Clinical Study to Evaluate the Long Term Efficacy, Safety and Tolerability of Miglustat in Patients With Stable Type 1 Gaucher Disease

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00319046
• Collaborator: (none)
• Enrollment: 42
• Locations: 20
• Arm: 1
• Duration (Months): 52.9
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Although miglustat has been approved as a treatment for mild to moderate type 1 Gaucher disease in patients who are unsuitable for enzyme replacement therapy (ERT), more data are required to establish the long term efficacy, safety and tolerability of miglustat in maintaining diseases stability after a switch from ERT.

Condition or Disease	Intervention/Treatment	Phase
Gaucher Disease Type 1	Drug: Miglustat	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Non Comparative, Multi-center Study to Evaluate the Long Term Efficacy, Safety and Tolerability of Oral Miglustat as a Maintenance Therapy After a Switch From Enzyme Replacement Therapy in Adult Patients With Stable Type 1 Gaucher Disease
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open-label miglustat Oral administration of miglustat 100 mg t.i.d. for a period of 2 years	Drug: Miglustat; Oral capsules containing miglustat 100 mg, administered three times daily (t.i.d.); Other Names: Zavesca

Outcome Measures

Primary Outcome Measures

1. Liver Volume at Baseline and at End of Treatment [Baseline and end of treatment (Month 24)]

   Liver volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.

2. Mean Within-patient Percent Change From Baseline in Liver Volume [End of treatment (Month 24)]

   Liver volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.

Secondary Outcome Measures

1. Spleen Volume at Baseline and End of Treatment [Baseline and end of treatment (Month 24)]

   Spleen volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.

2. Mean Percent Change From Baseline in Spleen Volume [End of treatment (Month 24)]

   Spleen volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males or females aged 18 years or older

2. Type 1 Gaucher disease, diagnosed by glucocerebrosidase assay or molecular analysis of the glucocerebrosidase gene.

3. Treatment with ERT for at least 3 years, with a stable dose regimen for at least the last 6 months.

4. Clinically and biologically stable disease for the previous 2 years, with at least 2 time points assessments (including baseline as one potential time point), defined as:

• Stable organomegaly (assessed by magnetic resonance imaging (MRI) or computed tomography (CT)):

• Liver volume within 10% of the mean.

• Spleen volume within 10% of the mean.

• Free of progressive symptomatic documented bone disease.

• Hemoglobin levels > 11g/dl

• Mean platelet count > 100x10^9 /l.

• Chitotriosidase activity within 20% of the mean.

• If chitotriosidase is not available (in the case of chitotriosidase deficiency, or if it was not determined), other relevant biomarkers (e.g., angiotensin converting enzyme (ACE), tartrate resistant acid phosphatase (TRAP) and ferritin) could be considered.

1. Written informed consent.

Exclusion Criteria:

1. History or evidence of oculomotor gaze palsy, ataxia or other clinical manifestations typically associated with neuronopathic type 3 Gaucher disease.

2. Not ambulant patients, or with progressive symptomatic documented bone disease.

3. Splenectomy before 18 years of age for splenomegaly and/or thrombocytopenia.

4. Peripheral polyneuropathy (not mononeuropathy) documented with both clinical signs and symptoms, and electrodiagnostic (EDX).

5. Patients (males and females) who do not agree to use reliable contraception throughout the study and for 3 months after cessation of miglustat treatment.

6. Female patients who are pregnant or breast feeding, or without pregnancy test prior to Day 1.

7. History of significant lactose intolerance.

8. Clinically significant diarrhea (>3 liquid stools per day for >7 days) without definable cause within 6 months prior to Day 1, or a history of clinically relevant gastrointestinal disorders.

9. History of cataracts or known increased risk of cataract formation.

10. Severe renal impairment i.e., with a creatinine clearance <30 ml/min/1.73m^2

11. Concomitant active medical condition such as human immunodeficiency virus (HIV) or hepatitis B/C that would render patients unsuitable for study.

