Methods
The international NPC Registry was initiated in May 2009 as a post-approval commitment to the European Medicines Agency (EMA) following approval of a new indication for miglustat for the treatment of progressive neurological deterioration in adults and children with NP-C [
4]. The Registry is a prospective, observational cohort study conducted in clinical practice settings. All patients with a diagnosis of NP-C are eligible for enrolment, regardless of the treatment they receive. A previous published report from this Registry described general methodological details and patient characteristics at enrolment [
14].
The NPC Registry collects data on demographics, diagnosis, disease characteristics and treatment. Before entering any clinical visit data, written informed consent is obtained from all patients (including children) and/or their legal guardians.
For the current longitudinal study, data were analyzed for patients that: 1) received miglustat therapy continuously between enrolment visit and last follow-up visit (where ‘continuously’ was defined as at least 90 % of the observation period with no single period without miglustat lasting more than 28 days); and 2) had a minimum of 1 year of observation time in the Registry.
Functional disability status is recorded at enrolment and at each follow-up visit in the Registry using an expert-based disease-specific disability scale that assesses four key neurological domains in NP-C (ambulation, manipulation, language and swallowing) [
15]. The scoring system of this scale originally ranged from 0 (normal) to 4 or 5 (worst) [
16], but has since been modified to provide an equal weighting in each domain, and ranges from 0 (normal) to 1 (worst) [
8,
15]. The 0–1 scoring system was chosen for use in the Registry [
14] as this scale has been employed in key studies on the natural history of NP-C [
8,
15], is listed among the useful assessment tools in the international recommendations for managing NP-C [
2,
3], and has been employed in describing miglustat treatment outcome on NP-C disease progression in previous national cohorts [
12].
For the current analysis, composite disability scores were calculated as the mean of all four domains. Disease progression was assessed by two statistical methods: 1) annual progression rates were calculated as the change in composite disability score from enrolment to last follow-up visit divided by time in years from enrolment to last follow-up visit; 2) categorical analysis, where patients were categorized as ‘improved/stable’ when at least three out of four individual disability domain scores were decreased or unchanged between enrolment and last follow-up visit, and patients with fewer than three out of four domain scores decreased or unchanged were categorized as ‘progressing’ [
8,
15].
Statistical analyses are descriptive. All percentages were calculated relative to the number of patients with available data per parameter. Data are presented for all patients and stratified according to internationally agreed age at neurological onset categories (early-infantile onset [<2 years], late-infantile onset [2 – <6 years], juvenile onset [6 – <15 years], and adolescent/adult onset [≥15 years]) [
1,
2]. One modification to these internationally agreed neurological onset categories was that in this analysis all patients with onset aged <2 years were included in the early-infantile subgroup due to the low number of cases. The participation rate of miglustat-treated patients in Europe was calculated as the number of miglustat-treated patients enrolled in the Registry divided by the estimated number of NP-C patients treated with miglustat in European countries.
Discussion
Here, we present a longitudinal analysis of functional disability in 92 miglustat-treated patients included from the international NPC Registry. The 92 patients described here received continuous miglustat therapy, with an average observation period of 2 years in the Registry. It should be noted that while the NPC Registry is a disease registry, we only describe findings from miglustat-treated patients here.
Functional disability, evaluated using an established disease-specific scale based on ambulation, manipulation, language, and swallowing [
3,
8], remained stable in most NP-C patients during continuous miglustat therapy, and improved in some of them. This is in line with published data from previous studies with miglustat. A retrospective cohort study in 66 NP-C patients demonstrated stable or improved neurological manifestations (using the same composite disability scale employed in the NPC Registry) in over three-quarters of patients during miglustat therapy over a median (range) of 1.46 (0.05–4.51) years [
3,
8]. Ambulation and swallowing were also shown to be stable or improved in miglustat-treated adults of a randomized, controlled clinical trial [
5]. A pediatric sub-study conducted in parallel with the main randomized trial showed similar findings in children aged 4–12 years [
5].
The low number of treatment-naïve patients currently enrolled in the NP-C Registry, and the differences in disease characteristics between these patients and enrolled, treated patients, prevented comparative analyses of miglustat treatment effectiveness. Nevertheless, a degree of comparison can be drawn against natural history data from two published retrospective cohort studies, which assessed disease progression from diagnosis to the start of miglustat therapy. Similar to the Registry, patients in these retrospective cohorts were assessed based on observational methods, from comparable regions and ages at diagnosis [
8,
15]. The mean (95 % CI) annual progression rates reported in these two analyses were 0.11 (0.04, 0.18) score units/year in 66 patients over a mean (SD) of 3.1 (3.4) years [
8], and 0.12 (0.09, 0.15) score units/year in 57 NP-C patients over a mean (SD) of 5.5 (4.8) years [
15]. In the current NPC Registry cohort of miglustat-treated patients, mean (95 % CI) disease progression appears slower (0.038 [0.018, 0.059] score units/year) than that observed among untreated patients in the retrospective cohort studies.
