Search

Abstract Introduction In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year 1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. Methods EVOLVE-MS-1—an open-label, 96-week, phase 3 study—assessed DRF safety and exploratory efficacy in patients with relapsing–remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week 96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to

BackgroundSmartphones and wearables are revolutionizing the assessment of cognitive and motor function in neurological disorders, allowing for objective, frequent, and remote data collection. However, these assessments typically provide a plethora of sensor-derived measures (SDMs), and selecting the most suitable measure for a given context of use is a challenging, often overlooked problem. ObjectiveThis analysis aims to develop and apply an SDM selection framework, including automated data quality checks and the evaluation of statistical properties, to identify robust SDMs that describe the cognitive and motor function of people with multiple sclerosis (MS). MethodsThe proposed framework was applied to data from a cross-sectional study involving 85 people with MS and 68 healthy participants who underwent in-clinic supervised and remote unsupervised smartphone-based assessments. The assessment provided high-quality recordings from cognitive, manual dexterity, and mobility tests, from which 47 SDMs, based on established literature, were extracted using previously developed and publicly available algorithms. These SDMs were first separately and then jointly screened for bias and normality by 2 expert assessors. Selected SDMs were then analyzed to establish their reliability, using an intraclass correlation coefficient and minimal detectable change at 95% CI. The convergence of selected SDMs with in-clinic MS functional measures and patient-reported outcomes was also evaluated. ResultsA total of 16 (34%) of the 47 SDMs passed the selection framework. All selected SDMs demonstrated moderate-to-good reliability in remote settings (intraclass correlation coefficient 0.5-0.85; minimal detectable change at 95% CI 19%-35%). Selected SDMs extracted from the smartphone-based cognitive test demonstrated good-to-excellent correlation (Spearman correlation coefficient, |ρ|>0.75) with the in-clinic Symbol Digit Modalities Test and fair correlation with Expanded Disability Status Scale (EDSS) scores (0.25≤|ρ|0.75) for mobility test SDMs. Overall, correlations were similar when smartphone-based tests were performed in a clinic or remotely. ConclusionsReported results highlight that smartphone-based assessments are suitable tools to remotely obtain high-quality SDMs of cognitive and motor function in people with MS. The presented SDM selection framework promises to increase the interpretability and standardization of smartphone-based SDMs in people with MS, paving the way for their future use in interventional trials.

Catherine Vasilakis-Scaramozza,1 Katrina Wilcox Hagberg,1 Rebecca Persson,1 George Kafatos,2 Joe Maskell,2 David Neasham,2 Susan Jick1,3 1Epidemiology, Boston Collaborative Drug Surveillance Program, Lexington, MA, USA; 2Center for Observational Research, Amgen Ltd, Uxbridge, UK; 3Epidemiology, Boston University School of Public Health, Boston, MA, USACorrespondence: Susan Jick, Boston Collaborative Drug Surveillance Program, 11 Muzzey Street, Lexington, MA, 02421, USA, Tel +1 781 862 6660, Fax +1 781 862 1680, Email sjick@bu.eduPurpose: To report distribution of codes associated with a rheumatoid arthritis (RA) diagnosis recorded in Clinical Practice Research Datalink (CPRD) Aurum compared to the previously validated CPRD GOLD database as a critical step toward making decisions about CPRD Aurum’s suitability for medical research.Patients and Methods: We analyzed the distribution of codes for RA diagnoses, labs, and treatments in the new CPRD Aurum database, compared to the CPRD GOLD database by selecting relevant indicators of RA diagnosis, treatment, and clinical care. We included all patients in England in CPRD Aurum and CPRD GOLD with an incident diagnosis code for RA on or after 1 January 2005 and at least two years recorded data before first RA diagnosis.Results: We found 53,083 and 18,167 patients with a new diagnosis code for RA in CPRD Aurum and CPRD GOLD, respectively. In both databases approximately 67% were female with similar mean ages at first diagnosis. There were few differences in RA-related recording patterns between the two data sources. Before first RA diagnosis, CPRD Aurum patients had more RA-specific labs and other supporting clinical codes. After diagnosis, CPRD Aurum patients had more RA diagnoses coded and more often had 10+ general RA labs than patients in CPRD GOLD. More CPRD GOLD patients had 10+ prescriptions for conventional disease-modifying antirheumatic drugs (cDMARD) compared to CPRD Aurum. Otherwise, the distribution of drugs used to treat RA was similar between databases. The standardized incidence of RA was similar between databases.Conclusion: Overall, among patients with a diagnosis code for RA, recording of diagnoses, prescription drugs, and labs were similar between CPRD Aurum and CPRD GOLD. Slight differences were found for a few variables, but overall, we found consistency between the databases. In addition, standardized incidence of RA was similar between databases.Keywords: Clinical Practice Research Datalink, CPRD Aurum, CPRD GOLD, validation, data quality