12. Previous treatment with miglustat.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143
2	Children's National Medical Center	Washington	District of Columbia	United States	20010
3	Emory University	Decatur	Georgia	United States	30033
4	NYU School of Medicine	New York	New York	United States	10016
5	Doembecher Children's Hospital, Oregon Health and Sciences University	Portland	Oregon	United States	97239
6	Medical College of Wisconsin	Wauwatosa	Wisconsin	United States	53226
7	Royal Perth Hospital	Perth		Australia
8	Royal Brisbane and Women's Hospital	Queensland		Australia
9	Royal Melbourne Hospital	Victoria		Australia
10	Hospital de Clinicas de Porto Alegre	Porto Alegre		Brazil
11	Mount Sinai Hospital	Toronto	Ontario	Canada	M5G 1X5
12	Klinika detskeho a dorostoveho lekarstvi	Prague		Czechia
13	Hopital Beaujon	Clichy		France	92118
14	Kinderklinik der Universitat Mainz	Mainz		Germany	55131
15	University of Debrecen	Debrecen		Hungary
16	Ospedale Burlo Garofolo	Trieste		Italy	34100
17	Academic Medical Center	Amsterdam		Netherlands	1100
18	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
19	National Taiwan University Hospital	Taipei		Taiwan
20	University of Cambridge	Cambridge		United Kingdom	CB2 2QQ

Sponsors and Collaborators

• Actelion

Investigators

• Principal Investigator: Timothy Cox, Prof, University of Cambridge

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT00319046
• Other Study ID Numbers: OGT 918-011
• First Posted: Apr 27, 2006
• Last Update Posted: Nov 21, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Actelion: enzyme replacement therapy; Type 1 Gaucher Disease; miglustat
• Additional relevant MeSH terms: Gaucher Disease; Miglustat

Study Results

Participant Flow

Recruitment Details	Patients were enrolled at 16 centers in 10 countries (Australia, Brazil, Canada, Czech Republic, France, Netherlands , Spain, Taiwan, UK, and USA. The first patient, first visit was 21 February 2006 and the last patient, last visit was 22 June 2010.

Arm/Group Title	Miglustat
Arm/Group Description	Oral administration of miglustat 100 mg t.i.d. for a period of 2 years
Period Title: Overall Study
STARTED	42
COMPLETED	34
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Miglustat
Arm/Group Description	Oral administration of miglustat 100 mg t.i.d. for a period of 2 years
Overall Participants	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.1 (12.7)
Age, Customized (participants) [Number]
Between 22 and 70 years	42 100%
Sex: Female, Male (Count of Participants)
Female	20 47.6%
Male	22 52.4%
Region of Enrollment (participants) [Number]
Australia	3 7.1%
Brazil	1 2.4%
Canada	5 11.9%
Czech Republic	2 4.8%
France	1 2.4%
Netherlands	3 7.1%
Spain	2 4.8%
Taiwan	1 2.4%
United Kingdom	6 14.3%
United States	18 42.9%

Outcome Measures

1. Primary Outcome

Title	Liver Volume at Baseline and at End of Treatment
Description	Liver volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.
Time Frame	Baseline and end of treatment (Month 24)

Outcome Measure Data

Analysis Population Description

One patient was excluded from analysis as the baseline liver volume not available

Arm/Group Title	Miglustat
Arm/Group Description	Oral administration of miglustat 100 mg t.i.d. for a period of 2 years
Measure Participants	41
Baseline	1774.6 (484.07)
End of treatment	1727.1 (381.73)

2. Primary Outcome

Title	Mean Within-patient Percent Change From Baseline in Liver Volume
Description	Liver volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.
Time Frame	End of treatment (Month 24)

Outcome Measure Data

Analysis Population Description

One patient was excluded from analysis as the baseline liver volume not available

Arm/Group Title	Miglustat
Arm/Group Description	Oral administration of miglustat 100 mg t.i.d. for a period of 2 years
Measure Participants	41
Mean (Standard Deviation) [Percentage change]	-1.1 (13.75)

