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 alpha-mannosidosis 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.
Populations for analysis include a velmanase alfa and a no-velmanase alfa safety and efficacy analysis set. The velmanase alfa safety analysis set includes all patients in the registry who have, at some time, received any study drug treatment with a minimum individual follow-up of ≥ 1 month after the last dose. The velmanase alfa efficacy analysis set consists of patients in the same safety analysis set with efficacy evaluations during velmanase alfa treatment and for 12 months thereafter. The no-velmanase alfa safety analysis set includes patients only for the time when they are not, and have not within 1 month, been taking velmanase alfa. The no-velmanase alfa efficacy analysis set includes patients only for the time when they are not, and have not within 12 months, been taking velmanase alfa.
Baseline and demographic variables
At the registry baseline visit (first visit after inclusion), it is suggested that the following information will be reported in the electronic Case Report Form (eCRF): demographics (ethnicity, age, gender), medical and disease history, concomitant illnesses, previous and concomitant medications and medical procedures, physical examination (including the ability to perform the endurance test and a hearing test), vital signs, and anthropometric measurements. For patients treated with velmanase alfa, the baseline data would be taken from the time treatment was initiated in order to provide a baseline for safety and effectiveness evaluations. Therefore, it is recommended to repeat a treatment baseline visit, if in accordance with routine clinical practice, in patients starting velmanase alfa treatment at any point during participation in the registry.
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.
Table 1
Effectiveness and safety outcomes
Effectiveness Outcomes | Safety Outcomes |
Laboratory assessments: • Serum oligosaccharides (µmol/L) • Serum IgG, IgA, and IgM Functional assessments: • 3MSCT (steps/min) • 6MWT (m)1 • 2MWT (m)1 • FVC (L and % of predicted)1 Health Assessment Questionnaires: • EQ-5D-5L • Zarit Burden Interview • QoL questionnaire • Behavior checklists for child and adult Other: • Psychotic events (rate) | • AEs: serious and nonserious • ADRs: including serious and nonserious • AEs leading to treatment discontinuation and death • Any identified risks including anti-VA-IgG antibody, infusion-related reactions, and hypersensitivity • Any potential risk of acute renal failure, loss of consciousness, and medication errors • Vital signs: SBP, DBP, and pulse rate • Electrocardiogram • Laboratory tests (hematology and chemistry) • Physical examination |
1In patients < 4 years of age, 3MSCT, 2MWT, and FVC% of predicted will be proposed upon the judgment of the physician. |
Abbreviations: 2MWT 2-min walk test; 3MSCT 3-min stair-climb test; 6MWT 6-min walk test; ADR adverse drug reaction; AE adverse event; DBP diastolic blood pressure; EQ-5D-5L European Quality of Life, Five-Dimension, Five-Level Scale; FVC forced vital capacity; FVC% forced vital capacity, percent of predicted; Ig immunoglobulin; QoL quality of life; SBP systolic blood pressure; VA velmanase alfa. |
Table 2
Procedure | Registry Inclusion Visit (~–7 Days) | Registry Baseline Visit (Time 0) | Unscheduled Follow-Up Routine Clinical Visit1 | Six-Month Follow-Up Routine Clinical Visits2 | Yearly Follow-Up Routine Clinical Visits |
Administrative |
Informed consent form | X | X3 | | | |
Inclusion/exclusion criteria | X | X3 | | | |
Medical and disease history (including disease onset, residual enzymatic activity, genotype mutations, bone marrow transplantation) and concomitant illnesses | X | X3 − 4 | | | |
Previous and concomitant medications, including VA in hospital or home infusion setting | | X4 | X | X | X |
Concomitant procedures | X | X | X | X | X |
Physical examination5 (vital signs and anthropometric measurements, including rate of growth) | | X | X | X | X |
Demographics | X | X3 | | | |
Administration of medication |
VA therapy, in hospital or home infusion setting6 | | X | X | X | X |
Assessments7 |
Standard hematological tests8 | | X | X | | X |
Laboratory chemistry9 | | X | X | | X |
Anti-VA-IgG antibody (ADA)10 | | X | X | | X |
Oligosaccharides in serum10 | | X | X | | X |