Katrina Wilcox Hagberg,1 Catherine Vasilakis-Scaramozza,2 Rebecca Persson,1 David Neasham,2 George Kafatos,2 Susan Jick1,3 1Epidemiology, Boston Collaborative Drug Surveillance Program, Lexington, MA, USA; 2Center for Observational Research, Amgen Ltd, Uxbridge, UK; 3Epidemiology, Boston University School of Public Health, Boston, MA, USACorrespondence: Susan Jick, Boston Collaborative Drug Surveillance Program, 11 Muzzey Street, Lexington, MA, 02421, USA, Tel +1 781 862 6660, Fax +1 781 862 1680, Email sjick@bu.eduPurpose: To evaluate the new Clinical Practice Research Datalink (CPRD) Aurum database, we estimated ‘correctness’ (ie accuracy, validity) and ‘completeness’ (ie presence, missingness) of malignant breast cancer diagnoses recorded in CPRD Aurum compared to external linked data sources: Hospital Episode Statistics (HES) Admitted Patient Care (APC), HES Outpatient (OP), and Cancer Registry (CR), and to the previously validated CPRD GOLD.Methods: Linkage-eligible, female patients with incident malignant breast cancer diagnosis recorded in at least one study data source were selected. Correctness was the proportion of malignant breast cancer cases recorded in CPRD Aurum or GOLD who also had a diagnosis recorded in HES APC/OP (2004– 2019) or CR (2004– 2016). Completeness was estimated by identifying all malignant breast cancer diagnoses in HES APC/OP or CR and calculating the proportion with a concordant diagnosis in CPRD Aurum or GOLD.Results: Compared to HES APC/OP, there were 85,659 and 31,452 eligible patients in CPRD Aurum and GOLD, respectively. Correctness estimates were high (CPRD Aurum 83.5%, GOLD 81.7%). Compared to CR, there were 70,190 and 29,597 eligible patients in CPRD Aurum and GOLD, respectively: correctness was 89.1% for CPRD Aurum and 88.2% for GOLD. Completeness estimates for CPRD Aurum and GOLD were high (> 90%). Diagnoses were recorded in CPRD Aurum within − 7 to 74 days of those in the linked sources. Reasons for discordant diagnostic coding included presence of treatment or other clinical codes only, diagnosis coded after end of follow-up, non-malignant breast cancer in linked data, and administrative codes in lieu of diagnostic codes.Conclusion: These results indicate that correctness and completeness of malignant breast cancer diagnoses in CPRD Aurum were high and similar to CPRD GOLD. This provides confidence in use of CPRD Aurum for research purposes. Where complete case capture is important, researchers should consider linkage to HES APC or CR.Keywords: CPRD Aurum, CPRD GOLD, breast cancer, validation

Katrina Wilcox Hagberg,1 Catherine Vasilakis-Scaramozza,2 Rebecca Persson,1 David Neasham,2 George Kafatos,2 Susan Jick1,3 1Epidemiology, Boston Collaborative Drug Surveillance Program, Lexington, MA, USA; 2Center for Observational Research, Amgen Ltd, Uxbridge, UK; 3Epidemiology, Boston University School of Public Health, Boston, MA, USACorrespondence: Susan Jick, Boston Collaborative Drug Surveillance Program, 11 Muzzey Street, Lexington, MA, 02421, USA, Tel +1 781 862 6660, Fax +1 781 862 1680, Email sjick@bu.eduPurpose: To evaluate the presence of data elements related to diagnosis and treatment of malignant breast cancer in CPRD Aurum compared to those in the previously validated CPRD GOLD.Methods: Females in CPRD Aurum or GOLD with a first-time code for malignant breast cancer, mastectomy, or ≥ 1 prescription for tamoxifen or aromatase inhibitors (2004– 2019) were selected. We compared the presence of the codes for breast cancer diagnosis, surgeries (mastectomy, lumpectomy), tamoxifen and aromatase inhibitor prescriptions, radiation, chemotherapy, and supporting clinical codes (suspected breast cancer, lump symptoms, biopsy, lumpectomy, cancer care, referral/visit to specialist, palliative care). Age standardized incidence rates of breast cancer diagnosis in CPRD Aurum and GOLD were calculated.Results: There were 131,936 eligible patients in CPRD Aurum and 69,102 patients in GOLD. A similar proportion of patients in CPRD Aurum and GOLD had codes for breast cancer diagnosis, mastectomy, drug prescriptions, lump, biopsy, lumpectomy, chemotherapy, and cancer and palliative care coded in their electronic record during follow-up. However, suspected breast cancer, radiation, and referral/visits to specialists were coded more frequently in patients in CPRD Aurum compared to GOLD. Age-standardized incidence rates were similar for CPRD Aurum and GOLD.Conclusion: Overall, there was consistency between data elements related to malignant breast cancer recorded in CPRD Aurum and GOLD, particularly for the most informative clinical details. These findings provide reassurance that breast cancer information recorded in CPRD Aurum is generally comparable to that recorded in the previously validated CPRD GOLD and support the use of CPRD Aurum for breast cancer research.Keywords: clinical practice research datalink, CPRD Aurum, CPRD GOLD, breast cancer, validation, data quality