When comparing the annual disease progression of the treated patients from the Registry with the annual disease progression of treated patients in the retrospective cohort [
8], it appears that the mean (95 % CI) progression rate in the Registry cohort was greater (0.038 [0.018, 0.059]), than that reported during miglustat treatment in the retrospective cohort (−0.01 [−0.08, 0.06]) [
8]. However, the progression rate reported for the retrospective cohort was based on the first 1.5 years of miglustat treatment (i.e., from treatment start), whereas the progression rate calculated for the Registry cohort was based on patients who had already received an average of 1.9 years of miglustat therapy before the observation period. Hence, despite being further along in their treatment course, a large proportion of the Registry patients still showed no progression of neurological disease.
Our analysis of annual disease progression revealed a trend for slower progression in the later neurological onset subgroups and more rapid progression in earlier neurological onset subgroups, which is in line with previous data [
1,
8,
15,
16]. Even though disease progression was fastest among the infantile-onset subgroups in this study, stable/improved neurological disease was observed in 33 % (early infantile) to 50 % (late infantile) of treated patients.
Given the progressive, degenerative nature of NP-C, it is difficult to distinguish safety-related, treatment emergent adverse events from those related to disease progression. Nevertheless, based on the safety information reported here we consider that no unexpected safety findings were recorded during the NPC Registry observation period. The most common safety-relevant findings were chronic diarrhea (11 %), thrombocytopenia (54 %) and seizures (33 %). Gastrointestinal disturbances such as mild or moderate diarrhea and flatulence have previously been reported as transient in clinical practice and during clinical trials with miglustat [
4,
17,
18].
The high rate of thrombocytopenia among patients in this NPC Registry cohort may be explained by the high proportion of patients in the Registry who had ongoing splenomegaly (39 %): patients with ongoing splenomegaly are more likely to exhibit a mild or moderate degree of thrombocytopenia [
3].
Seizures were present in 23 % of NPC Registry patients before miglustat therapy, and during the observation period, new seizures were reported in 33 % of treated patients. It is well known from the literature that seizures are a common feature of the natural history of NPC, and NPC Registry data on seizures that occurred before miglustat therapy (‘pre-miglustat’) support this. Effective seizure control using anti-epileptic agents is considered crucial in optimizing patient quality of life [
2,
19].
New occurrences of tremor and neuropathy were relatively infrequent during the observation period. Again, however, it should be borne in mind that 25 % of NPC Registry patients had tremor and 4 % had neuropathy before miglustat initiation.
The clinical profile of miglustat-treated patients from the Registry presented in this paper is consistent with data from previous large cohort studies [
1,
11,
12,
20,
21]. The disease characteristics at enrolment of this miglustat-treated group were similar to those reported for the whole NPC Registry cohort as of March 2012, where data from both miglustat-treated and untreated patients were pooled [
14]. In addition, the estimated overall participation rate for European countries at the time of data analysis was high (63 %). Given this high rate of patient/physician participation, as well as the wide global coverage of participating centers, the presented miglustat-treated cohort of NPC registry patients can be considered representative of the overall NP-C patient population treated with miglustat, both within the Registry and globally.
This analysis comes with some limitations in terms of recruitment and data interpretation. The fact that the majority of patients with a confirmed diagnosis of NP-C are currently being treated with miglustat has the drawback that there are only a few treatment-naïve patients available for comparison. Moreover, as per health authority commitments, patient recruitment in the NPC Registry is primarily focused on countries where miglustat is approved for the treatment of NP-C. Physicians may not treat patients if they consider miglustat therapy unsuitable for them. For instance, miglustat therapy is not recommended for patients without neurological manifestations [
2,
4]. Some patients, in particular pediatric patients, might not be treated with miglustat due to difficulties swallowing a capsule, and some patients might be considered as too severely affected by the disease to benefit from treatment. The Registry untreated cohort therefore might not represent the full spectrum of the disease, and as a consequence untreated Registry patients are considered to be inadequate controls for the treated group. This precludes meaningful comparative analyses of the effectiveness of miglustat therapy.