Serum IgG, IgA, IgM10 | | X | X | | X |
3MSCT, when applicable11 | | X | | | X |
6MWT, when applicable11 | | X | | | X |
2MWT, when applicable12 | | X | | | X |
FVC (L and % of predicted) | | X | X | | X |
Electrocardiogram | | X | X | | X |
Hearing test (PTA) | | X | X | | |
Psychotic events | | X | X | | X |
AEs/ADRs13 | X | X | X | X | X |
Health Assessment Questionnaires |
EQ-5D-5L | | X | | | X |
Zarit Burden Interview | | X | | | X |
CHAQ | | X | | | X |
Behavior checklists14 | | X | | | X |
Abbreviations: 3MSCT 3-min stair climbing test; 2MWT 2-min walk test; 6MWT 6-min walk test; ABCL Adult Behavior Checklist; AE adverse event; ADA alfa-immunoglobulin G antibody; ADR adverse drug reaction; ALP alkaline phosphatase; ALT alanine aminotransferase; ASR Adult Self-Report; AST aspartate transaminase; CBCL Child Behavior Checklist; CHAQ Childhood Health Assessment Questionnaire; EQ-5D-5L European Quality of Life, Five Dimension, Five-Level Scale; FVC forced vital capacity; Ig immunoglobulin; L liter; LDH lactate dehydrogenase; OABCL Older Adult Behavior Checklist; PTA pure tone audiometry; RMP risk management plan; VA velmanase alfa. |
Note: Actual assessments performed per participating center Standard Operating Procedures. |
1. Unscheduled follow-up visits can be performed at, but not limited to, 3 months after VA treatment start, or whenever deemed appropriate according to treating physician’s judgment for patients that start VA treatment within 1 year prior to Registry inclusion. |
2. Additional follow-up visit after 6 months is highly recommended for patients that start VA treatment within 1 year prior to registry inclusion. |
3. If not taken or collected at registry inclusion visit. |
4. Patients’ retrospective data may be collected at the time of registry enrolment if available. Baseline visits are recommended to be repeated for those patients who will start VA therapy during the course of the study, before therapy is initiated. |
5. Physical examination to collect vital signs, anthropometric measurements like height, weight, rate of growth, and the ability to perform the endurance test at the study visit. |
6. If applicable, information regarding weekly VA therapy received by the patient need to be recorded within all the registry duration. |
7. All assessments mentioned in the above table will be collected only if considered necessary and available as part of routine clinical practice by the treating physician and no additional tests specific to the registry will be done. |
8. Standard test for hematology assessed by local laboratory if available per clinical practice of the site: Hemoglobin, hematocrit, platelet count, red blood cells, and white blood cells with differential count (all expressed in %, as well as in absolute numbers). |
9. Standard test for hematology assessed by local laboratory if available per clinical practice: Biochemistry: 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 alpha-mannosidosis (proxy diseases) [9–12].
Table 3
Clinical domains, endpoints, and MCID thresholds for the GTR
Domain | Endpoint | Established MCID1 |
Pharmacodynamic | Serum-oligosaccharides | Last serum oligosaccharide value ≤ 4 µmol/L |
Functional | 3MSCT | Improvement ≥ 7 steps/min [9] |
6MWT | Improvement ≥ 30 m [11] |
FVC% | Improvement ≥ 10% [10] |
QoL | CHAQ DI | Improvement ≤ − 0.130 [12] |
CHAQ Pain VAS | Improvement ≤ − 0.246 [12] |
1MCID were derived from proxy diseases (3MSCT from MPS IV A clinical trials; 6MWT and FVC% from Pompe; CHAQ DI and CHAQ Pain VAS from juvenile arthritis). |
Abbreviations: 3MSCT 3-min stair-climb test; 6MWT 6-min walk test; CHAQ DI Child Health Assessment Questionnaire Disability Index; CHAQ Pain VAS Child Health Assessment Questionnaire Pain Visual Analog Scale; FVC% forced volume capacity, percentage of predicted; GTR Global Treatment Response; MCID minimal clinically important difference; MPS IV A mucopolysaccharidosis type IV A; QoL quality of life. |
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
Expected proportion | 95%CI lower limit | 95%CI upper limit | 95% actual width |
0.60 | 0.476 | 0.715 | 0.239 |
0.65 | 0.527 | 0.760 | 0.234 |
0.70 | 0.579 | 0.804 | 0.225 |
0.75 | 0.632 | 0.846 | 0.214 |
0.80 | 0.687 | 0.886 | 0.199 |
Abbreviation: CI confidence interval. |
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.