Mpox Diagnosis, Behavioral Risk Modification, and Vaccination Uptake among Gay, Bisexual, and Other Men Who Have Sex with Men, United Kingdom, 2022.

During the 2022 multicountry mpox outbreak, the United Kingdom identified cases beginning in May. UK cases increased in June, peaked in July, then rapidly declined after September 2022. Public health responses included community-supported messaging and targeted mpox vaccination among eligible gay, bisexual, and other men who have sex with men (GBMSM). Using data from an online survey of GBMSM during November-December 2022, we examined self-reported mpox diagnoses, behavioral risk modification, and mpox vaccination offer and uptake. Among 1,333 participants, only 35 (2.6%) ever tested mpox-positive, but 707 (53%) reported behavior modification to avoid mpox. Among vaccine-eligible GBMSM, uptake was 69% (95% CI 65%-72%; 601/875) and was 92% (95% CI 89%-94%; 601/655) among those offered vaccine. GBMSM self-identifying as bisexual, reporting lower educational qualifications, or identifying as unemployed were less likely to be vaccinated. Equitable offer and provision of mpox vaccine are needed to minimize the risk for future outbreaks and mpox-related health inequalities.

Long-term Retinal Morphology and Functional Associations in Treated Neovascular Age-Related Macular Degeneration: Findings from the Inhibition of VEGF in Age-Related Choroidal Neovascularisation Trial.

PURPOSE: To describe the frequency of long-term morphologic features and their relationships with visual function in participants who exited the Inhibition of VEGF in Age-Related Choroidal Neovascularisation (IVAN; ISRCTN92166560) trial. DESIGN: Multicenter cohort study up to 7 years after enrollment. PARTICIPANTS: Patients enrolled in the IVAN trial, excluding participants who died or withdrew during the trial. METHODS: Multimodal fundus images, best-corrected visual acuity (BCVA), and low-luminance visual acuity (LLVA) were obtained for a subset of 199 participants who attended a research visit. Clinical sites (n = 20) also provided all visual acuity and clinical information from usual care records for 532 participants and submitted the most recent color, OCT, and other fundus images for 468 participants to a reading center. MAIN OUTCOME MEASURES: Assessed the following from the most recent images: intralesional macular atrophy (ILMA) within the footprint of the neovascular lesion; hyperreflective material (HRM); intraretinal fluid (IRF); subretinal fluid (SRF); pigment epithelial detachment (PED); and disorganized retinal outer layers (DROLs). Cross-sectional relationships between morphologic features and BCVA/LLVA were estimated. RESULTS: Intralesional macular atrophy was present in 31.8% of the study eyes at IVAN exit (mean follow-up, 1.96 years) and 89.5% at the most recent imaging visit (mean follow-up, 6.18 years). Hyperreflective material, IRF, SRF, PED, and DROLs were present in 78.8%, 47.7%, 7.6%, 94.5%, and 55% of the study eyes, respectively. In the subset with complete imaging data, in eyes without DROL, the BCVA was worst in the thinnest outer fovea tertile (thinnest minus middle and thickest tertiles, -19.7 and -19.5 letters, respectively), whereas in eyes with DROL, the BCVA was worst in the thickest (thinnest and middle tertiles minus thickest, 12.5 and 12.2, respectively). Regression models showed that the presence of ILMA and HRM was independently associated with BCVA (22 letters worse [95% confidence interval {CI}, -11.2 to -32.8; P < 0.001] and 9.8 letters worse [95% CI, -0.1 to -19.4; P = 0.047], respectively). Subretinal fluid and foveal PED were associated with better BCVA (5.9 letters [95% CI, -7.9 to 19.7; P = 0.399] and 6.4 letters [95% CI, -1.1 to 14.0; P = 0.094], respectively). The model with LLVA was similar. A sensitivity analysis involving the entire eligible cohort yielded similar estimates. CONCLUSIONS: Macular atrophy and HRM were common after 7 years of follow-up and strongly associated with visual outcomes.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): defining and measuring functional impacts in pediatric patients.