3. Secondary Outcome

Title	Spleen Volume at Baseline and End of Treatment
Description	Spleen volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.
Time Frame	Baseline and end of treatment (Month 24)

Outcome Measure Data

Analysis Population Description

The analysis was performed on those non-splenectomized patients who had a post-baseline assessment of spleen volume while on treatment with miglustat

Arm/Group Title	Miglustat
Arm/Group Description	Oral administration of miglustat 100 mg t.i.d. for a period of 2 years
Measure Participants	22
Baseline	509.8 (371.77)
End of treatment	611.9 (442.44)

4. Secondary Outcome

Title	Mean Percent Change From Baseline in Spleen Volume
Description	Spleen volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.
Time Frame	End of treatment (Month 24)

Outcome Measure Data

Analysis Population Description

The analysis was performed on those non-splenectomized patients who had a post-baseline assessment of spleen volume while on treatment with miglustat

Arm/Group Title	Miglustat
Arm/Group Description	Oral administration of miglustat 100 mg t.i.d. for a period of 2 years
Measure Participants	22
Mean (Standard Deviation) [Percentage change]	21.1 (25.37)

Adverse Events

Time Frame	From study treatment start to the study treatment end date plus 2 days
Arm/Group Title	Miglustat
Arm/Group Description	Oral administration of miglustat 100 mg t.i.d. (median time exposure = 658 days)
All Cause Mortality
	Miglustat
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Miglustat
	Affected / at Risk (%)	# Events
Total	5/42 (11.9%)
Gastrointestinal disorders
ABDOMINAL DISCOMFORT	1/42 (2.4%)
HAEMATOCHEZIA	1/42 (2.4%)
Infections and infestations
PNEUMONIA	1/42 (2.4%)
Investigations
BLOOD URINE PRESENT	1/42 (2.4%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/42 (2.4%)
BACK PAIN	1/42 (2.4%)
JOINT SWELLING	1/42 (2.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
COLON CANCER	1/42 (2.4%)
CYST	1/42 (2.4%)
TRANSITIONAL CELL CARCINOMA	1/42 (2.4%)
Nervous system disorders
CEREBELLAR SYNDROME	1/42 (2.4%)
HYPERREFLEXIA	1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	Miglustat
	Affected / at Risk (%)	# Events
Total	40/42 (95.2%)
Blood and lymphatic system disorders
THROMBOCYTOPENIA	4/42 (9.5%)
ANAEMIA	3/42 (7.1%)
Gastrointestinal disorders
DIARRHOEA	31/42 (73.8%)
FLATULENCE	21/42 (50%)
ABDOMINAL DISTENSION	4/42 (9.5%)
ABDOMINAL PAIN	4/42 (9.5%)
NAUSEA	4/42 (9.5%)
ABDOMINAL PAIN UPPER	3/42 (7.1%)
General disorders
FATIGUE	8/42 (19%)
Infections and infestations
NASOPHARYNGITIS	4/42 (9.5%)
UPPER RESPIRATORY TRACT INFECTION	4/42 (9.5%)
Investigations
CHITOTRIOSIDASE INCREASED	6/42 (14.3%)
WEIGHT DECREASED	6/42 (14.3%)
PLATELET COUNT DECREASED	5/42 (11.9%)
HAEMOGLOBIN DECREASED	4/42 (9.5%)
ANGIOTENSIN CONVERTING ENZYME INCREASED	3/42 (7.1%)
BLOOD FOLATE DECREASED	3/42 (7.1%)
Musculoskeletal and connective tissue disorders
MUSCLE SPASMS	4/42 (9.5%)
BONE PAIN	3/42 (7.1%)
Nervous system disorders
TREMOR	15/42 (35.7%)
HEADACHE	9/42 (21.4%)
PARAESTHESIA	9/42 (21.4%)
DIZZINESS	7/42 (16.7%)
HYPOAESTHESIA	5/42 (11.9%)
Psychiatric disorders
DEPRESSION	3/42 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.