ACCELERATE: A Patient-Powered Natural History Study Design Enabling Clinical and Therapeutic Discoveries in a Rare Disorder

Abstract

Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.

Trial registration: ClinicalTrials.gov NCT02817997.

Keywords: Castleman disease; direct-to-patient; natural history registry; orphan disease; patient-powered.

Conflict of interest statement

A.L. reports employment and equity ownership from BridgeBio Pharma. A.R. reports consultancy to LabCorp and Consonance Capital, board member of Safeguard Biosystems, and member of academic advisory council to AMN. S.F. reports consultancy, advisory board membership, research funding, and speakers’ honoraria from Janssen Pharmaceuticals; consultancy, advisory board membership, and speakers’ honoraria from EUSA Pharma; advisory board membership in Clinigen; speakers’ honoraria from Servier; and research funding from Gilead. P.L.Z. reports consultancy to Verastem, MSD, EUSA Pharma, and Sanofi; speakers’ bureau of Verastem, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, Immune Design, Celgene, Portola, Roche, EUSA Pharma, and Kyowa Kirin; advisory board membership in Verastem, Celltrion, Gilead, and Janssen-Cilag, BMS, Servier, Sandoz, MSD, Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi. L.T. reports advisory board membership in EUSA Pharma. C.C. reports consultancy to EUSA Pharma. E.O. reports advisory board membership in and consultancy to EUSA Pharma. G.S. reports speakers’ bureau involvement with Takeda, Janssen Pharmaceuticals, Foundation Medicine, and EUSA Pharma. T.S.U. reports research support from Roche and Celgene and receives study drug for a clinical trial from Merck. F.v.R. reports a consultancy relationship with Takeda, Sanofi Genzyme, EUSA Pharma, Adicet Bio, Kite Pharma, and Karyopharm Therapeutics. D.C.F. reports research funding from Janssen Pharmaceuticals (former financial sponsor) and EUSA Pharma (current financial sponsor) for the ACCELERATE Natural History Registry, donation of study drug from Pfizer for NCT03933904, and a provisional patent application filed by the University of Pennsylvania for Methods of Treating Idiopathic Multicentric Castleman disease with JAK1/2 inhibition (62/989,437). All of the other authors report no competing interests.

© 2020 The Authors.

Figures

Graphical abstract

Figure 1

ACCELERATE Operations in the Patient-Powered Arm (PPA) and Physician-Directed Arm (PDA) In the PPA, patients consent electronically and provide demographic data, at which point the ACCELERATE Registry Team acquires and enters the medical data into the database. Upon completion, treatment regimen responses are assessed and assigned, and the case is reviewed by the principal investigator. See also Table S1 for metrics on each step in the PPA process. In the PDA, physicians approach patients for enrollment, extract medical data, and assign treatment regimen responses. PDA cases do not require principal investigator review as they are assessed directly by the treating physician. All of the cases are then routed to the expert panel for review of the diagnosis. Patients in both arms have the opportunity to complete quarterly patient-reported outcome surveys.

Figure 2

Enrollment Trends in ACCELERATE (A) The PPA is on trend to meet its overall goal of enrolling n = 450 patients over 5 years. As of March 2020, n = 372 patients have consented in the PPA, with n = 271 meeting inclusion criteria. (B) The PDA has successfully met and exceeded its goal to enroll n = 50 patients over 5 years. As of March 2020, n = 97 patients have consented in the PDA, with n = 94 meeting inclusion criteria.

Figure 3

Study Enrollment Flow Diagram Patients who receive a CD-diagnosis grade from the Certification and Access Subcommittee (CAS) will be included in select future analyses. PDA patients have not yet begun the CAS review process.

Figure 4

Geographic Trends in ACCELERATE (A) Patients have consented from 27 different countries, with the majority from the United States (n = 303), Germany (n = 24), France (n = 24), Canada (n = 18), Italy (n = 16), the United Kingdom (n = 15), Australia (n = 14), Norway (n = 10), and Spain (n = 9). (B) Enrollment within the United States is distributed across the country, with a cluster of patients near the Northeast. (C) Enrollment from the 9 PDA sites demonstrates an even distribution.

Figure 5

Data Entry Trends in the PPA and PDA (A) The proportion of patients who meet inclusion criteria and have data entered into the study database for the PDA (99%) and PPA (75%), and the proportion of patients with medical data entered in each arm with clinical (98% PPA, 52% PDA), laboratory (86% PPA, 37% PDA), imaging (70% PPA, 15% PDA), and all 3 (clinical, lab test, and imaging data) in the database (64% PPA, 5% PDA). (B) Violin plot showing the distribution (median, interquartile range, and range) of the number of required lab tests, positive or negatively assessed clinical features, and PET, PET/CT, CT, or MRI imaging studies entered in each arm. Data are represented on a log scale.

Figure 6

Use of ACCELERATE Clinical Data and Tissue Samples in Translational Research Key clinical data and tissue samples obtained through ACCELERATE have been used to further research CD etiology, signaling, cytokines, cell types, subgroups, and treatments. ACCELERATE clinical data have contributed to 5 published clinical and translational studies, 8 translational studies in progress, and 4 clinical studies in progress. §Planned research; ∗research in process; †published; ‡submitted for publication.