The SPARKLE registry: a multicenter, multinational, noninterventional, prospective cohort registry study in patients with alpha-mannosidosis

Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. Intracellular accumulation of mannose-rich oligosaccharides leads to a continuum of various heterogeneous clinical symptoms. Velmanase alfa (Lamzede®) is a human recombinant alpha-mannosidase approved in Europe in 2018 as the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild-to-moderate alpha-mannosidosis. SPARKLE is an alpha-mannosidosis registry study intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis and is a post-approval commitment to European marketing authorization. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively.

electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality of life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alphamannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alphamannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned.

Conclusion
This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.
Intracellular accumulation of mannose-rich oligosaccharides leads to different clinical symptoms, including hearing impairment, intellectual disabilities, impairment of motor function and speech development, recurrent infections, immunodeficiency, skeletal abnormalities, destructive polyarthropathy, muscular weakness, ataxia, and psychiatric disease [1]. Alpha-mannosidosis presents in a continuum of clinical symptoms and is a heterogeneous disorder due to the varied manifestations and their different severity, as well as various rates of progression in individual patients [4]. In the majority of patients, the disease is clinically recognized in the first decade of life, progression is slow, and ataxia develops between the ages of 20 to 30 years [1].
Long-term enzyme replacement therapy (ERT) is a therapeutic option for alphamannosidosis [5] and velmanase alfa is the first human recombinant form of alphamannosidase available for ERT. To date, velmanase alfa (Lamzede®, Chiesi Farmaceutici S.p.A., Parma, Italy) is the only authorized treatment for alphamannosidosis in Europe; it is approved for the treatment of non-neurologic manifestations in patients with mild-to-moderate alpha-mannosidosis [6].
Velmanase alfa targets the underlying cause of the disease by breaking down mannose-rich oligosaccharides that would otherwise accumulate in the lysosome [7]. The velmanase alfa molecule has an identical structure to naturally occurring alpha-mannosidase and is approved for use at 1 mg/kg body weight once weekly as an intravenous infusion [6]. After infusion, velmanase alfa is taken up by cells and transported to the lysosomes, where it replaces the patient's defective enzyme and thus reduces levels of accumulated oligosaccharides [7]. Velmanase alfa also has Orphan Drug designation in the United States and Europe.
In clinical trials, patients with alpha-mannosidosis treated with velmanase alfa achieved improvements in biomarkers, motor function, pulmonary function, immunologic profile, and quality of life (QoL) [3,5,8]. Importantly, a novel global treatment-response model composed of pharmacodynamic, functional, and QoL outcomes was applied post hoc to data from the pivotal, randomized controlled trial (RCT) of velmanase alfa in patients with alpha-mannosidosis (NCT01681953) and the longer-term integrated data from all patients in the clinical development program. A global response required positive responses in at least two outcome domains of the model [3]. In the pivotal RCT, 13 of 15 patients (86.7%) treated with velmanase alfa achieved a global response compared with three of 10 patients (30.0%) who received placebo [3]. Similarly, in the integrated data set, 29 of 33 treated patients (87.9%) were global responders (100% of pediatric patients [n = 19] and 71% of adults [n = 10]) [3].
SPARKLE is an alpha-mannosidosis registry study intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis and is a post-approval commitment to marketing authorization in Europe. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestation, progression, and natural history of the disease.

Methods
Study design SPARKLE is a post-authorization safety and efficacy registry in Europe, designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis (Fig. 1). The study will start in 2020 with an indefinite recruitment period. Patients will be followed for up to 15 years after inclusion. The end of the study is defined as the last visit of the last patient in the study. The study will be conducted under conditions of routine clinical practice, according to the treating physician, without mandatory registry assessments. Patients are eligible for the study irrespective of treatment (velmanase alfa, hematopoietic stem cell transplantation or any biologic substance received as part of a clinical trial during participation in the registry).
The study will be conducted in accordance with the Declaration of Helsinki,

International Council for Harmonisation Good Clinical Practice, Good
Pharmacovigilance Practice, and all other applicable laws and regulations. The study will also be conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.

