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Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia

Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of... Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vita- min D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1–12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient- Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (− 5.02, 95% CI − 9.29 to − 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline. Trial registration: ClinicalTrials.gov NCT02915705 Keywords Burosumab · X-linked hypophosphatemia · Patient-reported outcomes · Patient-reported outcomes measurement information system Introduction X-linked hypophosphatemia (XLH) is a rare, heritable, life- long phosphate-wasting disease. Loss-of-function mutations in the PHEX (phosphate-regulating endopeptidase homo- Supplementary information The online version of this article logue, X-linked) gene result in characteristic elevation of (https ://doi.org/10.1007/s0022 3-020-00797 -x) contains circulating fibroblast growth factor 23 (FGF23) levels, lead - supplementary material, which is available to authorized users. ing to reduced renal phosphate reabsorption and decreased production of active vitamin D (1,25[OH] D) manifesting as * Raja Padidela [email protected] chronic hypophosphatemia and impaired mineralization of bones and teeth, as well as muscle weakness [1, 2]. Extended author information available on the last page of the article Vol:.(1234567890) 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 623 XLH typically manifests in early childhood as rickets, Here, we present the PRO results from the phase 3 pediat- skeletal deformities, short stature, and in some children with ric trial, specifically the endpoints of PROMIS pain interfer - dental abscesses [1–4]. Untreated or inadequately treated ence, physical function mobility, and fatigue; health-related children commonly suffer impaired mobility and physical quality of life (HRQoL) according to SF-10; and pain inten- function, such as delayed walking, unusual gait, muscle sity according to FPS-R. We also conducted a subgroup weakness, bone, joint, and muscle pain, and emotional and analysis to investigate whether PRO scores varied with social challenges [2–4]. Short stature acquired in childhood rickets severity, sex, geographic region, or PHEX disease- and skeletal deformities are irreversible, without surgery, causing variant. after completion of growth. Elevated circulating FGF23 and hypophosphatemia persist into adulthood; adults often develop pseudofractures, fractures, enthesopathies, hyper- Subjects and Methods parathyroidism, and early-onset osteoarthritis, and suffer increasing pain, stiffness, and loss of physical function [3 ]. This open-label, randomized, active-controlled, phase 3 For the past 40  years, therapy for XLH has primarily trial was conducted at 16 international sites with experience consisted of multiple daily doses of oral phosphate supple- treating XLH. The institutional review board at each partici- mentation with active vitamin D (calcitriol or alfacalcidol; pating center approved the protocol. The trial was conducted “conventional therapy”). Oral phosphate preparations can be in accordance with the Declaration of Helsinki and the Good unpalatable and can cause gastrointestinal symptoms, and Clinical Practice guidelines developed at the International the frequent dosing regimen is burdensome for patients and Conference on Harmonization of Technical Requirements their caregivers [2, 3, 5]. Furthermore, regular monitoring for Registration of Pharmaceuticals for Human Use. Trial and appropriate dose adjustments are needed to minimize design details have been published previously [9] and are the risk of complications of conventional therapy including only briefly described here. nephrocalcinosis and hyperparathyroidism [1–3, 5]. Eligibility criteria for this trial were as follows: age Burosumab is a fully human monoclonal antibody (IgG1) 1–12 years when informed consent was obtained; confirmed that binds to FGF23 and inhibits its activity [6, 7]. The effi- diagnosis of XLH according to fasting serum phospho- cacy of burosumab in pediatric XLH has been demonstrated rus < 0.97 mmol/L (3.0 mg/dL); a confirmed PHEX disease- by increasing the levels of serum phosphorus in two phase causing variant or a variant of unknown significance in the 2 studies (UX023-CL201, NCT02163577; UX023-CL205, patient, or in a directly related family member with appropri- NCT02750618), as well as in children with rickets (rick- ate X-linked dominant inheritance; radiographic evidence of ets severity score [RSS] ≥ 2.0) in the randomized phase 3 rickets in the wrist and/or knee; a total Thacher RSS ≥ 2.0; trial of burosumab versus continued conventional therapy and prior treatment with conventional therapy for ≥ 6 con- (UX023-CL301, NCT02915705). These trials demonstrated secutive months (children aged < 3 years) or ≥ 12 consecu- improvement in clinical outcomes, including rickets, lower- tive months (children aged ≥ 3 years) up until enrollment. limb deformities, and mobility, as assessed by the 6-min Parents or guardians provided written informed consent walk test, with the CL301 trial demonstrating superiority of for their children to participate, and children gave written changing to burosumab over continuation of conventional assent according to local guidelines. Patients were randomly therapy [2, 8, 9]. assigned (1:1) to receive subcutaneous burosumab (starting In addition to clinical outcomes, patient-reported out- dose 0.8 mg/kg every 2 weeks) or continue conventional come (PRO) data were collected in the phase 3 pediatric trial therapy with oral phosphate and active vitamin D, the doses using Patient-Reported Outcomes Measurement Information of which were titrated and individualized based on published System (PROMIS) instruments, the Short Form-10 (SF-10) recommendations [1, 6]. Patients received study medication Health Survey for Children, and the Faces Pain Scale— for up to 64 weeks. PRO instruments were completed at Revised (FPS-R) to quantify the impairment and compare baseline and at weeks 24, 40, and 64. their evolution on burosumab versus continued conventional therapy. Pain is prevalent in pediatric patients with XLH Patient‑Reported Outcome Assessments and is most frequently observed in the lower limbs, but also occurs in the back and hips [4]. Children with XLH often PROs were assessed using linguistically validated, approved have trouble performing age-appropriate gross motor activi- instruments during the trial for patients aged ≥ 5 years only ties, such as walking, running, and jumping, due to bowing at the screening visit. PROMIS is a set of measures devel- of the femur, tibia, and fibula, and tibial rotation that causes oped by the US National Institutes of Health to evaluate the feet to turn in towards each other. Gait disturbance is physical, mental, and social health [10, 11]. A fixed-length common in pediatric patients with XLH, reported in > 80% short-form PROMIS instrument comprising the pain inter- of children [4]. ference, physical function mobility, and fatigue domains 1 3 624 R. Padidela et al. was created by selecting items from the three pediatric item disorder [ADHD], arthritis, and gastrointestinal disorders) banks of PROMIS (version 2.0; Online Resource, Table 2). [14]. Higher scores on the PROMIS pain interference and Pain interference consisted of four items scored using five fatigue domains indicate greater detriment (i.e., worse pain response options indicating the frequency of pain interfer- and more fatigue), whereas a higher score on the PROMIS ence (“never,” “almost never,” “sometimes,” “often,” and physical function mobility domain indicates less detriment “almost always”); physical function mobility consisted of 10 (i.e., better physical function mobility). items scored using five response options to indicate sever - Overall HRQoL was assessed using the SF-10 Health ity (“with no trouble,” “with a little trouble,” “with some Survey for Children, a validated 10-item, caregiver-com- trouble,” “with a lot of trouble,” and “not able to do”); and pleted questionnaire designed to assess physical and psy- fatigue consisted of eight items scored using five response chosocial HRQoL in healthy and ill children. Each ques- options indicating the severity (“never,” “almost never,” tion has five response options (“Excellent,” “Very good,” “sometimes,” “often,” and “almost always”). “Good,” “Fair,” and “Poor”) with a recall period of the past Items were selected using information from qualitative 4 weeks. Responses were used to generate two component interviews of five children with XLH aged 8–12 years and summary scores: physical health score (PHS-10) and psy- their parents: one parent of an 8-year-old child with XLH chosocial health score (PSS-10), scored according to pub- and four parents of children with XLH aged 5–7 years. Item lished methods [15]. The scale was scored so that a score appropriateness was based on evidence from the concept of 50 corresponds to the average score in a 2006 sample, elicitation, conceptual mapping, and cognitive debriefing which comprised a combination of children from the general exercises conducted as part of the qualitative interviews. population and a supplemental sample with disability and The pain interference, physical function mobility, and chronic conditions; higher global scores are associated with fatigue items were well understood and found to be rel- better HRQoL. evant and appropriate assessments of those concepts for The FPS-R was used to assess current pain at each study the children and their parents. These qualitative data there- visit. The self-reported scale uses graphical facial repre- fore established content validity of the selected PROMIS sentations of pain to allow self-reporting of current pain domains. An analysis of the psychometric properties of the intensity at rest (not during or immediately after physical PROMIS instrument (both the self-reported form for chil- activity) on a 0–10 scale (0 = no hurt to 10 = hurts worst; dren aged ≥ 8 years and the parent proxy report form for even numbers only) and has been validated in children