Susan Jick,1,2 Catherine Vasilakis-Scaramozza,1 Rebecca Persson,1 David Neasham,3 George Kafatos,3 Katrina Wilcox Hagberg1 1Epidemiology, Boston Collaborative Drug Surveillance Program, Lexington, MA, USA; 2Epidemiology, Boston University School of Public Health, Boston, MA, USA; 3Center for Observational Research, Amgen Ltd, Uxbridge, UKCorrespondence: Susan Jick, Boston Collaborative Drug Surveillance Program, 11 Muzzey Street, Lexington, MA, 02421, USA, Tel +1 781 862 6660, Fax +1 781 862 1680, Email sjick@bu.eduAbstract: Ongoing evaluation of any electronic health data source is critical to assess suitability for its use in medical research. In addition, familiarity with a data source’s history and recording practices is important for making informed data source selection, study design choices, and interpretation of results. In this commentary, the authors discuss three studies that assessed different aspects of the quality and completeness of information contained in Clinical Practice Research Datalink (CPRD) Aurum compared to the well-established CPRD GOLD and to other linked data sources, with the aim to describe insights gained through these data quality assessments. Our findings support the view that CPRD Aurum and GOLD are both valuable tools for studies based on information recorded in primary care but should not be used without critical consideration of strengths and limitations. Further, use of linked data should be considered for some studies, after taking into account all relevant factors.Keywords: clinical practice research datalink, CPRD Aurum, CPRD GOLD, validation, data quality

Stem cell heterogeneity is recognized as functionally relevant for tissue homeostasis and repair. The identity, context dependence, and regulation of skeletal muscle satellite cell (SC) subsets remains poorly understood. We identify a minor subset of Pax7+ SCs that is indelibly marked by an inducible Mx1-Cre transgene in vivo, is enriched for Pax3 expression, and has reduced ROS (reactive oxygen species) levels. Mx1+ SCs possess potent stem cell activity upon transplantation but minimally contribute to endogenous muscle repair, due to their relative low abundance. In contrast, a dramatic clonal expansion of Mx1+ SCs allows extensive contribution to muscle repair and niche repopulation upon selective pressure of radiation stress, consistent with reserve stem cell (RSC) properties. Loss of Pax3 in RSCs increased ROS content and diminished survival and stress tolerance. These observations demonstrate that the Pax7+ SC pool contains a discrete population of radiotolerant RSCs that undergo clonal expansion under severe stress.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival.

