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The ZAGAL Study: Long-term Management and Follow-up of use of Miglustat in type 1 Gaucher
disease in Spain.
Pilar GiraldoHaematology Department. Miguel Servet University Hospital
FEETEG
Disclosures
Received reimbursement of expenses and honoraria for lectures and occasional consultancies on the management of Gaucher disease, from Protalix, Genzyme, Actelion and Shire
June 29th 2012
The ZAGAL Study
Design Efficacy Safety Recommendations
June 29th 2012
• After approval miglustat in EU (2004)Objectives• To establish a set of recommendations for collecting
safety, efficacy and QoL data (12 months and longer follow-up)
• To guarantee the safe and proper use of miglustat in everyday clinical use
Treatment• Followed the recommendations of the European
Working Group on Gaucher Disease Advisory Council
ZAGAL study. (Zavesca en Gaucher Leve)
June 29th 2012
ZAGAL study
35092
Total 442
Mild: 72.7%
Moderate: 25.5% Severe: 1.7%
SSI in type 1 GD distribution
Mild: 72.7%
Moderate: 25.5% Severe: 1.7%
SSI in type 1 GD distribution
Age at diagnosis
ERT 58.7%Mean: 10.2 yW&W28.7%
RST 12.6%Mean: 3.1 y
Type of therapy
Giraldo P et al Orphanet J Rare Dis. 2012 June 29th 2012
ZAGAL study
Variables Tolerant Intolerant Total No(%) 28(53.8) 24(46.1) 52Mean age(range) 51(18-85) 48.9(22-71) 49.9(18-85)M/F(F%) (53.6) (41.6) (48.0)Age at Dx 31(2-78) 35(5-56) 33(2-78)SSI at Dx 6.5(3-7) 6.7(3-7.5) 6.6(3-7.5)Genotype N370S/N370S(%) 6(21.4) 2(8.3) 8(15.3)N370S/L444P(%) 9(32.1) 12(50.0) 21(40.3)N370S/other(%) 10(35.7) 8(33.3) 18(34.6)Other/other 3(10.7) 2(8.3) 5(9.6)SplenectomyNaïve/switch
6(21.4)8/20
2(8.3)3/21
8(15.3)11/41
Total 28 24 52
General characteristics GD1 patients treated with miglustat according tolerance
June 29th 2012
ZAGAL study
Baseline
0.5 1 2 3 4 5 6 711.5
12
12.5
13
13.5
14
14.5
Baseline
0.5 1 2 3 4 5 6 70
100
200
300
400
500
YearsBaseline
0.5 1 2 3 4 5 6 70
500
1000
1500
2000
Hb g/dLPlatelets x109/L
Spleen volume mL Liver volume mL
52 41 1533 24 203038 52 41 1533 24 203038
Base-line
1 2 3 4 5 6 70
20
40
60
80
100
120
140
160
52 41 1533 24 203038 52 41 1533 24 203038
June 29th 2012
Years
ZAGAL study
Baseline
0.5 1 2 3 4 5 6 70
500
1000
1500
2000
2500
3000
Baseline
0.5 1 2 3 4 5 6 70
100
200
300
400
500
600CCL18/PARC ng/mLQT nMol/mL.h
52 41 1533 24 203038 52 41 1533 24 203038
Years
June 29th 2012
ZAGAL study
S-MRI patternScore
Non-homogeneous diffuse 3 Non-homogeneous mottled 2 Non-homogeneous reticular 1 Normal 0 Homogeneous 4 Complications: bone infarct, avascular necrosis,
bone crisis and vertebral collapse 4
Roca M et al Eur J Radiol. 2007 June 29th 2012
ZAGAL study. Bone marrow changes after 2 years of miglustat
A. Baseline B. 2 years
SE T1 after 12 months on miglustatNon-homogeneous mottled pattern showing a perceptive change with increase of signal in both trochanters
SE T1 at baselineNon-homogeneous diffuse patternInvolvement of left trochanter
Roca et al., (unpublished observations) In Pastores GM et al 2008
Before miglustat After miglustatBefore miglustat After miglustat
SE T1 at baseline
Non-homogeneous diffuse pattern
Involvement of left trochanter
SE T1 after 12 months on miglustat
Non-homogeneous mottled pattern showing a perceptive change with increase of signal in both trochanter
SE T1 at baseline
Non-homogeneous diffuse pattern
Involvement of left trochanter
SE T1 after 12 months on miglustat
Non-homogeneous mottled pattern showing a perceptive change with increase of signal in both trochanter
SE T1 at baseline
Non-homogeneous diffuse pattern
Involvement of left trochanter
SE T1 after 12 months on miglustat
Non-homogeneous mottled pattern showing a perceptive change with increase of signal in both trochanter
SE T1 at baseline
Non-homogeneous diffuse pattern
Involvement of left trochanter
SE T1 after 12 months on miglustat
Non-homogeneous mottled pattern showing a perceptive change with increase of signal in both trochanter
REMARKS: Bone marrow-MRI improvement in naïve patients
Roca M et al. Eur J Radiol. 2007;62:132-7. June 29th 2012
ZAGAL study. Bone marrow changes after 2 years of miglustat
0
5
10
15
1 2 3 4 5 6 705
10152025
1 2 3 4 5 6 7
TRAP-5bS-MRI
1 2 3 4 5 6 7 1 2 3 4 5 6 7
0200
400060008000
1000012000
Chitotriosidase
nM/m
L.h
0
500
1000
1500
CCL18/PARC
ng/m
L
U/L
Sco
re
Baseline 2 years
June 29th 2012
ZAGAL study
BUA, Z-scores and T-scores for bone mineral density of calcaneous by ultrasound (CUBA CLINICAL BONE DENSITOMETER). In 24 patients on miglustat therapy.