aged children aged 5 to < 8 years) consisting of the three domains 5–16 years [16]. in the current trial (n = 35; children aged 5–12 years) con- firmed it to be a reliable, valid, and responsive method for Statistical Analysis use in clinical trials in children with XLH [12]. The PROMIS domains were each measured at study The primary endpoint for this trial, namely change in rickets assessment visits using a recall period of the previous severity from baseline to week 40, has been reported previ- 7  days. Children aged ≥ 8  years at screening completed ously [9]. Changes from baseline in PROMIS scores were a self-reported PROMIS instrument. For children aged 5 assessed as secondary endpoints, and changes from baseline to < 8 years at screening, the parent or legal guardian com- in SF-10 PHS-10 and PSS-10 were assessed as exploratory pleted the parent proxy version of the PROMIS instrument endpoints. Here, we report data for changes to week 64 to throughout the trial. PROMIS data were uploaded to the provide longer-term information on XLH in children. SAS® PROMIS online scoring system [13] to obtain the final software version 9.4 or higher (SAS Institute, Cary, NC, scores for each domain. All raw scores generated from USA) was used for statistical analyses. the PROMIS instrument were translated into standardized PRO endpoints were analyzed using a generalized esti- scores (termed T-scores), based on a calibration sample mating equation repeated-measures analysis. Treatment, resulting in a calibration population mean of 50 and stand- visit, and interaction of treatment-by-visit were included as ard deviation (SD) of 10. The calibration sample consisted categorical variables, and baseline measures and baseline of a US cohort of 4,129 children aged 8–17 years, with 55% total RSS stratification factor were included as independent aged 8–12 years. The majority of children in the calibration variables in the model. Total RSS was used in this model, as sample (94%) were recruited from hospital-based general it has been validated in 52 children with XLH, with higher pediatric and subspecialty clinics, with 6% from school set- total RSS associated with greater impairment in walking tings; 35% had consulted a clinician for a chronic illness ability as assessed by the 6-min walk test [17]. Data for diagnosis or treatment within 6 months, and 9% had two model-based estimates of the changes from baseline, stand- or more chronic illnesses (the most common chronic con- ard error (SE), and corresponding 95% confidence intervals ditions were asthma, affecting 18% of children, followed (CIs) were assessed for significance at the 5% level. Missing by attention-deficit disorder/attention-deficit hyperactivity data were treated as missing for all analyses. Only data for 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 625 patients with a baseline measurement and at least one post- and − 3.55 [1.873] at week 64), indicating reduced levels baseline measurement were included in analyses of change of pain interference, but changed little in the group who from baseline. continued to receive conventional therapy (− 0.29 [1.539] As the trial was not powered to assess differences in at week 40 and − 1.29 [1.267] at week 64). The change in between-group changes beyond the primary endpoint, pain interference score exceeded the 3-point MID threshold within-group changes from baseline were reported for in patients receiving burosumab at both weeks 40 and 64, variables with nonsignificant between-group differences. A consistent with a clinically meaningful reduction in pain change of 2–3 points is considered clinically meaningful for interference for this group. The change from baseline in the PROMIS pediatric scales [18]. To interpret within-group group continuing conventional therapy was less than the trial results, clinically relevant differences were explored 3-point MID threshold. Burosumab was associated with a based on a minimally important difference (MID) threshold significantly greater change from baseline than conventional of 3 points [19]. therapy at week 40 (between-group difference − 5.02, 95% In an exploratory analysis, testing for treatment-by- CI − 9.29 to − 0.75; p = 0.0212) but not at week 64 (− 2.26, subgroup was used to detect treatment effect heterogeneity 95% CI − 6.61 to + 2.09; p = 0.3091) (Fig. 2a). Descriptive across four subgroups (RSS: ≤ 2.5, > 2.5; sex: male, female; item-level results at baseline and week 64 can be found in region: Japan, rest of world; PHEX status: clearly pathogenic the appendix (Online Resource, Table 3). PHEX variants, or likely pathogenic/variant of unknown sig- nificance) on the PRO domains using week 40 and week 64 PROMIS Physical Function Mobility data. Higher scores on the PROMIS physical function mobility domain indicate less detriment (i.e., better physical function Results mobility), with increases in scores reflecting improvements in this domain. At baseline, the mean ± SD physical func- PRO assessments were completed (by the child or their par- tion mobility T-score was 45.2 ± 9.05 for burosumab and ent/guardian) for all participants aged ≥ 5 years at screening, 45.5 ± 9.86 for continued conventional therapy, similar to the which included 15/29 patients in the burosumab group and mean of 50 of the calibration sample [14]. Twelve of the 35 20/32 patients in the conventional therapy group. Baseline patients (34%) had impaired physical function indicated by assessments occurred at randomization for all participants physical function mobility scores ≥ 1 SD lower (worse) than after a 7-day washout period from prior conventional ther- the calibration sample average (Fig. 1b). Physical function apy. Baseline characteristics for all participants (patients mobility score increased numerically from baseline in the aged 1–12 years at screening) and those aged ≥ 5 years at burosumab group (LS mean [SE]: + 2.78 [1.336] at week screening are presented in Table 1. Overall, baseline charac- 40 and + 2.82 [1.648] at week 64), indicating improved teristics were similar between the two age cohorts; however, physical function mobility, but showed little change in serum 1,25(OH) D concentration was lower in the cohort the continued conventional therapy group (+ 0.10 [0.966] aged ≥ 5 years than in the total patient group (mean ± SD: at week 40 and + 0.92 [0.962] at week 64). Neither group 91 ± 36 vs 103 ± 43 pmol/L, respectively), particularly in the had achieved a meaningful change from baseline based on burosumab group (96 ± 38 vs 110 ± 48 pmol/L) (Table 1). a 3-point MID. Differences between treatment groups were Patients aged ≥ 5 years had received conventional therapy not statistically significant at either week 40 (+ 2.68, 95% for a mean of 5.54 years. CI − 0.52 to + 5.89; p = 0.1009) or week 64 (+ 1.90, 95% CI − 1.80 to + 5.59; p = 0.3145) (Fig. 2b). Descriptive item- PROMIS Pain Interference level results at baseline and week 64 can be found in the appendix (Online Resource, Table 3). Higher scores on the pain interference domain reflect pain having a greater impact on daily activities, with decreases in PROMIS Fatigue scores reflecting improvements in this domain. At baseline, the mean ± SD pain interference T-score was 53.1 ± 10.95 Higher scores on the PROMIS fatigue domain reflect for burosumab and 49.9 ± 12.02 for continued conventional greater levels of fatigue, with decreases in scores reflecting therapy, broadly comparable to the mean of the calibration improvements in this domain. At baseline, the mean ± SD sample of 50 [14]. Eight of the 35 patients (23%) had pain fatigue T-score was 48.8 ± 9.60 for burosumab and interference scores ≥ 1 SD higher (worse) than the cali- 47.0 ± 13.70 for continued conventional therapy, similar to bration sample average (Fig.  1a). Pain interference score the mean of 50 of the calibration sample [14]. Seven of the decreased from baseline in the burosumab group (least- 35 patients (20%) had fatigue scores at least 1 SD higher squares [LS] mean [SE] change: − 5.31 [1.705] at week 40 (worse) than the calibration sample average (Fig.  1c). 1 3 626 R. Padidela et al. Table 1 Patient demographic and baseline characteristics for participants ≥ 5 years at screening and for all patients (aged 1–12 years) Characteristic Patients aged ≥ 5 years at screening All patients Burosumab Conventional Total (n = 35) Burosumab Conventional Total (n = 61) (n = 15) therapy (n = 20) (n = 29) therapy (n = 32) Age, years, Mean (SD) 8.6 (2.4) 8.4 (2.2) 8.5 (2.2) 5.8 (3.4) 6.3 (3.2) 6.3 (3.3) Sex, n (%) Boys 10 (66.7) 9 (45.0) 54.3) 13 (44.8) 14 (43.8) 27 (44.3) Girls 5 (33.3) 11 (55.0) 16 (45.7) 16 (55.2) 18 (56.3) 34 (55.7) Ethnic origin, n (%) White 12 (80.0) 14 (70.0) 26 (74.3) 25 (86.2) 25 (78.1) 50 (82.0) Asian 1 (6.7) 5 (25.0) 6 (17.1) 2 (6.9) 6 (18.8) 8 (13.1) Other 1 (13.3) 1 (5.0) 3 (8.6) 2 (6.9) 1 (3.1) 3 (4.9) Geographic region, n (%) Japan 1 (6.7) 3 (15.0) 4 (11.4) 2 (6.9) 3 (9.4) 5 (8.2) ROW 14(93.3) 17(85.0) 31 (88.6) 27 (93.1) 28 (90.6) 56 (91.8) TmP/GFR, mmol/L Mean (SD) 0.67 (0.12) 0.66 (0.11) 0.67 (0.11) 0.65 (0.11) 0.71 (0.12) 0.68 (0.12) Height Z score Mean (SD) − 2.4 (1.2) − 1.9 (0.8) − 2.1 (1.0) − 2.3 (1.2) − 2.1 (0.9) − 2.2 (1.0) Median (min, max) − 2.0 (− 5.0, − 0.5) − 2.1 (− 3.1, − 0.1) − 2.0 (− 5.0, − 0.1) − 2.3 (− 3.1, − 1.5) − 2.1 (− 2.5, − 1.4) − 2.2 (− 5.0, − 0.1) Weight, Z score Mean (SD) − 1.0 (1.4) − 0.4 (0.8) − 0.9 (1.2) − 0.9 (1.2) − 0.6 (0.9) − 0.8 (1.0) Median (min, max) − 0.8 (− 3.2, 1.3) − 0.6 (− 1.6, 1.5) − 0.8 (− 3.2, 1.4) − 0.8 (− 3.2, 1.4) − 0.7 (− 2.3, 1.5) − 0 8 (− 3.2, 1.5) Serum phosphorus concentration, mmol/L Mean (SD) 0.75 (0.07) 0.73 (0.09) 0.74 (0.08) 0.78 (0.08) 0.74 (0.08) 0.76 (0.08) Serum 1,25(OH)2D concentration, pmol/L Mean (SD) 96 (38) 89 (36) 91 (36) 110 (48) 96 (36) 103 (43) Alkaline phos- phatase concen- tration, U/L Mean (SD) 493.3 (146.4) 516.8 (168.1) 506.7 (157.3) 510.8 (124.9) 523.4 (154.4) 517.4 (140.2) Total Thacher RSS Mean (SD) 3.1 (0.8) 3.0 (0.9) 3.0 (0.8) 3.2 (1.0) 3.2 (1.1) 3.2 (1.1) Median (min, max) 3.0 (2.0, 5.0) 3.0 (2.0, 4.5) 3.0 (2.0, 5.0) 3.0 (2.5, 4.0) 3.0 (2.5, 3.5) 3.0 (2.0, 6.5) Max maximum, min minimum, ROW rest of world, RSS Rickets Severity Score, SD standard deviation, TmP/GFR tubular maximum for phos- phate reabsorption per glomerular filtration rate Fatigue scores decreased from baseline to weeks 40 and burosumab group at weeks 40 and 64, based on a 3-point 64 in burosumab-treated patients (LS mean [SE], − 4.29 MID. There was no meaningful change for the conven- [1.709] at week 40 and − 3.65 [2.119] at week 64), reflect- tional therapy group at weeks 40 or 64. Between-group ing reduced levels of fatigue, but showed little change in differences did not reach statistical significance at either those continuing to receive conventional therapy (LS mean week 40 (− 3.25, 95% CI − 7.86 to + 1.37; p = 0.1676) or [SE], − 1.05 [1.754] at week 40 and − 2.57 [1.547] at week week 64 (− 1.08, 95% CI − 6.21 to + 4.06; p = 0.6810) 64). Meaningful change from baseline was achieved for the (Fig.  2c). Descriptive item-level results at baseline and 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 627 Fig. 1 Baseline PROMIS (a) pain interference, (b) physi- cal function mobility, and (c) fatigue scores for patients aged ≥ 5 years (n = 35). Data show standardized PROMIS T-scores; higher T-scores indicate more pain interference, better function mobility, and worse fatigue. Reference lines at ± 1 SD of the mean are based on a population mean of 50 and SD of 10. PROMIS Patient- Reported Outcomes Measure- ment Information System, SD standard deviation week 64 can be found in the appendix (Online Resource, between the burosumab and continued conventional therapy Table 3). groups did not meet statistical significance at either week 40 (+ 4.33 [2.82]) or week 64 (+ 5.49 [2.91]). There were SF‑10 Health Survey for Children no statistically significant changes in LS mean (SE) PSS-10 scores from baseline to weeks 40 or 64 for either burosumab The trial population had baseline scores below the 25th (+ 1.53 [1.52] and + 0.94 [1.176], respectively) or contin- percentile for PHS-10 (mean [SD] score; 40.47 [13.14] ued conventional therapy (− 0.66 [1.38] and + 1.44 [1.21], total population, 40.03 [10.07] burosumab, 40.74 [15.30] respectively), with no significant differences between the conventional therapy) and below the 50th percentile for two treatment groups (LS mean difference [SE]: + 2.19 PSS-10 (mean [SD] score; 51.92 [9.42] total population, [2.10] at week 40; − 0.50 [2.12] at week 64) (Fig. 4b). 50.76 [9.65] burosumab, 52.79 [9.40] conventional therapy) (Fig. 3). Patients receiving burosumab showed significant Faces Pain Scale—Revised improvements in LS mean (SE) PHS-10 scores from base- line at both week 40 (+ 5.98 [1.79]; p = 0.0008) and week Most children in both treatment groups reported no pain 64 (+ 5.93 [1.88]; p = 0.0016) (Fig. 4a). By contrast, there at baseline, week 40, or week 64 according to the FPS-R. were no statistically significant changes from baseline in Median FPS-R scores were 0 at all time points for both the conventional therapy group at week 40 (+ 1.65 [2.17]) groups, and there were no significant differences between or week 64 (+ 0.44 [2.22]). The LS mean (SE) differences groups (p = 0.8786). 1 3 628 R. Padidela et al. Fig. 2 Change from baseline in PROMIS (a) pain interference, (b) physical function mobil- ity, and (c) fatigue scores for patients aged ≥ 5 years (n = 35). Data are expressed as LS mean (standard error). *p < 0.05 for LS mean change at week 40 (burosumab–conventional therapy). Indicates the mean change is ≥ 3-point MID from baseline. LS least-squares, MID minimally important difference, PROMIS Patient-Reported Out- comes Measurement Informa- tion System Fig. 3 Baseline SF-10 Health Survey for Children (a) PHS-10 and (b) PSS-10 for patients aged ≥ 5 years (n = 35). P.25, P.50, and P.75 are the 25th, 50th, and 75th percentiles from the general population. Higher global scores indicate better HRQoL. HRQoL health-related quality of life, PHS-10 physical health score, PSS-10 psychoso- cial health score, SF-10 Short Form-10 Subgroup Analyses (n = 39); sex: male (n = 27), female (n = 34). Data by region (Japan [n = 5], rest of world [n = 56]) and PHEX status Treatment effect heterogeneity was assessed for the trial pop- (clearly pathogenic PHEX variant [n = 55], or PHEX variants that were likely pathogenic/variant of unknown significance ulation in predefined subgroups: RSS: ≤ 2.5 (n = 22), > 2.5 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 629 Fig. 4 Changes from baseline to weeks 40 and 64 for SF-10 Health Survey for Children (a) PHS-10 and (b) PSS-10 for all patients aged ≥ 5 years (n = 35). Data are expressed as LS mean ± standard error. *p < 0.01 for change from baseline to week 64; **p < 0.001 for change from baseline to week 40. LS least-squares, PHS-10 physical health score, PSS-10 psychoso- cial health score, SF-10 Short Form-10 [n = 6]) were removed from this analysis because of the for other lifetime diseases that start in childhood, such as imbalance in patient numbers in these groups. No statis- sickle cell disease, Crohn disease, juvenile arthritis, juvenile tically significant interactions (p < 0.05) were identified dermatomyositis, chronic kidney disease, or systemic lupus among the five PRO domains for the RSS and sex subgroup erythematosus [20–27]. categories. Baseline SF-10 scores indicate impaired HRQoL in the present trial population, especially with regard to physical health, with lower baseline PHS-10 scores (mean score, Discussion 40.03) than those seen in children with asthma, attention- deficit hyperactivity disorder, depression, or learning dis- Children with XLH whose PRO scores indicate pain inter- abilities (mean range, 43.83–48.23) [12]. However, SF-10 ference, fatigue, physical function mobility impairment, and is a caregiver-completed questionnaire, which may under- reduced HRQoL despite conventional therapy would benefit estimate the child’s health and well-being [28]. The FPS-R from a disease-modifying treatment that alleviates the dis- tool is validated to assess current pain, though it has not order’s long-term physical and psychosocial complications been psychometrically validated specifically in children with [4]. Our phase 3 CL301 trial demonstrated that burosumab XLH. At all study visits, the XLH patients indicated no pain, results in greater improvement in phosphorus homeostasis, suggesting that the FPS-R assessment of current pain at rest growth, lower-extremity deformities, and healing of rickets may not reliably assess the burden of pain severity in this in children with XLH compared with continuing conven- population. tional therapy [9]. In the present analyses, we determined In patients who received burosumab, the decrease from the impact of switching from conventional therapy to buro- baseline in pain interference was significantly greater than sumab treatment compared to continuing conventional ther- in those who continued conventional therapy, although only apy on PROs of pain interference, physical function mobil- up to week 40. The improvement with burosumab was not ity, fatigue, and HRQoL. fully sustained from week 40 to week 64 but did not return Baseline PROMIS pain interference, physical function to baseline levels. The lack of a persistent benefit with buro- mobility, and fatigue scores were similar to the PROMIS sumab up to week 64 may be explained by small patient calibration sample, which included 4,129 children primar- numbers and possible increased activity-related pain for ily from hospital-based general pediatric and subspecialty patients who had received early benefit from burosumab. clinics. In this sample, 35% of children had consulted a cli- Furthermore, pain and its associated impact in XLH is com- nician for a chronic illness diagnosis or treatment within plex and multifactorial [1, 4], and expected improvements 6 months, and 9% had two or more chronic illnesses [14]. in bone health with burosumab may not be sufficient to fully Baseline PROMIS pain interference, physical function address all aspects of pain syndrome over a short period of mobility, and fatigue scores were similar to those reported time. 1 3 630 R. Padidela et al. Improvements from baseline in the PROMIS physical or the degree of expected improvement with treatment for function mobility and fatigue domains were also achieved those with lower RSS scores is not known. This trial only with burosumab versus conventional therapy, although the randomized treatment for 64 weeks, while XLH is a lifelong die ff rences between groups were not statistically signic fi ant. chronic disease. Further follow-up is warranted to determine Patients receiving burosumab did have clinically meaning- longer-term effects on HRQoL and patient-reported pain ful changes (based on 3-point MIDs) in two of the three interference, physical function mobility, and fatigue. Fur- PROMIS domains (pain interference and fatigue) by week thermore, compared with the prior clinical standard of care, 40, which were maintained at week 64. Burosumab also sig- children on conventional treatment in this trial were perhaps nificantly improved the physical health domain (PHS-10) more meticulously monitored and managed, because of the by approximately 10% at week 40, which was maintained frequent visits and rigorous trial requirements. High levels at week 64. In patients receiving conventional therapy, of compliance and adherence to conventional treatment in changes in physical health from baseline were not seen; dif- clinical trial settings can result in greater improvements in ferences between treatment groups did not reach statistical outcomes with conventional therapy than that seen in routine significance, although the trial was not powered to show standard of care [34–37]. differences in these endpoints. There were no statistically In conclusion, in this phase 3 trial, changing from con- significant interactions among the five PRO domains for the ventional therapy to burosumab was associated with numeri- predefined subgroup categories investigated (RSS and sex). cal increases in PROMIS physical function mobility, clini- Improvements in PROs are reflected by mobility data cally meaningful reductions in PROMIS pain interference from the 6-min walk test reported in the primary manuscript and fatigue up to 64 weeks, and a statistically significant [9]. These data showed that patients randomized to buro- reduction in PROMIS pain interference up to 40 weeks. Sta- sumab had significantly greater improvements from baseline tistically significant improvements in SF-10 PHS-10 were in percent predicted distance walked over 6 min than those observed up to 64 weeks from baseline in children aged continuing to receive conventional therapy at week 64 (LS 5–12 years with XLH. mean change from baseline 9% vs 2%; 95% CI 0.01–14.52; Acknowledgements We thank the clinical nurse coordinators at our p = 0.0496) [9]. sites, who ensured that the questionnaires were completed by patients Improvements in pain interference, physical function or their caregivers. Medical writing and editorial support were provided mobility, fatigue, and HRQoL may be explained by the by OPEN Health Medical Communications, with funding provided by Kyowa Kirin International. LMW is supported by a University of mechanism of action of burosumab. Burosumab addresses Ottawa Research Chair Award. the deficiency of serum phosphate by directly binding to FGF23 and inhibiting its signaling, increasing tubular phos- Author Contributions RP, MPW, FHG, CFM, LMW, ON, AAP, JHS, phate reabsorption, as well as increasing serum 1,25(OH) D NN, HIC, PP, ES, WH, KM, HT, GSG, AB, FP, AC, AS, and EAI were levels and increasing gastrointestinal phosphate absorption involved in the trial design and data collection. AC accepts responsibil- [29]. Increased serum phosphate levels result in improved ity for the integrity of the trial data analysis. WS conducted exploratory subgroup analyses, and AN conducted PROMIS item-level and change bone mineralization [29], improved muscular function [30], score correlation analysis. AN and AW drafted the initial manuscript, and restoration of ATP synthesis [31–33], and thus ulti- with support from OPEN Health Medical Communications. All authors mately may manifest as improvements in patient-reported were involved in critically reviewing and revising the manuscript and symptoms, function, and HRQoL. providing final approval of the submitted version. In relation to PRO measurements, this trial has several Funding This study was funded by Kyowa Kirin International. limitations. Our trial was not powered to assess between- group differences for secondary and exploratory outcomes, Data Availability The corresponding author had full access to all the such as PROs, nor for subgroup analyses. For example, data in the study. sample size was insufficient to explore whether higher phosphate concentration or rapidity of correction of alka- Compliance with Ethical Standards line phosphatase reflected PRO measurements. Therefore, it remains unknown whether mid-range serum phosphate Conflict of interest The following authors served as clinical investi- gators for one or more studies, including this trial, sponsored by Ul- levels improve PROs to a greater extent than low-normal tragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin Inter- values. Children aged younger than 1 year or older than national plc: RP, MPW, FHG, CFM, LMW, ON, AAP, JHS, NN, HIC, 12  years were not recruited, and children younger than PP, ES, WH, KM, HT, GSG, AB, FP, and EAI. AAP, NN, FP, and EAI 5 years did not complete PROs, precluding extrapolation of have also received honoraria for serving as advisory board members or for lectures from Ultragenyx Pharmaceutical Inc. RP has received results to these age groups and limiting the sample size to 15 personal fees from Ultragenyx Pharmaceutical Inc. and Kyowa Kirin patients in the burosumab group and 20 patients in the con- International plc, a research grant, consultation fees, honoraria, and ventional therapy group. Further, only those with RSS ≥ 2 travel grants from Kyowa Kirin International plc and Alexion UK, were enrolled in this trial; thus, the baseline PRO scores 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 631 and non-financial support from Kyowa Kirin International plc. MPW 5. Collins M (2018) Burosumab: at long last, an effective treatment has received research grant support, honoraria, and travel from Alex- for FGF23-associated hypophosphatemia. J Bone Miner Res ion Pharmaceutical Inc. FHG has received personal fees from Kyowa 33:1381–1382. https ://doi.org/10.1002/jbmr.3544 Kirin International plc and research funding from Amgen and Mereo 6. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, BioPharma. LMW has served as a consultant to Ultragenyx, with Wooddell MM, Kawakami T, Ito T, Zhang Z, Humphrey J, funds to LMW’s institution. NN has received personal fees and non- Insogna KL, Peacock M (2014) Randomized trial of the anti- financial support from Kyowa Kirin International plc and Ultragenyx FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Pharmaceutical Inc. during the conduct of the study, and personal fees Invest 124:1587–1597. https ://doi.org/10.1172/JCI72 829 and non-financial support (honoraria, consulting fees, and travel sup- 7. Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, port) from Alexion UK outside the submitted work. PP has received Vergeire M, Humphrey JS, Glorieux FH, Portale AA, Insogna K, research funding from Ultragenyx Pharmaceutical Inc. and is currently Peacock M, Carpenter TO (2015) Prolonged correction of serum an employee of Ascendis Pharma Inc. WH has received honoraria, phosphorus in adults with X-linked hypophosphatemia using consulting fees, and travel support from Ultragenyx Pharmaceutical monthly doses of KRN23. J Clin Endocrinol Metab 100:2565– Inc. and research funding, honoraria, and travel support from Kyowa 2573. https ://doi.org/10.1210/jc.2015-1551 Kirin. GSG has received consulting fees from Ultragenyx Pharmaceu- 8. Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart tical Inc. AW and WS are employees of Kyowa Kirin International plc. A, Padidela R, Van’t Hoff W, Mao M, Chen C-Y, Skrinar A, AN is an employee of Chilli Consultancy and has received consultancy Kakkis E, San Martin J, Portale AA (2018) Burosumab therapy fees from Kyowa Kirin International plc to support the development of in children with X-linked hypophosphatemia. N Engl J Med this manuscript. AC and AS are employees and stockholders of Ultrag- 378:1987–1998. https ://doi.org/10.1056/NEJMo a1714 641 enyx Pharmaceutical Inc. 9. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukchee- Human and Animal Rights and Informed Consent The study was con- wanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman ducted in accordance with the Declaration of Helsinki and the Good GS, Biggin A, Perwad F, Mao M, Chen C-Y, Skrinar A, San Mar- Clinical Practice guidelines developed at the International Conference tin J, Portale AA (2019) Burosumab versus conventional therapy on Harmonization of Technical Requirements for Registration of Phar- in children with X-linked hypophosphataemia: a randomised, maceuticals for Human Use. Parents or guardians provided written active-controlled, open-label, phase 3 trial. Lancet 393:2416– informed consent for their children to participate, and children gave 2427. https ://doi.org/10.1016/S0140 -6736(19)30654 -3 written assent according to local guidelines. 10. 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Arthri- tis Care Res (Hoboken) 69:133–142. https ://doi.or g/10.1002/ acr.22927 Authors and Affiliations 1,2 3 4 5,6 7,8 Raja Padidela  · Michael P. Whyte  · Francis H. Glorieux  · Craig F. Munns  · Leanne M. Ward  · 9,10 11 12 13,14 15 Ola Nilsson  · Anthony A. Portale  · Jill H. Simmons  · Noriyuki Namba  · Hae Il Cheong  · 16 17 18,19 20 21 Pisit Pitukcheewanont  · Etienne Sochett  · Wolfgang Högler  · Koji Muroya  · Hiroyuki Tanaka  · 22 5 11 23 24 25 Gary S. Gottesman  · Andrew Biggin  · Farzana Perwad  · Angela Williams  · Annabel Nixon  · Wei Sun  · 26 26 27 Angel Chen  · Alison Skrinar  · Erik A. Imel 1 3 Department of Paediatric Endocrinology, Royal Manchester Shriners Hospitals for Children —Washington University Children’s Hospital, Manchester, UK School of Medicine in St Louis, St Louis, MO, USA 2 4 Faculty of Biology, Medicine and Health, University Shriners Hospital for Children — Canada, McGill University, of Manchester, Manchester, UK Montreal, QC, Canada 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 633 5 16 The University of Sydney Children’s Hospital Westmead Center of Endocrinology, Diabetes and Metabolism, Clinical School, The Children’s Hospital at Westmead, Children’s Hospital Los Angeles, Los Angeles, CA, USA Westmead, NSW, Australia Department of Paediatrics, Hospital for Sick Children, Department of Endocrinology, The Children’s Hospital Toronto, ON, Canada at Westmead, Westmead, NSW, Australia Department of Paediatrics and Adolescent Medicine, Department of Pediatrics, University of Ottawa, Ottawa, ON, Johannes Kepler University Linz, Linz, Austria Canada Institute of Metabolism and Systems Research, University Division of Endocrinology and Metabolism, Children’s of Birmingham, Birmingham, UK Hospital of Eastern Ontario, Ottawa, ON, Canada Department of Endocrinology and Metabolism, Kanagawa Division of Pediatric Endocrinology & Center for Molecular Children’s Medical Center, Yokohama, Japan Medicine, Karolinska Institute, Stockholm, Sweden Okayama Saiseikai General Hospital Outpatient Center, School of Medical Sciences, Örebro University, Örebro, Okayama, Japan Sweden Shriners Hospitals for Children, St Louis, MO, USA Department of Pediatrics, University of California, San Kyowa Kirin International, Marlow, UK Francisco, San Francisco, CA, USA Chilli Consultancy, Salisbury, UK Departments of Pediatrics, Division of Endocrinology and Diabetes, Vanderbilt University School of Medicine, Kyowa Kirin Pharmaceutical Development, Princeton, NJ, Vanderbilt University, Nashville, TN, USA USA 13 26 Department of Pediatrics, Osaka Hospital, Japan Community Ultragenyx Pharmaceutical, Novato, CA, USA Healthcare Organization, Osaka, Japan Department of Medicine and Department of Pediatrics, Department of Pediatrics, Osaka University Graduate School Indiana University School of Medicine, Indianapolis, IN, of Medicine, Osaka, Japan USA Seoul National University Children’s Hospital, Seoul, Republic of Korea 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Calcified Tissue International Springer Journals

Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia

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10.1007/s00223-020-00797-x
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Abstract

Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vita- min D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1–12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient- Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (− 5.02, 95% CI − 9.29 to − 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline. Trial registration: ClinicalTrials.gov NCT02915705 Keywords Burosumab · X-linked hypophosphatemia · Patient-reported outcomes · Patient-reported outcomes measurement information system Introduction X-linked hypophosphatemia (XLH) is a rare, heritable, life- long phosphate-wasting disease. Loss-of-function mutations in the PHEX (phosphate-regulating endopeptidase homo- Supplementary information The online version of this article logue, X-linked) gene result in characteristic elevation of (https ://doi.org/10.1007/s0022 3-020-00797 -x) contains circulating fibroblast growth factor 23 (FGF23) levels, lead - supplementary material, which is available to authorized users. ing to reduced renal phosphate reabsorption and decreased production of active vitamin D (1,25[OH] D) manifesting as * Raja Padidela [email protected] chronic hypophosphatemia and impaired mineralization of bones and teeth, as well as muscle weakness [1, 2]. Extended author information available on the last page of the article Vol:.(1234567890) 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 623 XLH typically manifests in early childhood as rickets, Here, we present the PRO results from the phase 3 pediat- skeletal deformities, short stature, and in some children with ric trial, specifically the endpoints of PROMIS pain interfer - dental abscesses [1–4]. Untreated or inadequately treated ence, physical function mobility, and fatigue; health-related children commonly suffer impaired mobility and physical quality of life (HRQoL) according to SF-10; and pain inten- function, such as delayed walking, unusual gait, muscle sity according to FPS-R. We also conducted a subgroup weakness, bone, joint, and muscle pain, and emotional and analysis to investigate whether PRO scores varied with social challenges [2–4]. Short stature acquired in childhood rickets severity, sex, geographic region, or PHEX disease- and skeletal deformities are irreversible, without surgery, causing variant. after completion of growth. Elevated circulating FGF23 and hypophosphatemia persist into adulthood; adults often develop pseudofractures, fractures, enthesopathies, hyper- Subjects and Methods parathyroidism, and early-onset osteoarthritis, and suffer increasing pain, stiffness, and loss of physical function [3 ]. This open-label, randomized, active-controlled, phase 3 For the past 40  years, therapy for XLH has primarily trial was conducted at 16 international sites with experience consisted of multiple daily doses of oral phosphate supple- treating XLH. The institutional review board at each partici- mentation with active vitamin D (calcitriol or alfacalcidol; pating center approved the protocol. The trial was conducted “conventional therapy”). Oral phosphate preparations can be in accordance with the Declaration of Helsinki and the Good unpalatable and can cause gastrointestinal symptoms, and Clinical Practice guidelines developed at the International the frequent dosing regimen is burdensome for patients and Conference on Harmonization of Technical Requirements their caregivers [2, 3, 5]. Furthermore, regular monitoring for Registration of Pharmaceuticals for Human Use. Trial and appropriate dose adjustments are needed to minimize design details have been published previously [9] and are the risk of complications of conventional therapy including only briefly described here. nephrocalcinosis and hyperparathyroidism [1–3, 5]. Eligibility criteria for this trial were as follows: age Burosumab is a fully human monoclonal antibody (IgG1) 1–12 years when informed consent was obtained; confirmed that binds to FGF23 and inhibits its activity [6, 7]. The effi- diagnosis of XLH according to fasting serum phospho- cacy of burosumab in pediatric XLH has been demonstrated rus < 0.97 mmol/L (3.0 mg/dL); a confirmed PHEX disease- by increasing the levels of serum phosphorus in two phase causing variant or a variant of unknown significance in the 2 studies (UX023-CL201, NCT02163577; UX023-CL205, patient, or in a directly related family member with appropri- NCT02750618), as well as in children with rickets (rick- ate X-linked dominant inheritance; radiographic evidence of ets severity score [RSS] ≥ 2.0) in the randomized phase 3 rickets in the wrist and/or knee; a total Thacher RSS ≥ 2.0; trial of burosumab versus continued conventional therapy and prior treatment with conventional therapy for ≥ 6 con- (UX023-CL301, NCT02915705). These trials demonstrated secutive months (children aged < 3 years) or ≥ 12 consecu- improvement in clinical outcomes, including rickets, lower- tive months (children aged ≥ 3 years) up until enrollment. limb deformities, and mobility, as assessed by the 6-min Parents or guardians provided written informed consent walk test, with the CL301 trial demonstrating superiority of for their children to participate, and children gave written changing to burosumab over continuation of conventional assent according to local guidelines. Patients were randomly therapy [2, 8, 9]. assigned (1:1) to receive subcutaneous burosumab (starting In addition to clinical outcomes, patient-reported out- dose 0.8 mg/kg every 2 weeks) or continue conventional come (PRO) data were collected in the phase 3 pediatric trial therapy with oral phosphate and active vitamin D, the doses using Patient-Reported Outcomes Measurement Information of which were titrated and individualized based on published System (PROMIS) instruments, the Short Form-10 (SF-10) recommendations [1, 6]. Patients received study medication Health Survey for Children, and the Faces Pain Scale— for up to 64 weeks. PRO instruments were completed at Revised (FPS-R) to quantify the impairment and compare baseline and at weeks 24, 40, and 64. their evolution on burosumab versus continued conventional therapy. Pain is prevalent in pediatric patients with XLH Patient‑Reported Outcome Assessments and is most frequently observed in the lower limbs, but also occurs in the back and hips [4]. Children with XLH often PROs were assessed using linguistically validated, approved have trouble performing age-appropriate gross motor activi- instruments during the trial for patients aged ≥ 5 years only ties, such as walking, running, and jumping, due to bowing at the screening visit. PROMIS is a set of measures devel- of the femur, tibia, and fibula, and tibial rotation that causes oped by the US National Institutes of Health to evaluate the feet to turn in towards each other. Gait disturbance is physical, mental, and social health [10, 11]. A fixed-length common in pediatric patients with XLH, reported in > 80% short-form PROMIS instrument comprising the pain inter- of children [4]. ference, physical function mobility, and fatigue domains 1 3 624 R. Padidela et al. was created by selecting items from the three pediatric item disorder [ADHD], arthritis, and gastrointestinal disorders) banks of PROMIS (version 2.0; Online Resource, Table 2). [14]. Higher scores on the PROMIS pain interference and Pain interference consisted of four items scored using five fatigue domains indicate greater detriment (i.e., worse pain response options indicating the frequency of pain interfer- and more fatigue), whereas a higher score on the PROMIS ence (“never,” “almost never,” “sometimes,” “often,” and physical function mobility domain indicates less detriment “almost always”); physical function mobility consisted of 10 (i.e., better physical function mobility). items scored using five response options to indicate sever - Overall HRQoL was assessed using the SF-10 Health ity (“with no trouble,” “with a little trouble,” “with some Survey for Children, a validated 10-item, caregiver-com- trouble,” “with a lot of trouble,” and “not able to do”); and pleted questionnaire designed to assess physical and psy- fatigue consisted of eight items scored using five response chosocial HRQoL in healthy and ill children. Each ques- options indicating the severity (“never,” “almost never,” tion has five response options (“Excellent,” “Very good,” “sometimes,” “often,” and “almost always”). “Good,” “Fair,” and “Poor”) with a recall period of the past Items were selected using information from qualitative 4 weeks. Responses were used to generate two component interviews of five children with XLH aged 8–12 years and summary scores: physical health score (PHS-10) and psy- their parents: one parent of an 8-year-old child with XLH chosocial health score (PSS-10), scored according to pub- and four parents of children with XLH aged 5–7 years. Item lished methods [15]. The scale was scored so that a score appropriateness was based on evidence from the concept of 50 corresponds to the average score in a 2006 sample, elicitation, conceptual mapping, and cognitive debriefing which comprised a combination of children from the general exercises conducted as part of the qualitative interviews. population and a supplemental sample with disability and The pain interference, physical function mobility, and chronic conditions; higher global scores are associated with fatigue items were well understood and found to be rel- better HRQoL. evant and appropriate assessments of those concepts for The FPS-R was used to assess current pain at each study the children and their parents. These qualitative data there- visit. The self-reported scale uses graphical facial repre- fore established content validity of the selected PROMIS sentations of pain to allow self-reporting of current pain domains. An analysis of the psychometric properties of the intensity at rest (not during or immediately after physical PROMIS instrument (both the self-reported form for chil- activity) on a 0–10 scale (0 = no hurt to 10 = hurts worst; dren aged ≥ 8 years and the parent proxy report form for even numbers only) and has been