Rebecca Persson,1 Katrina Wilcox Hagberg,1 Catherine Vasilakis-Scaramozza,1 Eleanor Yelland,2 Tim Williams,2 Puja Myles,2 Susan S Jick1,3 1Boston Collaborative Drug Surveillance Program, Lexington, MA, USA; 2Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory Agency, London, UK; 3Boston University School of Public Health, Boston, MA, USACorrespondence: Rebecca Persson, Boston Collaborative Drug Surveillance Program, 11 Muzzey Street, Lexington, MA, 02421, USA, Email rpersson@bcdsp.orgBackground: Assessments of strengths and limitations of new data sources are critical for making decisions about suitability for specific research questions. For some studies, it is necessary to capture a drug’s indication for use.Objective: To assess the presence of indications for prescription use in Clinical Practice Research Datalink (CPRD) Aurum (January 1988–June 2021) by describing the proportion of men in CPRD Aurum who had a recorded indication for use of prescriptions for 5-alpha reductase inhibitors (5-ARI), alpha blockers (AB), or tadalafil, which have multiple indications.Methods: From a random sample of 154 practices of CPRD Aurum data, we selected 85,597 male patients with a prescription for a 5-ARI, an AB, or tadalafil. Among these patients, we described presence of codes indicating whether the patient had benign prostatic hyperplasia, hypertension, erectile dysfunction, or alopecia using three indication definitions: narrow (specific diagnoses recorded within one year before and up to 90 days after the prescription), broad (specific diagnoses or supporting clinical codes in the time period described above), and widest (diagnoses or supporting codes recorded at any time before the prescription and up to 90 days after the prescription).Results: Using the narrow indication definition limited to diagnoses only, 39,861 (46.6%) patients’ records contained an indication for use. The broad definitions, which additionally included supporting codes, captured indications for 62,912 (73.5%) patients and the widest definition, which additionally included supporting codes and all available data before the first prescription date, captured indications for 71,478 (83.5%) patients. Indications were present more often for prescriptions in 2005 and later (85.9%).Conclusion: The findings of this assessment suggest that CPRD Aurum can be used for studies that require information on treatment indications for BPH and potentially for treatments of other chronic diseases managed in the primary care setting.Keywords: Clinical Practice Research Datalink, CPRD Aurum, data element presence, pharmacoepidemiology, indication for use, prostatic hyperplasia

Rebecca Persson,1 Todd Sponholtz,1 Catherine Vasilakis-Scaramozza,1 Katrina Wilcox Hagberg,1 Tim Williams,2 Dipak Kotecha,3 Puja Myles,2 Susan S Jick1,4 1Epidemiology, Boston Collaborative Drug Surveillance Program, Lexington, MA, USA; 2Clinical Practice Research Datalink, Medicines and Healthcare Products Regulatory Agency, London, UK; 3Institute of Cardiovascular Sciences, University of Birmingham & University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 4Epidemiology, Boston University School of Public Health, Boston, MA, USACorrespondence: Susan S Jick Email sjick@bu.eduBackground: Validation studies of the Clinical Practice Research Datalink (CPRD) Aurum database in the UK are critical for making decisions about its suitability and validity for research purposes.Objective: To examine data source agreement of myocardial infarction (MI) diagnoses recorded in CPRD Aurum compared with linked Hospital Episode Statistics (HES) data. This comparison provides information on CPRD Aurum data correctness (accuracy, validity) and completeness (presence, missingness).Methods: Patients with MI diagnoses recorded in either data source were selected from a random sample of 50,000 patients in CPRD Aurum with HES linkage (1997– 2017). Correctness was defined as the proportion of MI cases in CPRD Aurum with a concordant MI diagnosis recorded in HES or with strong supporting evidence in either data source. Completeness was defined as the proportion of patients with primary HES-coded MIs with strong supporting evidence that were also present in CPRD Aurum.Results: There were 1260 patients with MI recorded in the CPRD Aurum sample. The overall correctness of the recorded MI diagnoses was 94%: 986 patients (78%) had concordant diagnoses in HES within 90 days; 123 (10%) were concordant with HES, but with an inconclusive date and another 71 (6%) had strong supporting evidence for being a true MI case. There were 1125 patients with MI recorded in HES primary diagnosis fields with strong supporting evidence in either data source. Of these, 880 (78%) were present in CPRD Aurum, with completeness somewhat higher in more recent years.Conclusion: MI diagnoses recorded in CPRD Aurum were highly likely to be correct, supporting its use in clinical research studies. Completeness was lower, indicating the need for data linkage for some studies.Keywords: clinical practice research datalink, CPRD Aurum, data validation, data completeness, data quality

Selective inhibition of tyrosine kinase 2 (TYK2) may offer therapeutic promise in inflammatory conditions, with its role in downstream pro‐inflammatory cytokine signaling. In this first‐in‐human study, we evaluated the safety, tolerability, and pharmacokinetics (PK) of a novel TYK2 inhibitor, PF‐06826647, in healthy participants. This phase I, randomized, double‐blind, placebo‐controlled, parallel‐group study included two treatment periods (single ascending dose (SAD) and multiple ascending dose (MAD)) in healthy participants and a cohort of healthy Japanese participants receiving 400 mg q.d. or placebo in the MAD period (NCT03210961). Participants were randomly assigned to PF‐06826647 or placebo (3:1). Participants received a single oral study drug dose of 3, 10, 30, 100, 200, 400, or 1,600 mg (SAD period), then 30, 100, 400, or 1,200 mg q.d. or 200 mg b.i.d. for 10 days (MAD period). Safety (adverse events (AEs), vital signs, and clinical laboratory parameters), tolerability, and PK were assessed. Overall, 69 participants were randomized to treatment, including six Japanese participants. No deaths, serious AEs, severe AEs, or AEs leading to dose reduction or temporary/permanent discontinuation were observed. All AEs were mild in severity. No clinically relevant laboratory abnormalities or changes in vital signs were detected. PF‐06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (

Background: The Konectom™ smartphone-based cognitive processing speed (CPS) test is designed to assess processing speed and account for impact of visuomotor function on performance. Objective: Evaluate reliability and validity of Konectom CPS Test, performed in clinic and remotely. Methods: Data were collected from people with multiple sclerosis (PwMS) aged 18–64 years and healthy control participants (HC) matched for age, sex, and education. Remote test–retest reliability (intraclass correlation coefficients, ICC); correlation with established clinical measures (Spearman correlation coefficients); group analyses between cognitively impaired/unimpaired PwMS; and influence of age, sex, education, and upper limb motor function on CPS Test measures were assessed. Results: Eighty PwMS and 66 HC participated. CPS Test measures from remote tests had good test–retest reliability (ICC of 0.67–0.87) and correlated with symbol digit modalities test (highest |ρ| = 0.80, p < 0.0001). Remote measures were stable (change from baseline < 5%) and correlated with MS disability (highest |ρ| = 0.39, p = 0.0004) measured by Expanded Disability Status Scale. CPS Test measures displayed sensitivity to cognitive impairment (highest d = 1.47). Demographics and motor function had the lowest impact on CPS Test substitution time, a measure accounting for visuomotor function. Conclusion: Konectom CPS Test measures provide valid, reliable remote measurements of cognitive processing speed in PwMS. [ABSTRACT FROM AUTHOR]

Katrina Wilcox Hagberg,1 Rebecca Persson,1 Catherine Vasilakis-Scaramozza,1 Steve Niemcryk,2 Michael Peng,2 Maria Paris,2 Anders Lindholm,2 Susan Jick1,3 1Boston Collaborative Drug Surveillance Program, Lexington, MA 02421, USA; 2Celgene Corporation, Summit, NJ 07901, USA; 3Boston University School of Public Health, Lexington, MA 02421, USACorrespondence: Susan JickBoston Collaborative Drug Surveillance Program, 11 Muzzey Street, Lexington, MA 02421, USATel +1-781-862-6660Fax +1-781-862-1680Email sjick@bu.eduPurpose: Psoriasis and psoriatic arthritis (PsA) are associated with an increased infection risk. In this cohort study of patients with treated psoriasis or PsA, we used MarketScan (2014– 2018) to estimate rates of herpes zoster, hepatitis C (HepC) and tuberculosis (TB) with apremilast compared to other systemic treatments.Materials and Methods: Patients were exposed from first apremilast [APR], DMARD, TNF-inhibitor [TNF], IL-inhibitor [IL], or corticosteroids [CS] prescription after March 21, 2014. Study exposures were APR, DMARDs only, TNF-only, IL-only, CS-only, DMARDs+CS, TNF+DMARDs and/or CS, IL+DMARDs and/or CS. Cases had treated herpes zoster, HepC, or TB event. We calculated incidence rates (IRs) [95% confidence intervals] per 1000 patient-years.Results: The study population included 131,604 patients. For herpes zoster (N=2271), IRs were highest for users of DMARDs+CS (12.5 [9.8– 15.7]), CS-only (12.5 [10.4– 14.1]), and TNF+DMARDs and/or CS (11.9 [10.6– 13.4]), compared with DMARDs only (9.9 [8.7– 11.2]). IRs were lowest for users of IL-only (6.7 [5.8– 7.8]) and APR (7.0 [5.8– 8.4]). IRs of HepC (N=150) and TB (N=81) were low and between-treatment differences were not significant.Conclusion: Rates of herpes zoster varied by treatment: highest among those who received polytherapy, lowest in users of apremilast only. IRs for HepC and TB were low for all exposures.Keywords: apremilast, psoriasis, psoriatic arthritis, herpes zoster, hepatitis C, tuberculosis

Abstract Objectives Bruton's tyrosine kinase (BTK) plays a non‐redundant signaling role downstream of the B‐cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small‐molecule inhibitor of BTK. Methods BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial. Results In vitro, BIIB091 potently inhibited BTK‐dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC50s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell‐targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long‐lived complexes with BTK with t1/2 of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC50s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo, BIIB091 blocked B‐cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B‐cell activation, with an in vivo IC50 of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing. Conclusion Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials.