enrollment ◽

Asian Pacific

128 Background: Sparse data exists on the diversity clinical trial enrollment in community settings. This information is important to ensure equity of care and generalizability of results. Methods: We conducted a retrospective cohort study of members of an integrated healthcare system diagnosed with invasive malignancies (excluding non-melanoma skin cancers) between 2013-2017 to examine demographics of the oncology population compared to those who enrolled in a clinical trial. Logistic regression was used to assess correlates of clinical trial participation, comparing general and screened samples to enrolled sample. Odds ratios were adjusted for gender, geocoded median household income, cancer type, and stage. Results: Of the 84,977 patients with a cancer diagnosis, N = 2606 were screened for clinical trial participation and consented, and of those N = 1372 enrolled. The percent of Latinx (25.8% vs 24.0%; OR 0.9? CI 0.72-1.05) and African American/Black (10.9% vs 11.1%; OR 0.92 CI 0.75-1.11) clinical trial participation mirrored that of the general oncology population, respectively using Non-Hispanic Whites as reference. Asian/Pacific Islander had equal odds of clinical trial enrollment (OR 1.08 CI 0.92-1.27). The enrolled population was younger than the general oncology population. Conclusions: This study suggests that in an integrated healthcare system with equal access to care, the clinical trials population is well representative of its general oncology population.[Table: see text]

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Dedicated clinical trial tissue tracking database to improve turn-around time at high-volume center.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1543 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1543-1543

Author(s):

Peter Blankenship ◽

David DeLaRosa ◽

Marc Burris ◽

Steven Cusson ◽

Kayla Hendricks ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Tissue Sample ◽

High Volume ◽

Trial Participation ◽

Fresh Tissue ◽

Oncology Clinical Trials ◽

The Status ◽

Unique Source

1543 Background: Tissue requirements in oncology clinical trials are increasingly complex due to prescreening protocols for patient selection and serial biopsies to understand molecular-level treatment effects. Novel solutions for tissue processing are necessary for timely tissue procurement. Based on these needs, we developed a Tissue Tracker (TT), a comprehensive database for study-related tissue tasks at our high-volume clinical trial center. Methods: In this Microsoft Access database, patients are assigned an ID within the TT that is associated with their name, medical record number, and study that follows their request to external users: pathology departments, clinical trial coordinators and data team members. To complete tasks in the TT, relevant information is required to update the status. Due to the high number of archival tissue requests from unique pathology labs, the TT has a “Follow-Up Dashboard” that organizes information needed to conduct follow-up on all archival samples with the status “Requested”. This results in an autogenerated email and pdf report sent to necessary teams. The TT also includes a kit inventory system and a real-time read only version formatted for interdepartmental communication, metric reporting, and other data-driven efforts. The primary outcome in this study was to evaluate our average turnaround time (ATAT: average time from request to shipment) for archival and fresh tissue samples before and after TT development. Results: Before implementing the TT, between March 2016 and March 2018, we processed 2676 archival requests from 235 unique source labs resulting in 2040 shipments with an ATAT of 19.29 days. We also processed 1099 fresh biopsies resulting in 944 shipments with an ATAT of 7.72 days. After TT implementation, between April 2018 and April 2020, we processed 2664 archival requests from 204 unique source labs resulting in 2506 shipments (+28.0%) with an ATAT of 14.78 days (-23.4%). During that same period, we processed 1795 fresh biopsies (+63.3%) resulting in 2006 shipments (+112.5%) with an ATAT of 6.85 days (-11.3%). Conclusions: Oncology clinical trials continue to evolve toward more extensive tissue requirements for prescreening and scientific exploration of on-treatment molecular profiling. Timely results are required to optimize patient trial participation. During the intervention period, our tissue sample volume and shipments increased, but the development and implementation of an automated tracking system allowed improvement in ATAT of both archival and fresh tissue. This automation not only improves end-user expectations and experiences for patients and trial sponsors but this allows our team to adapt to the increasing interest in tissue exploration.