BACKGROUND: Research about pediatric patients' perspective on mucopolysaccharidosis type VI (MPS VI) and its impact on daily life is limited. We aimed to identify the disease concepts of interest that most impact function and day-to-day life of pediatric patients with MPS VI, and to consider clinical outcome assessments (COAs) that may potentially measure meaningful improvements in these concepts. METHODS: Potential focus group participants were identified by the National MPS Society (USA) and invited to participate if they self-reported a clinician-provided diagnosis of MPS VI and were 4 to 18 years, receiving enzyme replacement therapy (ERT), and available to attend a 1-day focus group with their caregiver in Dallas, TX, USA. The focus group consisted of a series of polling and open-ended concept elicitation questions and a cognitive debriefing session. The discussion was audio recorded, transcribed verbatim, and analyzed to identify disease concepts of interest and functional impacts most relevant to participants. RESULTS: Overall, caregivers (n = 9) and patients with MPS VI (n = 9) endorsed that although their children/they receive ERT, residual symptoms exist and impact health-related quality of life. The key disease concepts of interest identified were impaired mobility, upper extremity and fine motor deficits, pain, and fatigue. Pain was unanimously reported by all patients across many areas of the body and impacted daily activity. Key disease concepts were mapped to a selection of pediatric COAs including generic measures such as PROMIS®, PODCI, CHAQ, and PedsQL™. Caregivers endorsed the relevance of PODCI and PROMIS Upper Extremity, Mobility, and Pain items and all patients completed the NIH Toolbox Pegboard Dexterity Test. Additional COAs that aligned with the disease concepts included range of motion, the 2- and 6-min walk tests, timed stair climbs, Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition, grip strength, pain visual analog scale, and the Faces Pain Scale-Revised. CONCLUSION: An MPS VI focus group of pediatric patients and their caregivers identified impaired mobility, upper extremity and fine motor deficits, pain, and fatigue as key disease concepts of interest. These disease concepts were mapped to existing pediatric COAs, which were provided to the group for endorsement of their relevance.

Long-term outcomes of patients with mucopolysaccharidosis VI treated with galsulfase enzyme replacement therapy since infancy.

OBJECTIVE: Long-term outcomes of patients with mucopolysaccharidosis (MPS) VI treated with galsulfase enzyme replacement therapy (ERT) since infancy were evaluated. METHODS: The study was a multicenter, prospective evaluation using data from infants with MPS VI generated during a phase 4 study (ASB-008; Clinicaltrials.govNCT00299000) and clinical data collected ≥5 years after completion of the study. RESULTS: Parents of three subjects from ASB-008 (subjects 1, 2, and 4) provided written informed consent to participate in the follow-up study. One subject was excluded as consent was not provided. Subjects 1, 2, and 4 were aged 0.7, 0.3, and 1.1 years, respectively, at initiation of galsulfase and 10.5, 7.9, and 10.5 years, respectively, at follow-up. All subjects had classical MPS VI based on pre-treatment urinary glycosaminoglycans and the early onset of clinical manifestations. At follow-up, subject 4 had normal stature for age; subjects 1 and 2 had short stature, but height remained around the 90th percentile of growth curves for untreated classical MPS VI. Six-minute walk distance was normal for age/height in subjects 1 (550 m) and 4 (506 m), and reduced for subject 2 (340 m). Subject 2 preserved normal respiratory function, while percent predicted forced vital capacity and forced expiratory volume in 1 s decreased over time in the other subjects. Skeletal dysplasia was already apparent in all subjects at baseline and continued to progress. Cardiac valve disease showed mild progression in subject 1, mild improvement in subject 4, and remained trivial in subject 2. All subjects had considerably reduced pinch and grip strength at follow-up, but functional dexterity was relatively normal for age and there was limited impact on activities of daily living. Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) results showed that subjects 2 and 4 had numerous fine and gross motor competencies. Corneal clouding progressed in all subjects, while progression of hearing impairment was variable. Liver size normalized from baseline in subjects 1 and 4, and remained normal in subject 2. CONCLUSION: Very early and continuous ERT appears to slow down the clinical course of MPS VI, as shown by preservation of endurance, functional dexterity, and several fine and gross motor competencies after 7.7-9.8 years of treatment, and less growth impairment or progression of cardiac disease than could be expected based on the patients' classical phenotype. ERT does not seem to prevent progression of skeletal or eye disease in the long term.

Use of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance.

X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population.