Another limitation is the retrospective nature of data collection regarding onset of neurological manifestations, which might be subject to recall bias, especially in older patients for whom onset of neurological manifestations may be in the distant past. Despite this potential threat of patient misclassification, the most common disease forms are late-infantile and juvenile- onset NP-C, as previously described [
22].
Acknowledgements
The authors thank the following principal investigators who enrolled patients in this international NP-C Registry: Amado-Fondo A, Amraoui Y, Andria G, Arellano M, Audoin B, Azcona C, Barr C, Baruteau J, Baumgartner C, Bell L, Bembi B, Benneddif K, Bernard G, Bobocea N, Bodzioch M, Boettcher T, Bonnan M, Broue P, Bruni A, Caceres M, Camino R, Campbell E, Cances C, Cannell P, Cesar J, Chabrol B, Chakrapani A, Colao R, Collet A, Corsetti T, Cousins A, Covanis A, Cox T, Cuisset JM, Dardis A, Das A, Deegan P, Dengler T, Deodato F, Derralynn H, Di Donato I, Di Rocco M, Dinopoulos A, DomanskaPakiela, Eckehard S, Engelen M, Eyer D, Fecarotta S, Federico A, Filla A, Fiumara A, Fonseca MJ, Gabrielli O, Garcia T, Garrote J, Gissen P, Giugliani L, Greenberg C, Heron B, Hertzberg C, Higgins F, Hill A, Hiwot T, Hlavata A, Hörbe-Blindt A, Howley E, Hussain N, Illsinger S, Imrie J, Jacklin E, Jones S, Jovanovic A, Kaczmarek V, Kaphan E, Kibaek M, Kleinhans P, Klünemann KH, Koch SM, Koegl-Wallner W, Kolnikova M, Korenke GC, Korinthenberg R, Kumari S, Lachmann R, Lee Ann L, Likopoulou L, Lilienthal E, Link B, Lippold M, Lopez-Laso E, Luecke T, Lundgren J, Mackrell M, Madruga M, Maletta R, Malinova V, Manners J, Marinei R, Marquardt T, Martins E, Martins AM, Martins N, McAlister L, McCabe A, McKie M, McMahon S, Meehan M, Meldgaard Lund A, Mendozah C, Mengel E, Meyer A, Mielke S, Milligan A, Mir P, Moisa M, Mombelli C, Morris L, Müller vom Hagen J, Munoz B, Murphy E, Nagarajan L, Neto PB, Nevsimalova S, Nia S, Nicolai J, Niemann D, Niktari G, O‘Callaghan MDM, Paucar-Arce M, Peers K, Peintinger L, Peralta M, Pérez J, Perez-Poyato M, Petrariu A, Pineda M, Puschmann A, Raiman J, Rask O, Rataj J, Raymond-Gaynor C, Reichelt G, Ribeiro E, Riches V, Roberts A, Roelants J, Rohrbach M, Rokicki D, Rolfs A, Russo C, Rutsch F, Saleem R, Santos M, Schmutz P, Schwahn B, Sedel F, Semotok J, Sharma R, Silska S, Silva A, Simmons L, Sivera R, Skorpen J, Sole G, Souza C, Stadlober-Degwerth M, Starling J, Temudo T, Tomas M, Tranchant C, Uziel G, Valayannopoulous V, Van den Hout H, Van der Tol L, Van Spronsen F, Vellodi A, Verdu A, Vilchez JJ, Vinaixa A, Visser G, Voelker J, Waldek S, Walter A, Walterfang M, Wein U, Widner H, Wilcke C, Wildish L, Wraith E, Wright N, Xaidara A, Yamamoto M, Zallocco F, Zielke S.
This Registry is sponsored by Actelion Pharmaceuticals Ltd. Matthew Reilly PhD at InTouch Medical Ltd provided medical writing assistance paid for by Actelion Pharmaceuticals Ltd.
Competing interests
MCP has received research grants from the National Institutes of Health [NS 65768–01], the National MS Society and Actelion Pharmaceuticals Ltd. He has also received honoraria and consulting fees from Actelion Pharmaceuticals Ltd, Orphazyme, Shire HGT, Stem Cells, Inc, and Up-To-Date. EM has received consulting fees, honoraria and research grants from Actelion Pharmaceuticals Ltd. MTV has received travel expenses, consulting fees and presentation honoraria from Actelion Pharmaceuticals Ltd and Shire HGT. AM, BS and PC are permanent employees of Actelion Pharmaceuticals Ltd. MP has received consulting fees, honoraria and research grants from Actelion Pharmaceuticals Ltd and Biomarin.