Novel findings from the multinational <scp>DOVE</scp> study on geographic and age‐related differences in pain perception and analgesic usage in children with sickle cell anaemia

The DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) study was a recently completed phase 3, double-blind, placebo-controlled, parallel-group trial that assessed the potential efficacy of the antiplatelet agent, Prasugrel, to reduce veno-occlusive crisis (VOC) (Heeney et al, 2016).The study included participants from four regions: Africa (Ghana, Kenya), the Americas (Brazil, Canada, United States), Europe (Belgium, Italy, United Kingdom) and the Middle East (Egypt, Lebanon, Oman, Saudi Arabia, Turkey, United Arab Emirates). While the study did not meet its primary endpoint, as the first multinational prospective study to assess daily-reported pain frequency, pain intensity, and analgesic use in children and adolescents with sickle cell anaemia (SCA), the study outcomes were notable for new findings of age and regional differences in pain characteristics and analgesic use. VOC is the primary reason that SCA patients of all ages seek medical care and is a frequent endpoint in clinical trials. Previous studies have also noted that while pain in children with SCA is episodic and intermittent, many adults with SCA experience daily (or chronic) pain in addition to recurrent acute VOC (Smith et al, 2005; Blinder et al, 2013) implying a pattern of escalating pain frequency in childhood that is poorly characterized. Given the world-wide prevalence of SCA, it is also surprising that potential geographic differences in the rate or intensity of pain in SCA have not been previously explored. This was the first prospective study comparing reported pain rates, pain intensity, or home opioid use in children in different geographic regions. The DOVE study population included children and adolescents aged 2 to <18 years with SCA. Participants receiving hydroxycarbamide (HC, also termed hydroxyurea) were included if the prescribed dose was stable at screening and enrolment. Notably, pre-HC data was not available and markers of HC adherence were not collected, rendering conclusions regarding the use or efficacy of HC beyond the scope of this discussion. DOVE participants completed daily diaries on a mobile electronic patient-reported outcome device (ePRO) to report pain rate and intensity and analgesic use throughout the first 9 months of the study(Hoppe et al, 2016; Heath et al, 2017). This sub-study combined data from all participants, regardless of treatment arms, given the lack of statistically significant treatment effects in the principal trial. Rates of pain and analgesic use were calculated for each participant by summing the number of ePRO days on which pain or analgesic use was reported and dividing by the number of non-missing diary entries from randomisation to 9 months. Although ePRO reports included all types of analgesic medications, only opioid analgesic use was analysed because oftentimes non-analgesic medication was also recorded in the non-opioid category (such as HC). Pain intensity was measured with the modified Faces Pain Scale-Revised (FPS-R) adapted for use in SCA (Gupta et al, 2016). Due to concerns with usability of the ePRO, diary-reported pain rate and intensity were only evaluated in participants aged ≥7 years. Rate of ePRO-reported opioid (Inusa et al, 2016)analgesic use was similarly analysed in participants aged ≥7 years. To accurately capture pain intensity, only the days on which pain was reported were included in this analysis. Days on which participants reported pain as “0” were excluded. Baseline haematological laboratory values were also evaluated for association with pain rate and intensity. The combined data from both treatment arms were analysed by univariable and multivariable methods. Analysis of variance was used to test for differences in pain rate, pain intensity and opioid analgesic use. Four models were implemented, each with a single covariate (age group, HC use, region and VOC occurrence) during the treatment period. A generalized linear model including all four covariates was also used. Of the 341 children and adolescents randomized in the DOVE trial, 311 participants aged 4 to <18 years were included in the overall analysis. The majority of participants (90·3%) had HbSS SCA, and 153 (44·9%) reported taking HC. In multivariable analysis, older participants (aged 12 to <18 years) reported more frequent pain than younger participants (aged 7 to <12 years; P = 0·0320) (Table 1, Fig 1). Mean pain intensity scores were not significantly different between age groups (P = 0·8989). When age was examined as a continuous variable, the rate of pain increased, on average, by 