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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Orphanet Journal of Rare Diseases 1/2014

Intra-Erythrocyte Infusion of Dexamethasone Reduces Neurological Symptoms in Ataxia Teleangiectasia Patients: Results of a Phase 2 Trial

Zeitschrift:
Orphanet Journal of Rare Diseases > Ausgabe 1/2014
Autoren:
Luciana Chessa, Vincenzo Leuzzi, Alessandro Plebani, Annarosa Soresina, Roberto Micheli, Daniela D’Agnano, Tullia Venturi, Anna Molinaro, Elisa Fazzi, Mirella Marini, Pierino Ferremi Leali, Isabella Quinti, Filomena Monica Cavaliere, Gabriella Girelli, Maria Cristina Pietrogrande, Andrea Finocchi, Stefano Tabolli, Damiano Abeni, Mauro Magnani
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1172-9-5) contains supplementary material, which is available to authorized users.

Competing interests

MM hold stock ownership in EryDel S.p.A. No competing interests for all other authors.

Authors’ contributions

All authors participated to the conception, design, analysis and interpretation of the content, manuscript preparation and revision and have read and approved the final version of the manuscript. All authors read and approved the final manuscript.

Abstract

Background

Ataxia Teleangiectasia [AT] is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer. No therapies are available for this devastating disease. Recent observational studies in few patients showed beneficial effects of short term treatment with betamethasone. To avoid the characteristic side effects of long-term administration of steroids we developed a method for encapsulation of dexamethasone sodium phosphate (DSP) into autologous erythrocytes (EryDex) allowing slow release of dexamethasone for up to one month after dosing. Aims of the study were: the assessment of the effect of EryDex in improving neurological symptoms and adaptive behaviour of AT patients; the safety and tolerability of the therapy.

Methods

Twenty two patients (F:M = 1; mean age 11.2 ± 3.5) with a confirmed diagnosis of AT and a preserved or partially supported gait were enrolled for the study. The subjects underwent for six months a monthly infusion of EryDex. Ataxia was assessed by the International Cooperative Ataxia Rating Scale (ICARS) and the adaptive behavior by Vineland Adaptive Behavior Scales (VABS). Clinical evaluations were performed at baseline and 1, 3, and 6 months.

Results

An improvement in ICARS (reduction of the score) was detected in the intention-to-treat (ITT) population (n = 22; p = 0.02) as well as in patients completing the study (per protocol PP) (n = 18; p = 0.01), with a mean reduction of 4 points (ITT) or 5.2 points (PP). When compared to baseline, a significant improvement were also found in VABS (increase of the score) (p < 0.0001, ITT, RMANOVA), with statistically significant increases at 3 and 6 months (p < 0.0001). A large inter-patient variability in the incorporation of DSP into erythrocytes was observed, with an evident positive effect of higher infusion dose on ICARS score decline. Moreover a more marked improvement was found in less neurologically impaired patients. Finally, a 19 month-extension study involving a subgroup of patients suggested that Erydex treatment can possibly delay the natural progression of the disease.
EryDex was well tolerated; the most frequent side effects were common AT pathologies.

Conclusions

EryDex treatment led to a significant improvement in neurological symptoms, without association with the typical steroid side effects.

Trial registration

Current Controlled Trial2010-022315-19SpA
Zusatzmaterial
Additional file 1: Table S1: Demographic data (ITT population). (DOCX 81 KB)
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Additional file 2: Table S2: Number of treatments for patients (divided for Trial Center: 1–Roma, and 2-Brescia), mean DSP loading for patient, ICARS and VABS variation (ITT population). (DOC 54 KB)
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Additional file 3: Figure S1: Study disposition. (DOCX 70 KB)
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Additional file 4:Video Legend. Basal and V7 neurological examinations in patient 01–01 showing improvement in ICARS subtests. (MP4 13 MB)
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Additional file 5: Table S3: ICARS and VABS scores in 4 patients treated for an adjunctive 19-month period as compared with 4 ICARS score matched controls. (DOCX 18 KB)
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Additional file 6: Table S4: Values for Special Laboratory Parameters and adverse events in 4 patients treated for an adjunctive 19-month period as compared with 4 ICARS score matched controls. (DOCX 29 KB)
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Additional file 7: Table S5: Changes from Baseline to the Final Visit for special laboratory parameters (ITT Population). (DOCX 20 KB)
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Additional file 8: Table S6: Group data for Vital and Physical Signs at V1 and V7 (ITT Population). (DOCX 16 KB)
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Authors’ original file for figure 1
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Authors’ original file for figure 2
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Literatur
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