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A Study on the Characteristics of Healthy Volunteers who Participate in Phase I Clinical Trials in Korea

Journal of Empirical Research on Human Research Ethics ◽

10.1177/15562646211034275 ◽

2021 ◽

pp. 155626462110342

Author(s):

Ji-Hye Seo ◽

Ock-Joo Kim ◽

Sang-Ho Yoo ◽

Eun Kyung Choi ◽

Ji-Eun Park

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Phase I ◽

Healthy Volunteers ◽

Health Science ◽

Trial Participation ◽

Phase I Clinical Trials ◽

Financial Reward ◽

Therapeutic Purpose ◽

The Republic

The phase I trial is the first step in administering a drug to humans, but it has no therapeutic purpose. Under the absence of therapeutic purpose, healthy volunteers demonstrated different motivations, unlike the actual patients participating in trials. There were many reported motivations, such as financial motivation, contributing to the health science, accessing ancillary health care benefits, scientific interest or interest in the goals of the study, meeting people, and general curiosity. The aim of this study was to identify the motivation and characteristics of healthy volunteers participating in phase I trials in the Republic of Korea. We gave surveys to 121 healthy volunteers to study their demographic characteristics and the reasons of participation. We identified whether the decision to participate in the research was influenced by demographic factors and whether the perception and attitudes toward the research were influenced by the characteristics of the healthy volunteers. After completion of the first survey, 12 healthy volunteers who had participated in a phase I clinical trial were selected to answer the second interview. According to our survey, most healthy volunteers were unmarried men and economically dependent. Most of them participated in the study because of financial reward. The most important factor to measure financial reward was the research period. Also, 43% of the volunteers were university students, 42% answered “university graduation” and 55% were residing in family-owned houses. Many healthy volunteers were found to be living in family homes and to have a student status or lack of economic independence. Results of the survey showed that 64% of respondents indicated having more than one clinical trial participation. In-depth interviews showed that healthy volunteers had diverse motivation to participate in research and that healthy volunteer perceive the clinical trial positively. The main motivation for healthy volunteers’ participation in research was “financial reward.” Healthy volunteers also considered research schedules, processes, and safety, and had a positive perception of clinical trials, but they thought that the public has a negative perception.

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Abstract 16910: High-Frequency In-Person Visits During Clinical Trial Enrollment is Associated With Relative Reduction in Event Rates in Heart Failure Patients Followed Longitudinally

Circulation ◽

10.1161/circ.142.suppl_3.16910 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Liana C Brooks ◽

Rohan R Bhat ◽

Robyn F Farrell ◽

Mark W Schoenike ◽

John A Sbarbaro ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

High Frequency ◽

Trial Participation ◽

Trial Period ◽

Single Center ◽

Hospitalization Rates ◽

Visit Frequency ◽

Clinical Trial Enrollment ◽

Event Rates

Introduction: The COVID-19 Pandemic has mandated limiting routine visit frequency for patients with chronic cardiovascular (CV) diseases. In patients with heart failure (HF) followed longitudinally, the period of clinical trial participation provides an opportunity to evaluate the influence of high-frequency per-protocol in-person visits compared to less frequent routine visits during longitudinal clinical care. Hypothesis: Patients enrolled in clinical trials will have a lower CV and HF event rates during periods of trial enrollment than during non-trial periods. Methods: We examined clinical characteristics, CV and HF hospitalization rates, and outcomes in patients with HF receiving longitudinal HF care at a single center. We evaluated hospitalization rates during the 1-year preceding trial enrollment and hospitalization and death rates during enrollment in clinical trials and for up to 1 year following trial completion. Results: Among the 121 patients enrolled in HF clinical trials, 72% were HFrEF (age 62±11, 19% females, BMI 30.4±6.0, LVEF 25±7, NYHA 2.7±0.6, NT-proBNP 2336±2671) and 28% were HFpEF (age 69±9, BMI 32.1±5.5, 29% females, LVEF 60±10, NYHA 2.4±0.5, NT-proBNP 957±997). Average clinical trial exposure was 8±6.6 months. Per-protocol visit frequency was 16±7 per year during clinical trial enrollment. In the one-year pre-trial period, compared to the within-trial period, CV hospitalizations were 0.88/patient-year vs. 0.32/patient-year (p<0.001) and HF hospitalizations were 0.63/patient-year and 0.24/patient-year (p<0.001), with a mortality rate of 0.04/patient-year during trial participation. In the period of up-to 1 year following the end of trial enrollment CV and HF hospitalizations were intermediate at 0.51/patient-year and 0.27/patient-year with an annualized incremental mortality rate of 0.03/patient-year. Conclusion: In HF patients followed longitudinally at a single center, periods of clinical trial enrollment were associated with high visit frequency and lower CV and HF hospitalization rates. These findings highlight the potential benefits of trial enrollment and high-frequency visits for HF patients at a time when routine visit frequency is being carefully considered during the COVID-19 Pandemic.

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1374. Integrated Safety Summary of Omadacycline: A Novel Aminomethylcycline Antibiotic

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1205 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S421-S421 ◽

Cited By ~ 1

Author(s):

Steven Opal ◽

Thomas M File ◽

Tom Van Der Poll ◽

Paul McGovern ◽

Evan Tzanis ◽

...

Keyword(s):

Adverse Events ◽

Fungal Infections ◽

Vital Signs ◽

Study Drug ◽

Drug Discontinuation ◽

Once Daily ◽

Atypical Pathogens ◽

Safety Parameters ◽

Study Drug Discontinuation ◽

Electrocardiogram Ecg

Abstract Background Omadacycline (OMC) is a novel aminomethylcycline with activity against Gram-positive, many Gram-negative, anaerobic, and atypical pathogens. It is in clinical development as once-daily oral (PO) and intravenous (IV) monotherapy for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Cumulative safety results from Phase 3 clinical trials are reported. Methods This pooled safety analysis is based on 2,150 subjects: OASIS-1 (N = 645), OASIS-2 (N = 735) in ABSSSI; OPTIC (N = 770) in CABP. Comparators were linezolid (LZD) 600 mg IV then PO in ABSSSI (n = 689); moxifloxacin (MOX) 400 mg IV then PO in CABP (n = 388). Safety parameters included treatment-emergent adverse events (TEAEs), laboratory evaluations, vital signs, and electrocardiogram (ECG) findings. Results A total of 1,073 subjects received OMC: 705 received OMC IV then PO (ABSSSI, n = 323; CABP, n = 382); 368 received OMC PO only for ABSSSI. Overall, 60.6% were male and 91.6% white; mean age ranges were 44.7–45.1 and 60.9–62.1 years in ABSSSI and CABP studies, respectively. TEAEs were observed in 47.5% (OMC), 41.2% (LZD), and 48.5% (MOX) of subjects, with gastrointestinal events the most common TEAEs. Serious TEAEs were low (3.6% OMC, 1.9% LZD, 6.7% MOX). Nausea (14.9% OMC, 8.7% LZD, 5.4% MOX) and vomiting (8.3% OMC, 3.9% LZD, 1.5% MOX) were the most frequently reported TEAEs. Diarrhea was observed in 2.4% OMC, 2.9% LZD, and 8.0% MOX subjects, with no cases of Clostridium difficile in OMC-treated subjects. Most TEAEs were mild to moderate and did not result in study drug discontinuation (3.1% OMC, 1.5% LZD, 7.0% MOX); 4 OMC, 1 LZD, and 0 MOX subjects discontinued for nausea and vomiting. Frequency of hepatic TEAEs was similar for OMC, LZD, and MOX: 4.3% OMC, 4.1% LZD, and 4.5% MOX subjects had post-baseline ALT >3× upper limit of normal. Vital signs and ECGs had comparable clinically notable values post-baseline in each treatment group. Known tetracycline class adverse events such as fungal infections were similar in all groups. Conclusion Pooled analyses demonstrate a favorable OMC safety profile, consistent with its tetracycline heritage. OMC was generally well tolerated in subjects with ABSSSI and CABP, with infrequent treatment discontinuations. Disclosures T. M. File Jr., BioMerieux: Consultant, Consulting fee; Curetis: Consultant, Consulting fee; Melinta Therapeutics: Consultant, Consulting fee; Merck: Consultant, Consulting fee; Motif Bio: Consultant, Consulting fee; Nabriva Therapeutics: Consultant and Investigator, Consulting fee and Research grant; Paratek Pharmaceuticals: Consultant, Consulting fee; Pfizer: Consultant, Consulting fee. T. Van Der Poll, Paratek Pharmaceuticals: Consultant, Consulting fee. P. McGovern, Paratek Pharmaceuticals: Employee, Salary. E. Tzanis, Paratek Pharmaceuticals: Employee, Salary.

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A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder

Clinical Trials ◽

10.1177/1740774519855715 ◽

2019 ◽

Vol 16 (5) ◽

pp. 555-560 ◽

Cited By ~ 1

Author(s):

Heather R Adams ◽

Sara Defendorf ◽

Amy Vierhile ◽

Jonathan W Mink ◽

Frederick J Marshall ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Rare Diseases ◽

Trial Design ◽

Neurodegenerative Disorder ◽

Clinical Trial Design ◽

Trial Participation ◽

Local Participation ◽

Cln3 Disease ◽

Study Participants

Background Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. Methods We created a “hub and spoke” model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the “hub,” conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating “spoke” site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. Results A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6–9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. Conclusions This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

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