validated in children aged children aged 5 to < 8 years) consisting of the three domains 5–16 years [16]. in the current trial (n = 35; children aged 5–12 years) con- firmed it to be a reliable, valid, and responsive method for Statistical Analysis use in clinical trials in children with XLH [12]. The PROMIS domains were each measured at study The primary endpoint for this trial, namely change in rickets assessment visits using a recall period of the previous severity from baseline to week 40, has been reported previ- 7  days. Children aged ≥ 8  years at screening completed ously [9]. Changes from baseline in PROMIS scores were a self-reported PROMIS instrument. For children aged 5 assessed as secondary endpoints, and changes from baseline to < 8 years at screening, the parent or legal guardian com- in SF-10 PHS-10 and PSS-10 were assessed as exploratory pleted the parent proxy version of the PROMIS instrument endpoints. Here, we report data for changes to week 64 to throughout the trial. PROMIS data were uploaded to the provide longer-term information on XLH in children. SAS® PROMIS online scoring system [13] to obtain the final software version 9.4 or higher (SAS Institute, Cary, NC, scores for each domain. All raw scores generated from USA) was used for statistical analyses. the PROMIS instrument were translated into standardized PRO endpoints were analyzed using a generalized esti- scores (termed T-scores), based on a calibration sample mating equation repeated-measures analysis. Treatment, resulting in a calibration population mean of 50 and stand- visit, and interaction of treatment-by-visit were included as ard deviation (SD) of 10. The calibration sample consisted categorical variables, and baseline measures and baseline of a US cohort of 4,129 children aged 8–17 years, with 55% total RSS stratification factor were included as independent aged 8–12 years. The majority of children in the calibration variables in the model. Total RSS was used in this model, as sample (94%) were recruited from hospital-based general it has been validated in 52 children with XLH, with higher pediatric and subspecialty clinics, with 6% from school set- total RSS associated with greater impairment in walking tings; 35% had consulted a clinician for a chronic illness ability as assessed by the 6-min walk test [17]. Data for diagnosis or treatment within 6 months, and 9% had two model-based estimates of the changes from baseline, stand- or more chronic illnesses (the most common chronic con- ard error (SE), and corresponding 95% confidence intervals ditions were asthma, affecting 18% of children, followed (CIs) were assessed for significance at the 5% level. Missing by attention-deficit disorder/attention-deficit hyperactivity data were treated as missing for all analyses. Only data for 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 625 patients with a baseline measurement and at least one post- and − 3.55 [1.873] at week 64), indicating reduced levels baseline measurement were included in analyses of change of pain interference, but changed little in the group who from baseline. continued to receive conventional therapy (− 0.29 [1.539] As the trial was not powered to assess differences in at week 40 and − 1.29 [1.267] at week 64). The change in between-group changes beyond the primary endpoint, pain interference score exceeded the 3-point MID threshold within-group changes from baseline were reported for in patients receiving burosumab at both weeks 40 and 64, variables with nonsignificant between-group differences. A consistent with a clinically meaningful reduction in pain change of 2–3 points is considered clinically meaningful for interference for this group. The change from baseline in the PROMIS pediatric scales [18]. To interpret within-group group continuing conventional therapy was less than the trial results, clinically relevant differences were explored 3-point MID threshold. Burosumab was associated with a based on a minimally important difference (MID) threshold significantly greater change from baseline than conventional of 3 points [19]. therapy at week 40 (between-group difference − 5.02, 95% In an exploratory analysis, testing for treatment-by- CI − 9.29 to − 0.75; p = 0.0212) but not at week 64 (− 2.26, subgroup was used to detect treatment effect heterogeneity 95% CI − 6.61 to + 2.09; p = 0.3091) (Fig. 2a). Descriptive across four subgroups (RSS: ≤ 2.5, > 2.5; sex: male, female; item-level results at baseline and week 64 can be found in region: Japan, rest of world; PHEX status: clearly pathogenic the appendix (Online Resource, Table 3). PHEX variants, or likely pathogenic/variant of unknown sig- nificance) on the PRO domains using week 40 and week 64 PROMIS Physical Function Mobility data. Higher scores on the PROMIS physical function mobility domain indicate less detriment (i.e., better physical function Results mobility), with increases in scores reflecting improvements in this domain. At baseline, the mean ± SD physical func- PRO assessments were completed (by the child or their par- tion mobility T-score was 45.2 ± 9.05 for burosumab and ent/guardian) for all participants aged ≥ 5 years at screening, 45.5 ± 9.86 for continued conventional therapy, similar to the which included 15/29 patients in the burosumab group and mean of 50 of the calibration sample [14]. Twelve of the 35 20/32 patients in the conventional therapy group. Baseline patients (34%) had impaired physical function indicated by assessments occurred at randomization for all participants physical function mobility scores ≥ 1 SD lower (worse) than after a 7-day washout period from prior conventional ther- the calibration sample average (Fig. 1b). Physical function apy. Baseline characteristics for all participants (patients mobility score increased numerically from baseline in the aged 1–12 years at screening) and those aged ≥ 5 years at burosumab group (LS mean [SE]: + 2.78 [1.336] at week screening are presented in Table 1. Overall, baseline charac- 40 and + 2.82 [1.648] at week 64), indicating improved teristics were similar between the two age cohorts; however, physical function mobility, but showed little change in serum 1,25(OH) D concentration was lower in the cohort the continued conventional therapy group (+ 0.10 [0.966] aged ≥ 5 years than in the total patient group (mean ± SD: at week 40 and + 0.92 [0.962] at week 64). Neither group 91 ± 36 vs 103 ± 43 pmol/L, respectively), particularly in the had achieved a meaningful change from baseline based on burosumab group (96 ± 38 vs 110 ± 48 pmol/L) (Table 1). a 3-point MID. Differences between treatment groups were Patients aged ≥ 5 years had received conventional therapy not statistically significant at either week 40 (+ 2.68, 95% for a mean of 5.54 years. CI − 0.52 to + 5.89; p = 0.1009) or week 64 (+ 1.90, 95% CI − 1.80 to + 5.59; p = 0.3145) (Fig. 2b). Descriptive item- PROMIS Pain Interference level results at baseline and week 64 can be found in the appendix (Online Resource, Table 3). Higher scores on the pain interference domain reflect pain having a greater impact on daily activities, with decreases in PROMIS Fatigue scores reflecting improvements in this domain. At baseline, the mean ± SD pain interference T-score was 53.1 ± 10.95 Higher scores on the PROMIS fatigue domain reflect for burosumab and 49.9 ± 12.02 for continued conventional greater levels of fatigue, with decreases in scores reflecting therapy, broadly comparable to the mean of the calibration improvements in this domain. At baseline, the mean ± SD sample of 50 [14]. Eight of the 35 patients (23%) had pain fatigue T-score was 48.8 ± 9.60 for burosumab and interference scores ≥ 1 SD higher (worse) than the cali- 47.0 ± 13.70 for continued conventional therapy, similar to bration sample average (Fig.  1a). Pain interference score the mean of 50 of the calibration sample [14]. Seven of the decreased from baseline in the burosumab group (least- 35 patients (20%) had fatigue scores at least 1 SD higher squares [LS] mean [SE] change: − 5.31 [1.705] at week 40 (worse) than the calibration sample average (Fig.  1c). 1 3 626 R. Padidela et al. Table 1 Patient demographic and baseline characteristics for participants ≥ 5 years at screening and for all patients (aged 1–12 years) Characteristic Patients aged ≥ 5 years at screening All patients Burosumab Conventional Total (n = 35) Burosumab Conventional Total (n = 61) (n = 15) therapy (n = 20) (n = 29) therapy (n = 32) Age, years, Mean (SD) 8.6 (2.4) 8.4 (2.2) 8.5 (2.2) 5.8 (3.4) 6.3 (3.2) 6.3 (3.3) Sex, n (%) Boys 10 (66.7) 9 (45.0) 54.3) 13 (44.8) 14 (43.8) 27 (44.3) Girls 5 (33.3) 11 (55.0) 16 (45.7) 16 (55.2) 18 (56.3) 34 (55.7) Ethnic origin, n (%) White 12 (80.0) 14 (70.0) 26 (74.3) 25 (86.2) 25 (78.1) 50 (82.0) Asian 1 (6.7) 5 (25.0) 6 (17.1) 2 (6.9) 6 (18.8) 8 (13.1) Other 1 (13.3) 1 (5.0) 3 (8.6) 2 (6.9) 1 (3.1) 3 (4.9) Geographic region, n (%) Japan 1 (6.7) 3 (15.0) 4 (11.4) 2 (6.9) 3 (9.4) 5 (8.2) ROW 14(93.3) 17(85.0) 31 (88.6) 27 (93.1) 28 (90.6) 56 (91.8) TmP/GFR, mmol/L Mean (SD) 0.67 (0.12) 0.66 (0.11) 0.67 (0.11) 0.65 (0.11) 0.71 (0.12) 0.68 (0.12) Height Z score Mean (SD) − 2.4 (1.2) − 1.9 (0.8) − 2.1 (1.0) − 2.3 (1.2) − 2.1 (0.9) − 2.2 (1.0) Median (min, max) − 2.0 (− 5.0, − 0.5) − 2.1 (− 3.1, − 0.1) − 2.0 (− 5.0, − 0.1) − 2.3 (− 3.1, − 1.5) − 2.1 (− 2.5, − 1.4) − 2.2 (− 5.0, − 0.1) Weight, Z score Mean (SD) − 1.0 (1.4) − 0.4 (0.8) − 0.9 (1.2) − 0.9 (1.2) − 0.6 (0.9) − 0.8 (1.0) Median (min, max) − 0.8 (− 3.2, 1.3) − 0.6 (− 1.6, 1.5) − 0.8 (− 3.2, 1.4) − 0.8 (− 3.2, 1.4) − 0.7 (− 2.3, 1.5) − 0 8 (− 3.2, 1.5) Serum phosphorus concentration, mmol/L Mean (SD) 0.75 (0.07) 0.73 (0.09) 0.74 (0.08) 0.78 (0.08) 0.74 (0.08) 0.76 (0.08) Serum 1,25(OH)2D concentration, pmol/L Mean (SD) 96 (38) 89 (36) 91 (36) 110 (48) 96 (36) 103 (43) Alkaline phos- phatase concen- tration, U/L Mean (SD) 493.3 (146.4) 516.8 (168.1) 506.7 (157.3) 510.8 (124.9) 523.4 (154.4) 517.4 (140.2) Total Thacher RSS Mean (SD) 3.1 (0.8) 3.0 (0.9) 3.0 (0.8) 3.2 (1.0) 3.2 (1.1) 3.2 (1.1) Median (min, max) 3.0 (2.0, 5.0) 3.0 (2.0, 4.5) 3.0 (2.0, 5.0) 3.0 (2.5, 4.0) 3.0 (2.5, 3.5) 3.0 (2.0, 6.5) Max maximum, min minimum, ROW rest of world, RSS Rickets Severity Score, SD standard deviation, TmP/GFR