Measuring What Matters to Individuals with Angelman Syndrome and Their Families: Development of a Patient-Centered Disease Concept Model.

Angelman syndrome (AS) is a complex, heterogeneous, and life-long neurodevelopmental disorder. Despite the considerable impact on individuals and caregivers, no disease-modifying treatments are available. To support holistic clinical management and the development of AS-specific outcome measures for clinical studies, we conducted primary and secondary research identifying the impact of symptoms on individuals with AS and their unmet need. This qualitative research adopted a rigorous step-wise approach, aggregating information from published literature, then evaluating it via disease concept elicitation interviews with clinical experts and caregivers. We found that the AS-defining concepts most relevant for treatment included: impaired expressive communication, seizures, maladaptive behavior, cognitive impairment, motor function difficulties, sleep disturbance, and limited self-care abilities. We highlight the relevance of age in experiencing these key AS concepts, and the difference between the perceptions of clinicians and caregivers towards the syndrome. Finally, we outline the impact of AS on individuals, caregivers, and families.

Long-term Visual Outcomes after Release from Protocol in Patients who Participated in the Inhibition of VEGF in Age-related Choroidal Neovascularisation (IVAN) Trial.

PURPOSE: To describe visual outcomes, frequency of treatment and monitoring visits, and anti-vascular endothelial growth factor drugs used in usual care in participants who exited a trial in which treatment for neovascular age-related macular degeneration (nAMD) was initiated with bevacizumab or ranibizumab. DESIGN: Multicenter cohort study up to 7 years after trial exit. PARTICIPANTS: Patients enrolled in the Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial; after excluding participants from 2 sites and who died or withdrew during the trial, 537 were included in this follow-up cohort. METHODS: Data were collected between May 26, 2016, and August 24, 2017. Distance visual acuity (DVA) (letters read) in both eyes and treatments for nAMD administered to either eye at all usual care visits were extracted from medical records of all participants until the point of data collection (duration of study eye monitoring). MAIN OUTCOME MEASURES: Rate of change of DVA during active surveillance of the study eye (study eye monitoring), estimated using a multivariable linear random effects model. Other outcome measures were visit and treatment frequency and switches in anti-vascular endothelial growth factor (VEGF) drug. RESULTS: Data were obtained for 99% (532/537) of eligible participants. The median duration of study eye monitoring after IVAN exit was 3.3 years (interquartile range [IQR], 1.3-4.7), and median DVA was 58.0 letters (IQR, 34.0-73.0). Study eye DVA deteriorated by 4.3 (95% confidence interval [CI], 3.7-4.9) letters per year. Injection rate did not influence the rate of change in DVA after adjusting for key covariates. After IVAN exit, 174 participants (32%) received no treatment; 332 of 358 (93%) were treated first with ranibizumab, 78 (23%) of whom switched to aflibercept. The DVA was similar among participants who switched or did not switch at the end of study monitoring. CONCLUSIONS: Approximately 5 years after the IVAN study finished, with unprecedented completeness of follow-up for such a trial, the trajectory of functional decline in the study eye was shown to be greater than that previously reported for incomplete trial cohorts. Anti-VEGF injection rates and treatment switches were not important factors in determining visual acuity outcomes.

Use of the Bruininks-Oseretsky test of motor proficiency (BOT-2) to assess efficacy of velmanase alfa as enzyme therapy for alpha-mannosidosis.

OBJECTIVES: Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. Clinical manifestations include progressive balance disorders, immune deficiency, skeletal abnormalities and cognitive deficits beginning in early childhood. Enzyme replacement therapy with recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in cases of mild to moderate disease. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults. METHODS: Integrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years. RESULTS: Patients showed global developmental delays at baseline. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients <18 years (mean percent increase from baseline to last observation 23%) compared to adults (mean decrease of -0.7%). Subtest analysis of individual BOT-2 items captured some improvement following velmanase alfa treatment in pediatric patients. CONCLUSIONS: There was limited ability to assess the BOT-2 change responses in adults. Pediatric patients showed stability or improvement in scaled scores relative to healthy peers, indicating continued skill acquisition, which may increase independence and contribute to improved patient quality of life.

The OMACS-PIL study: a randomised controlled trial within the OMACS observational study.