Bone BUABaselin Mean (range)
Month24 Mean (range)
p Score Baseline Mean (SD)
Month24 Mean (SD)
Change 95%CI
p
Rigth calcaneous
82.4 (47-101)
84.2 (66-100)
0.04 Z-score
-1.30(0.9)
-1.10(0.9) 0.09, 0.42
0.01
T-score
-1.33(0.9)
-1.28(0.9) 0.09, 0.48
0.01
Left calcaneous
74.2 (32-100)
75.6 (48-101)
0.06 Z-score
-1.06(0.9)
-0.92 (0.5) 0.09, 0.30
0.01
T-score
-1.46(1.1)
-1.07(0.4) 0.08, 0.45
0.01
June 29th 2012
Quality of life: SF-36 scales
0
10
20
30
40
50
60
70
80
90
100
PF RP Pain GH Vit SF RE MH
Spanish Population
before therapy
after 24 m ERT
after 24 m SRT
June 29th 2012
ZAGAL study
Changes in the atherogenic profile of patients with type 1 Gaucher disease after miglustat therapy.
In 26 GD1 patients treated with miglustat for up to 36 months:
Group A: 10 patients therapy-naïve
significantly: plasma HDL-c and apoA-I, and slightly increased TC; TG, CRP concentrations, and TC/HDL-c ratios decreased significantly
Group B: 16 patients switched from enzyme replacement therapy (ERT); No changes in HDL-c and apoA-I, or in the TC/HDL-c ratio. CRP was observed after 12 months.LDL-c and apoB were not significantly altered in either patient groupMiglustat appears to have beneficial effects on plasma lipid, lipoprotein, and CRP concentrations in therapy-naïve GD1 patients, resulting in an improved atherogenic lipid profile. .
Puzo J et al Atherosclerosis. 2010 June 29th 2012
ZAGAL study
• In summary: 42 patients are on miglustat therapy and 15 patients have more than 7 years under therapy.
• The goals of therapy have been achieved. • 3 patients died by non-related causes (2 neoplasia
and 1 hearth attack), • 1 patient have discontinued by planning to become
pregnant • 6 discontinuing by poor filling or intolerance. • 8 patients had transitory diarrhea and flatulence.
June 29th 2012
ZAGAL study. Adverse events and discontinuation
June 29th 2012
ZAGAL study. Recommendations
• In order to avoid gastrointestinal disturbances during Miglustat therapy, we are recommending two strategies:
• To administrate therapy without meals for example 2 hours before breakfast, lunch and dinner
• To start therapy in scalating doses: during the first week only 100 mg /day during the second week only 200 mg/dayduring third week and later total therapy with 300 mg/day
• Simultaneously it is convennient consider the content of carbohidrates in the diet according the following suggestions:
Giraldo P et al. Haematologica. 2009;94(12):1771-1775.June 29th 2012
Dietary Recommendations
June 29th 2012
Dietary Recommendations
June 29th 2012
Dietary Recommendations
June 29th 2012
Dietary Recommendations
June 29th 2012
Dietary Recommendations
June 29th 2012
Dietary Recommendations
June 29th 2012
Dietary Recommendations
June 29th 2012
FEETEG
Pilar GiraldoSº Hematología. HU Miguel Servet
FEETEG
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