tubular maximum for phos- phate reabsorption per glomerular filtration rate Fatigue scores decreased from baseline to weeks 40 and burosumab group at weeks 40 and 64, based on a 3-point 64 in burosumab-treated patients (LS mean [SE], − 4.29 MID. There was no meaningful change for the conven- [1.709] at week 40 and − 3.65 [2.119] at week 64), reflect- tional therapy group at weeks 40 or 64. Between-group ing reduced levels of fatigue, but showed little change in differences did not reach statistical significance at either those continuing to receive conventional therapy (LS mean week 40 (− 3.25, 95% CI − 7.86 to + 1.37; p = 0.1676) or [SE], − 1.05 [1.754] at week 40 and − 2.57 [1.547] at week week 64 (− 1.08, 95% CI − 6.21 to + 4.06; p = 0.6810) 64). Meaningful change from baseline was achieved for the (Fig.  2c). Descriptive item-level results at baseline and 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 627 Fig. 1 Baseline PROMIS (a) pain interference, (b) physi- cal function mobility, and (c) fatigue scores for patients aged ≥ 5 years (n = 35). Data show standardized PROMIS T-scores; higher T-scores indicate more pain interference, better function mobility, and worse fatigue. Reference lines at ± 1 SD of the mean are based on a population mean of 50 and SD of 10. PROMIS Patient- Reported Outcomes Measure- ment Information System, SD standard deviation week 64 can be found in the appendix (Online Resource, between the burosumab and continued conventional therapy Table 3). groups did not meet statistical significance at either week 40 (+ 4.33 [2.82]) or week 64 (+ 5.49 [2.91]). There were SF‑10 Health Survey for Children no statistically significant changes in LS mean (SE) PSS-10 scores from baseline to weeks 40 or 64 for either burosumab The trial population had baseline scores below the 25th (+ 1.53 [1.52] and + 0.94 [1.176], respectively) or contin- percentile for PHS-10 (mean [SD] score; 40.47 [13.14] ued conventional therapy (− 0.66 [1.38] and + 1.44 [1.21], total population, 40.03 [10.07] burosumab, 40.74 [15.30] respectively), with no significant differences between the conventional therapy) and below the 50th percentile for two treatment groups (LS mean difference [SE]: + 2.19 PSS-10 (mean [SD] score; 51.92 [9.42] total population, [2.10] at week 40; − 0.50 [2.12] at week 64) (Fig. 4b). 50.76 [9.65] burosumab, 52.79 [9.40] conventional therapy) (Fig. 3). Patients receiving burosumab showed significant Faces Pain Scale—Revised improvements in LS mean (SE) PHS-10 scores from base- line at both week 40 (+ 5.98 [1.79]; p = 0.0008) and week Most children in both treatment groups reported no pain 64 (+ 5.93 [1.88]; p = 0.0016) (Fig. 4a). By contrast, there at baseline, week 40, or week 64 according to the FPS-R. were no statistically significant changes from baseline in Median FPS-R scores were 0 at all time points for both the conventional therapy group at week 40 (+ 1.65 [2.17]) groups, and there were no significant differences between or week 64 (+ 0.44 [2.22]). The LS mean (SE) differences groups (p = 0.8786). 1 3 628 R. Padidela et al. Fig. 2 Change from baseline in PROMIS (a) pain interference, (b) physical function mobil- ity, and (c) fatigue scores for patients aged ≥ 5 years (n = 35). Data are expressed as LS mean (standard error). *p < 0.05 for LS mean change at week 40 (burosumab–conventional therapy). Indicates the mean change is ≥ 3-point MID from baseline. LS least-squares, MID minimally important difference, PROMIS Patient-Reported Out- comes Measurement Informa- tion System Fig. 3 Baseline SF-10 Health Survey for Children (a) PHS-10 and (b) PSS-10 for patients aged ≥ 5 years (n = 35). P.25, P.50, and P.75 are the 25th, 50th, and 75th percentiles from the general population. Higher global scores indicate better HRQoL. HRQoL health-related quality of life, PHS-10 physical health score, PSS-10 psychoso- cial health score, SF-10 Short Form-10 Subgroup Analyses (n = 39); sex: male (n = 27), female (n = 34). Data by region (Japan [n = 5], rest of world [n = 56]) and PHEX status Treatment effect heterogeneity was assessed for the trial pop- (clearly pathogenic PHEX variant [n = 55], or PHEX variants that were likely pathogenic/variant of unknown significance ulation in predefined subgroups: RSS: ≤ 2.5 (n = 22), > 2.5 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 629 Fig. 4 Changes from baseline to weeks 40 and 64 for SF-10 Health Survey for Children (a) PHS-10 and (b) PSS-10 for all patients aged ≥ 5 years (n = 35). Data are expressed as LS mean ± standard error. *p < 0.01 for change from baseline to week 64; **p < 0.001 for change from baseline to week 40. LS least-squares, PHS-10 physical health score, PSS-10 psychoso- cial health score, SF-10 Short Form-10 [n = 6]) were removed from this analysis because of the for other lifetime diseases that start in childhood, such as imbalance in patient numbers in these groups. No statis- sickle cell disease, Crohn disease, juvenile arthritis, juvenile tically significant interactions (p < 0.05) were identified dermatomyositis, chronic kidney disease, or systemic lupus among the five PRO domains for the RSS and sex subgroup erythematosus [20–27]. categories. Baseline SF-10 scores indicate impaired HRQoL in the present trial population, especially with regard to physical health, with lower baseline PHS-10 scores (mean score, Discussion 40.03) than those seen in children with asthma, attention- deficit hyperactivity disorder, depression, or learning dis- Children with XLH whose PRO scores indicate pain inter- abilities (mean range, 43.83–48.23) [12]. However, SF-10 ference, fatigue, physical function mobility impairment, and is a caregiver-completed questionnaire, which may under- reduced HRQoL despite conventional therapy would benefit estimate the child’s health and well-being [28]. The FPS-R from a disease-modifying treatment that alleviates the dis- tool is validated to assess current pain, though it has not order’s long-term physical and psychosocial complications been psychometrically validated specifically in children with [4]. Our phase 3 CL301 trial demonstrated that burosumab XLH. At all study visits, the XLH patients indicated no pain, results in greater improvement in phosphorus homeostasis, suggesting that the FPS-R assessment of current pain at rest growth, lower-extremity deformities, and healing of rickets may not reliably assess the burden of pain severity in this in children with XLH compared with continuing conven- population. tional therapy [9]. In the present analyses, we determined In patients who received burosumab, the decrease from the impact of switching from conventional therapy to buro- baseline in pain interference was significantly greater than sumab treatment compared to continuing conventional ther- in those who continued conventional therapy, although only apy on PROs of pain interference, physical function mobil- up to week 40. The improvement with burosumab was not ity, fatigue, and HRQoL. fully sustained from week 40 to week 64 but did not return Baseline PROMIS pain interference, physical function to baseline levels. The lack of a persistent benefit with buro- mobility, and fatigue scores were similar to the PROMIS sumab up to week 64 may be explained by small patient calibration sample, which included 4,129 children primar- numbers and possible increased activity-related pain for ily from hospital-based general pediatric and subspecialty patients who had received early benefit from burosumab. clinics. In this sample, 35% of children had consulted a cli- Furthermore, pain and its associated impact in XLH is com- nician for a chronic illness diagnosis or treatment within plex and multifactorial [1, 4], and expected improvements 6 months, and 9% had two or more chronic illnesses [14]. in bone health with burosumab may not be sufficient to fully Baseline PROMIS pain interference, physical function address all aspects of pain syndrome over a short period of mobility, and fatigue scores were similar to those reported time. 1 3 630 R. Padidela et al. Improvements from baseline in the PROMIS physical or the degree of expected improvement with treatment for function mobility and fatigue domains were also achieved those with lower RSS scores is not known. This trial only with burosumab versus conventional therapy, although the randomized treatment for 64 weeks, while XLH is a lifelong die ff rences between groups were not statistically signic fi ant. chronic disease. Further follow-up is warranted to determine Patients receiving burosumab did have clinically meaning- longer-term effects on HRQoL and patient-reported pain ful changes (based on 3-point MIDs) in two of the three interference, physical function mobility, and fatigue. Fur- PROMIS domains (pain interference and fatigue) by week thermore, compared with the prior clinical standard of care, 40, which were maintained at week 64. Burosumab also sig- children on conventional treatment in this trial were perhaps nificantly improved the physical health domain (PHS-10) more meticulously monitored and managed, because of the by approximately 10% at week 40, which was maintained frequent visits and rigorous trial requirements. High levels at week 64. In patients receiving conventional therapy, of compliance and adherence to conventional treatment in changes in physical health from baseline were not seen; dif- clinical trial settings can result in greater improvements in ferences between treatment groups did not reach statistical outcomes with conventional therapy than that seen in routine significance, although the trial was not powered to show standard of care [34–37]. differences in these endpoints. There were no statistically In conclusion, in this phase 3 trial, changing from con- significant interactions among the five PRO domains for the ventional therapy to burosumab was associated with numeri- predefined subgroup categories investigated (RSS and sex). cal increases in PROMIS physical function mobility, clini- Improvements in PROs are reflected by mobility data cally meaningful reductions in PROMIS pain interference from the 6-min walk test reported in the primary manuscript and fatigue up to 64 weeks, and a statistically significant [9]. These data showed that