BACKGROUND: There has been little research to investigate whether the appearance of paper patient information leaflets (PILs) used to describe research studies to potential participants influences their decision to take part. Embedding a study within a trial (SWAT) is an efficient way of answering this type of methodological question. We included a randomised SWAT within a large cohort study, Outcome Monitoring after Cardiac Surgery (OMACS), to address this question. METHODS: Potential participants for the OMACS study were randomised to receive one of three PILs, which were identical in content but with varying formatting and use of colour: PIL A (enhanced format), PIL B (hybrid format) and PIL C (standard format). Consent to OMACS was the primary outcome. Consent rates using the three different PIL formats were collected and compared. Qualitative feedback on the different formats was obtained from a public and patient involvement (PPI) group. RESULTS: For the SWAT, 1517 PILs were sent to potential participants, of whom 640 (42%) consented to take part in OMACS. PIL B had the highest recruitment rate, with 45% of patients consenting to participation; 40% and 41% of patients consented to participation after receiving PILs A and C, respectively. Compared to PIL C, the consent rate was 4% higher with PIL B (45% versus 41%, 95% confidence interval (CI) -2% to + 10%, p = 0.16) and 1% lower with PIL A (40% versus 41%, 95% CI - 7% to + 5%, p = 0.72). CONCLUSIONS: Consent rates were similar for all three PIL formats. PIL B is being used for the remainder of the host study and will be used to inform the design of PILs for other research studies, as it was the preferred format of the PPI group. TRIAL REGISTRATION: International Clinical Trials Registry, ISRCTN90204321. Registered on 21 January 2015.

Reliability and Validity of the 6-Minute Walk Test in Hypophosphatasia.

This investigation evaluated the reliability and validity of the 6-Minute Walk Test (6MWT) in patients with pediatric hypophosphatasia (HPP). Children (aged 6 to 12 years; n = 11), adolescents (13 to 17 years; n = 4), and adults (18 to 65 years; n = 9) completed the 6MWT at screening and baseline in two clinical studies of asfotase alfa. Test-retest reliability of the 6MWT, evaluated with Pearson's correlation coefficients (r) for screening versus baseline, was high for children (r = 0.95; p < 0.0001), adolescents (r = 0.81; p = 0.125), and adults (r = 0.94; p = 0.0001). The most conservative minimal clinically important differences, estimated using distribution-based methods, were 31 m (children and adults) and 43 m (adolescents). In children, the 6MWT correlated significantly with scores on measures of skeletal disease, which included the Radiographic Global Impression of Change scale (r = 0.50; p < 0.0001) and the Rickets Severity Scale (r = -0.78; p < 0.0001), such that distance walked increased as the severity of skeletal disease decreased. Significant (p < 0.0001) correlations with the 6MWT distance walked were also observed for children with scores on parent-reported measures of disability (r = -0.67), ability to function in activities of daily living (r = 0.71 to 0.77), and parent-reported measures of pain (r = -0.39). In adolescents and adults, 6MWT distance walked correlated significantly (p < 0.05) with measures of lower extremity function (r = 0.83 and 0.60, respectively), total pain severity (r = -0.41 and -0.36, respectively), and total pain interference (r = -0.41 and -0.49, respectively). Collectively, these data indicate that the 6MWT is a reliable, valid measure of physical functioning in patients with pediatric HPP. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial.