Patient population
Any patient in the European Union with a genetic confirmed diagnosis of alphamannosidosis who is willing to participate will be eligible for inclusion. Inclusion criteria are limited to a signed and dated informed consent form, including agreement to permit the Investigator to enter assessment data in the registry that has been recorded prior to inclusion in the registry, which has been obtained from the patient's medical record. The inclusion form is signed by the patient, parents or a legally acceptable representative according to local regulation. There are no exclusion criteria.

Safety variables
The primary safety outcomes of interest are rates of adverse events (AEs), with identified risks being anti-velmanase alfa-immunoglobulin G antibody (ADA), infusion-related reactions, and hypersensitivity (Table 1). Secondary safety outcomes include the evaluation of medical events (including but not limited to acute renal failure and loss of consciousness), change in vital signs (including systolic and diastolic blood pressure), laboratory tests (hematology and chemistry), physical examination, and electrocardiogram results. The suggested schedule of assessments is shown in Table 2, but assessments will be made based on the participating centers' Standard Operating Procedures.  serum electrolytes, creatinine, creatine-kinase, amylase, AST, ALT, ALP, albumin, bilirubin (total and direct), LDH. 10. The markers (oligosaccharides in serum, IgG, IgA, and ADA) will be evaluated through a central laboratory in European countries other than Germany. In Germany, marker testing will take place according to local routine clinical practice. 11. In patients 4 years and older, and when applicable according to the judgment of treating physician. 12. In patients under 4 years of age and when applicable according to the judgment of treating physician. 13. AEs/ADRs based on all risk categories associated with VA European RMP, including infusion related reactions and hypersensitivity (as identified risks), acute renal failure, loss of consciousness and medication errors (as potential risks). Data on pregnancy (including birth and newborn data) and lactation (as missing information) will be also collected if available. 14. One of the behavior checklists (CBCL pre-scholar/scholar, ABCL/ASR [self-reporting], OABCL) will be used to the applicable age and according to the judgment of treating physician.

Effectiveness variables
Efficacy outcomes to be assessed during routine clinical care are shown in Table 1.
For patients under 4 years of age, a 3-min stair climb test (3MSCT) and 2-min walk test (2MWT) are suggested. The forced vital capacity (% volume predicted) is suggested for patients over 4 years of age, and according to the judgment of the treating physician. The proposed schedule of assessments is shown in Table 2, but, again, assessments will be made based on the participating centers' Standard Operating Procedures.
A Global Treatment Response (GTR) to velmanase alfa will be evaluated in velmanase alfa-naïve patients able to perform the functional tests after 3 years of treatment. The GTR will assess patients in three clinical domains (pharmacodynamic, functional, and QoL) consisting of 1 or > 1 endpoint (Table 3).
The pharmacodynamic domain comprises a measure of the accumulated substrate in alpha-mannosidase deficiency, the main pathogenic factor for disease manifestations; a decrease in oligosaccharides is a key biomarker of the pharmacologic effect of the ERT [3]. The second domain includes pulmonary function, endurance, and fine and gross motor proficiency, i.e., all the functional endpoints of the disease [3]. The QoL domain relates to patient-related outcomes of disease burden, disability, and pain [3]. A global response is defined as improvements exceeding the established minimal clinical important difference (MCID) ( Table 3) in ≥ 1 endpoint in ≥ 2 of the domains [3]. The MCIDs are derived on the basis of those used in clinical conditions with the highest similarity to alphamannosidosis (proxy diseases) [9][10][11][12].

Data management
Data sources will be the patient's medical record and any other medical record of clinical findings accrued as part of routine care; retrospective data may be obtained from the patient's medical record. All data related to the study will be entered in the eCRF and will be checked for accuracy and completeness as a component of ongoing study monitoring by an independent contract research organization (CRO) designated by Chiesi Farmaceutici S.p.A. Access to the eCRF will be granted to authorized personnel; sites will only be able to access data of patients enrolled at their site and the CRO will be entitled to access all data in a read-only mode.

Study size
As this is an observational study and there is no formal hypothesis testing, the size of the study was conceptualized based on assumed different proportions of GTR in treatment-naïve patients who can perform functional tests after 3 years of treatment. Assuming at least 70 treated patients are enrolled, and assuming a GTR of at least 0.60 or more, the lower limit of the two-sided 95% confidence interval (Clopper-Pearson) is always above 45.0% (Table 4), which is considered a clinically relevant response. Thus, the efficacy analysis is based on a hypothetical treated population of at least 70 patients. Table 4 Efficacy analysis based on hypothetical treated population of at least 70 patients

Statistical analyses
Baseline demographic and disease characteristics will be presented by means of descriptive statistics and frequency distributions, as appropriate. Descriptive safety outcomes will be presented and summarized over time. For AEs, both the frequency of patients with an AE and the number of events will be presented by year from baseline. Safety variables will be presented based on person-years at risk.
Effectiveness variables will be summarized by means of descriptive statistics or frequency of distribution, as appropriate, and all variables (actual values and change from baseline, if applicable) will be presented by time point. The effects of baseline characteristics on effectiveness will be evaluated by means of regression/logistic models. Covariates in the model will be age (< 18 and ≥ 18 years), gender (male, female), sibships, genotype (Groups 1, 2, and 3, per Borgwardt et al.) [13], residual enzymatic activity (< 10, 10 to < 15, and ≥ 15 nmol/h/mg), and Childhood Health Assessment Questionnaire Disability Index (0-1, 1-2, and 2-3).
Provided that a sufficient number of nontreated patients with adequate data are enrolled, a comparison will be conducted between the velmanase alfa-treated and nontreated groups. Propensity score (PS) analysis will be used to compare GTRs after 3 years; the PS will be calculated as the predicted probability of response using logistic regression, with the same covariates as used for the baseline characteristics regression. Subgroup analyses may be performed depending on overall sample size; results will be presented descriptively.

Discussion
SPARKLE is the first European-wide registry for alpha-mannosidosis that includes all patients, irrespective of treatment or study inclusion, who are willing to participate.
The registry will expand the current understanding of alpha-mannosidosis by collecting natural history data, disease modifiers, and confounding factors in treated and untreated patients. Rare disease registries provide a valuable resource to enhance understanding of the diagnosis, heterogeneity, progression, burden of disease, and natural history of these conditions [14]. Committee of Experts on Rare Diseases [19]. In contrast to other registries that evaluate orphan medicinal products for the treatment of lysosomal storage disorders [20], the eligibility criteria for participation in SPARKLE are minimal, in order to allow the largest possible number of patients to participate. Methodologic rigor will be exercised to ensure the highest-quality data and data analysis. In addition, SPARKLE is the only alpha-mannosidosis registry, avoiding duplication of data collection; it is designed to collect both safety and efficacy data, as well as information on patient and disease characteristics; and it is not restricted to patients receiving a particular treatment, or a time when treatment is initiated.
Some limitations need to be acknowledged. As information in the registry will be collected during routine clinical care, the assessments performed and data collected may vary from center to center, as may the interpretation of data by the individual Investigators. In addition, bias may be introduced by patient self-selection into the study and it is unknown whether all patients with alpha-mannosidosis will be included as some may be treated in centers not participating in the registry. Thus, bias will be of unknown size and direction.

Conclusion
The SPARKLE study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in European patients with alpha-mannosidosis during routine clinical care and will increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease in both treated and untreated patients.

Ethics approval and consent to participate
Before the study commences, the protocol will be submitted to the Ethics Committee according to the requirements of each country. Informed consent will be obtained from each patient prior to the collection of any data.

Consent for publication
Not applicable.

Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.  Figure 1 Study design. Abbreviation: VA velmanase alfa. aIf applicable in accordance with routine clin