patients randomized to buro- reduction in PROMIS pain interference up to 40 weeks. Sta- sumab had significantly greater improvements from baseline tistically significant improvements in SF-10 PHS-10 were in percent predicted distance walked over 6 min than those observed up to 64 weeks from baseline in children aged continuing to receive conventional therapy at week 64 (LS 5–12 years with XLH. mean change from baseline 9% vs 2%; 95% CI 0.01–14.52; Acknowledgements We thank the clinical nurse coordinators at our p = 0.0496) [9]. sites, who ensured that the questionnaires were completed by patients Improvements in pain interference, physical function or their caregivers. Medical writing and editorial support were provided mobility, fatigue, and HRQoL may be explained by the by OPEN Health Medical Communications, with funding provided by Kyowa Kirin International. LMW is supported by a University of mechanism of action of burosumab. Burosumab addresses Ottawa Research Chair Award. the deficiency of serum phosphate by directly binding to FGF23 and inhibiting its signaling, increasing tubular phos- Author Contributions RP, MPW, FHG, CFM, LMW, ON, AAP, JHS, phate reabsorption, as well as increasing serum 1,25(OH) D NN, HIC, PP, ES, WH, KM, HT, GSG, AB, FP, AC, AS, and EAI were levels and increasing gastrointestinal phosphate absorption involved in the trial design and data collection. AC accepts responsibil- [29]. Increased serum phosphate levels result in improved ity for the integrity of the trial data analysis. WS conducted exploratory subgroup analyses, and AN conducted PROMIS item-level and change bone mineralization [29], improved muscular function [30], score correlation analysis. AN and AW drafted the initial manuscript, and restoration of ATP synthesis [31–33], and thus ulti- with support from OPEN Health Medical Communications. All authors mately may manifest as improvements in patient-reported were involved in critically reviewing and revising the manuscript and symptoms, function, and HRQoL. providing final approval of the submitted version. In relation to PRO measurements, this trial has several Funding This study was funded by Kyowa Kirin International. limitations. Our trial was not powered to assess between- group differences for secondary and exploratory outcomes, Data Availability The corresponding author had full access to all the such as PROs, nor for subgroup analyses. For example, data in the study. sample size was insufficient to explore whether higher phosphate concentration or rapidity of correction of alka- Compliance with Ethical Standards line phosphatase reflected PRO measurements. Therefore, it remains unknown whether mid-range serum phosphate Conflict of interest The following authors served as clinical investi- gators for one or more studies, including this trial, sponsored by Ul- levels improve PROs to a greater extent than low-normal tragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin Inter- values. Children aged younger than 1 year or older than national plc: RP, MPW, FHG, CFM, LMW, ON, AAP, JHS, NN, HIC, 12  years were not recruited, and children younger than PP, ES, WH, KM, HT, GSG, AB, FP, and EAI. AAP, NN, FP, and EAI 5 years did not complete PROs, precluding extrapolation of have also received honoraria for serving as advisory board members or for lectures from Ultragenyx Pharmaceutical Inc. RP has received results to these age groups and limiting the sample size to 15 personal fees from Ultragenyx Pharmaceutical Inc. and Kyowa Kirin patients in the burosumab group and 20 patients in the con- International plc, a research grant, consultation fees, honoraria, and ventional therapy group. Further, only those with RSS ≥ 2 travel grants from Kyowa Kirin International plc and Alexion UK, were enrolled in this trial; thus, the baseline PRO scores 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 631 and non-financial support from Kyowa Kirin International plc. MPW 5. Collins M (2018) Burosumab: at long last, an effective treatment has received research grant support, honoraria, and travel from Alex- for FGF23-associated hypophosphatemia. J Bone Miner Res ion Pharmaceutical Inc. FHG has received personal fees from Kyowa 33:1381–1382. https ://doi.org/10.1002/jbmr.3544 Kirin International plc and research funding from Amgen and Mereo 6. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, BioPharma. LMW has served as a consultant to Ultragenyx, with Wooddell MM, Kawakami T, Ito T, Zhang Z, Humphrey J, funds to LMW’s institution. NN has received personal fees and non- Insogna KL, Peacock M (2014) Randomized trial of the anti- financial support from Kyowa Kirin International plc and Ultragenyx FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Pharmaceutical Inc. during the conduct of the study, and personal fees Invest 124:1587–1597. https ://doi.org/10.1172/JCI72 829 and non-financial support (honoraria, consulting fees, and travel sup- 7. Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, port) from Alexion UK outside the submitted work. PP has received Vergeire M, Humphrey JS, Glorieux FH, Portale AA, Insogna K, research funding from Ultragenyx Pharmaceutical Inc. and is currently Peacock M, Carpenter TO (2015) Prolonged correction of serum an employee of Ascendis Pharma Inc. WH has received honoraria, phosphorus in adults with X-linked hypophosphatemia using consulting fees, and travel support from Ultragenyx Pharmaceutical monthly doses of KRN23. J Clin Endocrinol Metab 100:2565– Inc. and research funding, honoraria, and travel support from Kyowa 2573. https ://doi.org/10.1210/jc.2015-1551 Kirin. GSG has received consulting fees from Ultragenyx Pharmaceu- 8. Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart tical Inc. AW and WS are employees of Kyowa Kirin International plc. A, Padidela R, Van’t Hoff W, Mao M, Chen C-Y, Skrinar A, AN is an employee of Chilli Consultancy and has received consultancy Kakkis E, San Martin J, Portale AA (2018) Burosumab therapy fees from Kyowa Kirin International plc to support the development of in children with X-linked hypophosphatemia. N Engl J Med this manuscript. AC and AS are employees and stockholders of Ultrag- 378:1987–1998. https ://doi.org/10.1056/NEJMo a1714 641 enyx Pharmaceutical Inc. 9. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukchee- Human and Animal Rights and Informed Consent The study was con- wanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman ducted in accordance with the Declaration of Helsinki and the Good GS, Biggin A, Perwad F, Mao M, Chen C-Y, Skrinar A, San Mar- Clinical Practice guidelines developed at the International Conference tin J, Portale AA (2019) Burosumab versus conventional therapy on Harmonization of Technical Requirements for Registration of Phar- in children with X-linked hypophosphataemia: a randomised, maceuticals for Human Use. Parents or guardians provided written active-controlled, open-label, phase 3 trial. Lancet 393:2416– informed consent for their children to participate, and children gave 2427. https ://doi.org/10.1016/S0140 -6736(19)30654 -3 written assent according to local guidelines. 10. 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Arthri- tis Care Res (Hoboken) 69:133–142. https ://doi.or g/10.1002/ acr.22927 Authors and Affiliations 1,2 3 4 5,6 7,8 Raja Padidela  · Michael P. Whyte  · Francis H. Glorieux  · Craig F. Munns  · Leanne M. Ward  · 9,10 11 12 13,14 15 Ola Nilsson  · Anthony A. Portale  · Jill H. Simmons  · Noriyuki Namba  · Hae Il Cheong  · 16 17 18,19 20 21 Pisit Pitukcheewanont  · Etienne Sochett  · Wolfgang Högler  · Koji Muroya  · Hiroyuki Tanaka  · 22 5 11 23 24 25 Gary S. Gottesman  · Andrew Biggin  · Farzana Perwad  · Angela Williams  · Annabel Nixon  · Wei Sun  · 26 26 27 Angel Chen  · Alison Skrinar  · Erik A. Imel 1 3 Department of Paediatric Endocrinology, Royal Manchester Shriners Hospitals for Children —Washington University Children’s Hospital, Manchester, UK School of Medicine in St Louis, St Louis, MO, USA 2 4 Faculty of Biology, Medicine and Health, University Shriners Hospital for Children — Canada, McGill University, of Manchester, Manchester, UK Montreal, QC, Canada 1 3 Patient‑Reported Outcomes from a Randomized, Active‑Controlled, Open‑Label, Phase 3 Trial… 633 5 16 The University of Sydney Children’s Hospital Westmead Center of Endocrinology, Diabetes and Metabolism, Clinical School, The Children’s Hospital at Westmead, Children’s Hospital Los Angeles, Los Angeles, CA, USA Westmead, NSW, Australia Department of Paediatrics, Hospital for Sick Children, Department of Endocrinology, The Children’s Hospital Toronto, ON, Canada at Westmead, Westmead, NSW, Australia Department of Paediatrics and Adolescent Medicine, Department of Pediatrics, University of Ottawa, Ottawa, ON, Johannes Kepler University Linz, Linz, Austria Canada Institute of Metabolism and Systems Research, University Division of Endocrinology and Metabolism, Children’s of Birmingham, Birmingham, UK Hospital of Eastern Ontario, Ottawa, ON, Canada Department of Endocrinology and Metabolism, Kanagawa Division of Pediatric Endocrinology & Center for Molecular Children’s Medical Center, Yokohama, Japan Medicine, Karolinska Institute, Stockholm, Sweden Okayama Saiseikai General Hospital Outpatient Center, School of Medical Sciences, Örebro University, Örebro, Okayama, Japan Sweden Shriners Hospitals for Children, St Louis, MO, USA Department of Pediatrics, University of California, San Kyowa Kirin International, Marlow, UK Francisco, San Francisco, CA, USA Chilli Consultancy, Salisbury, UK Departments of Pediatrics, Division of Endocrinology and Diabetes, Vanderbilt University School of Medicine, Kyowa Kirin Pharmaceutical Development, Princeton, NJ, Vanderbilt University, Nashville, TN, USA USA 13 26 Department of Pediatrics, Osaka Hospital, Japan Community Ultragenyx Pharmaceutical, Novato, CA, USA Healthcare Organization, Osaka, Japan Department of Medicine and Department of Pediatrics, Department of Pediatrics, Osaka University Graduate School Indiana University School of Medicine, Indianapolis, IN, of Medicine, Osaka, Japan USA Seoul National University Children’s Hospital, Seoul, Republic of Korea 1 3

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