BACKGROUND: Our previous phase 2, open-label study of 11 infants and young children with life-threatening perinatal or infantile hypophosphatasia showed 1 year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We aimed to report the long-term outcomes over approximately 7 years of treatment. METHODS: We did a prespecified, end of study, 7 year follow-up of our single-arm, open-label, phase 2 trial in which children aged 3 years or younger with life-threatening perinatal or infantile hypophosphatasia were recruited from ten hospitals (six in the USA, two in the UK, one in Canada, and one in the United Arab Emirates). Patients received asfotase alfa (1 mg/kg three times per week subcutaneously, adjusted to 3 mg/kg three times per week if required) for up to 7 years (primary treatment period plus extension phase) or until the product became commercially available; dosage adjustments were made at each visit according to changes in the patient's weight. The primary objectives of this extension study were to assess the long-term tolerability of asfotase alfa, defined as the number of patients with one or more treatment-emergent adverse events, and skeletal manifestations associated with hypophosphatasia, evaluated using the Radiographic Global Impression of Change (RGI-C) scale (-3 indicating severe worsening, and +3 complete or near-complete healing). Respiratory support, growth, and cognitive and motor functions were also evaluated. All efficacy and safety analyses were done in all patients who received any asfotase alfa (full-analysis population). This study and extension phase are registered with ClinicalTrials.gov, number NCT01205152, and EudraCT, number 2009-009369-32. FINDINGS: 11 participants were recruited between Oct 6, 2008, and Dec 4, 2009. Ten patients completed a 6 month treatment period and entered the extension phase; nine received asfotase alfa for at least 6 years and completed the study, with four being treated for more than 7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores of at least +2 at year 6 (n=9; median score +2·0 [range 2·0-3·0]) and year 7 (n=7; median score +2·3 [2·0-3·0]). No patient who completed the study required respiratory support after year 4. Weight Z scores improved to within normal range from year 3 to study end; length or height Z scores improved but remained below normal. Age-equivalent scores on gross motor, fine motor, and cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. All 11 patients had at least one treatment-emergent adverse event. The most common adverse events were pyrexia (eight [73%] of 11 patients), upper respiratory tract infection (eight [73%]), craniosynostosis (seven [64%]), and pneumonia (seven [64%]). Serious adverse events related to asfotase alfa occurred in three (27%) patients (severe chronic hepatitis; moderate immediate post-injection reaction; and severe craniosynostosis with severe conductive deafness). INTERPRETATION: Patients with perinatal or infantile hypophosphatasia treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralisation. Respiratory function, growth, and cognitive and motor function also improved, and asfotase alfa was generally well tolerated. FUNDING: Alexion Pharmaceuticals, Inc.

Development and validation of a modified performance-oriented mobility assessment tool for assessing mobility in children with hypophosphatasia.

PURPOSE: To modify the Performance-Oriented Mobility Assessment-Gait (POMA-G) subtest and validate this modified POMA-G (mPOMA-G) in children with hypophosphatasia (HPP), a rare metabolic disorder that can manifest with musculoskeletal symptoms that impair mobility and ambulation. METHODS: Based on feedback from an expert panel, the POMA-G was modified by removing gait initiation/path assessments and expanding the rating scale for step length/continuity to capture aspects of observational gait analysis relevant to children with HPP. Three trained physical therapists used the mPOMA-G for video-based assessments of gait in 14 children with childhood HPP who participated in a clinical study of asfotase alfa or in a natural history study. Intraclass correlation coefficients (ICCs) were calculated to determine interrater and intrarater agreement. Concurrent validity was evaluated by correlations with other validated assessment tools. RESULTS: Across 192 observations from available videos, interrater and intrarater agreement of mPOMA-G scores was significant (ICCs: 0.76 for both; P< 0.001). mPOMA-G scores had strong concurrent validity with the Childhood Health Assessment Questionnaire, Pediatric Outcomes Data Collection Instrument Transfer and Mobility Scale, Sports and Physical Function subscale, and 6-Minute Walk Test (all P⩽ 0.0002). CONCLUSION: The mPOMA-G is a reliable and valid measure for detecting clinically significant impairments in children with HPP.

Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis.

INTRODUCTION: Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM). METHODS: Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT). RESULTS: Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P < 0.001) and remained statistically significant at last observation (-62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation. CONCLUSIONS: Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.

Clinical Outcome Assessments: Use of Normative Data in a Pediatric Rare Disease.

Pediatric rare diseases present unique challenges in clinical trial design and in selection of clinical outcome assessments (COAs) used to support claims in medical product labeling. COAs that discriminate level of function relative to a normative sample are particularly important in the pediatric rare disease setting because the literature is often void of natural history data. Pediatric rare disease clinical trials will often include a wide age distribution. Gross and fine motor skills, communication, cognition, and independence in activities of daily living vary by age, and it may be difficult to distinguish between treatment effect and change due to developmental maturation. Asfotase alfa was granted breakthrough therapy designation and subsequently approved for the treatment of hypophosphatasia (HPP; a genetic metabolic musculoskeletal disorder) and is used in this discussion to illustrate COA selection in a pediatric rare disease. Multiple COAs with normative data in HPP clinical trials for asfotase alfa are presented. The assessment instruments included the Bayley Scales of Infant and Toddler Development-Third Edition, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, the Childhood Health Assessment Questionnaire, the Pediatric Outcomes Data Collection Instrument, handheld dynamometry, the 6-minute walk test, and the Modified Performance-Oriented Mobility Assessment-Gait scale. Multiple end points were required to adequately capture the impact of asfotase alfa treatment on the multiple systems affected in HPP. These data illustrate the importance of using multiple COAs that provide normative data and to use COAs early in the drug development process for rare pediatric disease.