0·919 percentage points for each 1-year increase in age, suggesting a gradual development of daily pain beginning in pre-adolescence (r = 0·126, P = 0·044) (Fig 1). Although patient-reported pain rates were similar in all regions, participants from regions of the Americas and Europe reported significantly higher pain intensity than participants from Africa and the Middle East (Table 1). Values for baseline haematological laboratory markers (Inusa et al, 2016) showed no statistically significant relationship with reported pain rate or pain intensity in any age group (data not shown). Analgesic use was captured by ePROs and characterized as opioid versus non-opioid in all participants. Opioid use varied significantly by region and was much higher in the Americas compared with other regions (P = 0·0003) (Table 1). Of note, the availability of opioid (or other) medications may contribute to the rate, intensity, and perception of pain in SCA, and may also influence when patients seek hospital-based care. Differences in access to pain treatment may influence a variety of potential pain-related endpoints in clinical trials. Overall, this sub-study begins to identify pre-adolescence as a transition point in the development of chronic pain (before the transfer to adult care). Additionally, these findings suggest geographic differences in pain perception, pain intensity and analgesic use that must be accounted for in further multi-national studies of SCA and highlight the need for further cross-cultural and multiregional evaluation. This study was sponsored by Daiichi-Sankyo Company, Ltd and Eli Lilly and Company. Medical writing assistance was provided by Gayle Scott, PharmD, CMPP of ProScribe – Envision Pharma Group, and was funded by Eli Lilly and Company. ProScribe's services complied with international guidelines for Good Publication Practice (GPP3). Eli Lilly and Company was involved in the study design, data collection, data analysis and preparation of the manuscript. All authors participated in the interpretation of study results, and in the drafting, critical revision and approval of the final version of the manuscript. This report does not deal with the pharmaceutical product tested in the initial study which was previously published; however, the identified authors were committed to the publication of all study results that would enhance care in sickle cell disease regardless of the medication's level of efficacy. J Kanter conceived the design of this work, contributed to the acquisition and interpretation of data, the drafting and critical revisions of the manuscript. LE Heath made substantial contributions to the conception and design of this work, to the interpretation of the data and to critical revisions of the manuscript. J Knorr made substantial contributions to the analysis and interpretation of data for this work, the drafting of the manuscript and critical revisions of the manuscript. T Agbenyega made substantial contributions to the acquisition of data and critical revisions of the manuscript. R Colombatti made substantial contributions to the interpretation of data, manuscript drafting and critical revisions of the manuscript. C Dampier made substantial contributions to the acquisition, analysis, and interpretation of data. H Hassab made substantial contributions to the conception of this work and critical revisions of the manuscript. D Manwani made substantial contributions to the acquisition and interpretation of data and critical revision of the manuscript. N Robitaille made substantial contributions to the acquisition of data for this work. PB Brown made substantial contributions to the design of the work, analysis and interpretation of data, drafting the manuscript, and critical revisions of the manuscript. JA Jakubowski made substantial contributions to the analysis and interpretation of data and critical revisions of the manuscript. S Yao made substantial contributions to the analysis of data. CC Hoppe conceived the design of this work, contributed to the acquisition and interpretation of data, the drafting and critical revisions of the manuscript. LE Heath, J Knorr, PB Brown, JA Jakubowski, and S Yao are employees or former employees of Eli Lilly and Company. J Kanter and CC Hoppe have received research support for performance of clinical trials from Eli Lilly, and Selexys Pharmaceuticals, and consulting fees from Global Blood Therapeutics, and Cydan. C Dampier has received consulting fees from Pfizer, Eli Lilly and Company, Baxter, Biogen Idec, and GlycoMimetics and grant support for performance of clinical trials from Pfizer, AstraZeneca, Eli Lilly and Company, and the National Institutes of Health.

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