Service Evaluation of an Exercise on Referral Scheme for Adults with Existing Health Conditions in the United Kingdom.

PURPOSE: This paper outlines a service evaluation of an exercise referral scheme for adults suffering from a variety of physical or mental health conditions or who were deemed are at risk of developing such conditions. The evaluation aimed to assess the impact of the scheme at increasing physical activity and at reducing BMI and waist circumference. METHOD: This was a retrospective evaluation looking at levels of physical activity and changes to anthropometric measures over a period of 6 months. Each participant self-reported their levels of physical activity for the previous 7 days at three time points: baseline (T1), at 12-week exit from the scheme (T2), and at 6-month follow-up (T3). Waist circumference and BMI were also recorded by either a health professional or self-reported at these time points. RESULTS: Six hundred seventy participants were referred during the evaluation period, of whom 494 were eligible. Of those 494, 211 completed the 12-week scheme and 135 completed a 6-month follow-up. Significant increases in levels of physical activity were recorded between T1 and T2 and between T1 and T3. Furthermore, significant reductions in waist circumference were noted between T1 and T2 and between T1 and T3, and BMI significantly decreased between T1 and T2 but significantly increased between T2 and T3. CONCLUSION: The service has proven effective at increasing levels of physical activity among participants and has had a positive impact on waist circumference and body for clients who remain engaged with the programme.

Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis: Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase)

Abstract Alpha-mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequelae leading to intellectual disability, ataxia, impaired hearing and speech, recurrent infections, skeletal abnormalities, muscular pain, and weakness. This study aimed to investigate disability, pain, and overall health using the Childhood Health Assessment Questionnaire (CHAQ) and the EuroQol 5 Dimension-5 Level Questionnaire (EQ-5D-5L) in patients with alpha-mannosidosis participating in rhLAMAN-10, a phase III open-label, clinical trial of velmanase alfa, a recombinanthumanlysosomalalpha-mannosidase. Long-termprognosesformost patients withuntreatedalpha-mannosidosisarepoor due to progressive neuromuscular, skeletal, and intellectual deterioration, leading to increased dependence in mobility and activities of daily living and increased caregiver and health-care burden. Long-term CHAQ and EQ-5D-5L data highlight improvement trends in health-related quality of life and a reduction in disability and pain in patients receiving up to 48 months of velmanase alfa treatment.

Asfotase alfa therapy for children with hypophosphatasia.

Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6-12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti-asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.

Physical therapy management of infants and children with hypophosphatasia.

Hypophosphatasia (HPP) is a rare inborn error of metabolism resulting in undermineralization of bone and subsequent skeletal abnormalities. The natural history of HPP is characterized by rickets and osteomalacia, increased propensity for bone fracture, early loss of teeth in childhood, and muscle weakness. There is a wide heterogeneity in disease presentation, and the functional impact of the disease can vary from perinatal death to gait abnormalities. Recent clinical trials of enzyme replacement therapy have begun to offer an opportunity for improvement in survival and function. The role of physical therapy in the treatment of the underlying musculoskeletal dysfunction in HPP is underrecognized. It is important for physical therapists to understand the disease characteristics of the natural history of a rare disease like HPP and how the impairment and activity limitations may change in response to medical interventions. An understanding of when and how to intervene is also important in order to optimally impact body function, lessen structural impairment, and facilitate increased functional independence in mobility and activities of daily living. Individualizing treatment to the child's needs, medical fragility, and setting (home/school/hospital), while educating parents, caregivers, and school staff regarding approved activities and therapy frequency, may improve function and development in children with HPP.

Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease.

Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20 mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20 mg/kg/week or 40 mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n = 4), infantile-onset (n = 9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.