A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease (ENGAGE)

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00891202
• Collaborator: (none)
• Enrollment: 40
• Locations: 18
• Arms: 2
• Duration (Months): 74
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This Phase 3 study was designed to confirm the efficacy and safety of eliglustat tartrate (Genz-112638) in participants with Gaucher disease Type 1.

Condition or Disease	Intervention/Treatment	Phase
Gaucher Disease, Type 1	Drug: Eliglustat tartrate; Drug: Placebo	Phase 3

Detailed Description

Gaucher disease is characterized by lysosomal accumulation of glucosylceramide due to impaired glucosylceramide hydrolysis. Type 1 Gaucher disease, the most common form accounts for greater than (>) 90% of cases and does not involve the central nervous system (CNS). Typical manifestations of Type 1 Gaucher disease include splenomegaly, hepatomegaly, thrombocytopenia, anemia, skeletal pathology and decreased quality of life. The disease manifestations are caused by the accumulations of glucosylceramide (storage material) in Gaucher cells which have infiltrated the spleen and liver as well as other tissue. Eliglustat tartrate is a small molecule developed as an oral therapy which acts to specifically inhibit production of this storage material in Gaucher cells.

This study was designed to determine the efficacy, safety, and pharmacokinetics (PK) of eliglustat tartrate in adult participants (>16 years) with Gaucher disease Type 1. The study consisted of 2 periods: The Double-Blind Primary Analysis Period (PAP [Day 1 to Week 39]) and the Long Term Treatment Period (LTTP/Open-Label Period (post-Week 39 [Day 1 of the Open-Label Period] through study completion).

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study Confirming the Efficacy and Safety of Genz-112638 in Patients With Gaucher Disease Type 1 (ENGAGE)
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active Eliglustat	Drug: Eliglustat tartrate; PAP: Eliglustat tartrate (ET) capsule 50 mg orally on Day 1 followed by ET 50 mg capsule twice daily (BID) from Day 2 to Week 4, then either ET 50 mg capsule BID (participants with Genz-99067 [active moiety of ET in plasma] trough plasma concentration >=5 ng/mL) or ET 100 mg capsule BID (participants with Genz-99067 trough plasma concentration <5 ng/mL), up to Week 39. PK assessment at Week 2 used for dose adjustment after Week 4. LTTP: Participants of the eliglustat arm in PAP who completed PAP were included in LTTP and received ET capsule 50 mg BID orally from Day 1 (post Week 39) until Week 43 followed by ET 50 mg or 100 mg capsule BID up to Week 47, then ET 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.; Other Names: Genz-112638
Placebo Comparator: Placebo Placebo	Drug: Placebo; PAP: Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39. LTTP: Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline for LTTP. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.

Outcome Measures

Primary Outcome Measures

1. PAP: Percent Change From Baseline in Spleen Volume (in Multiples of Normal [MN]) at Week 39 of the Primary Analysis Period With Eliglustat Tartrate Treatment as Compared to Placebo [PAP Baseline (Day 1), Week 39]

   Percent change in spleen volume = ([spleen volume at Week 39 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.

Secondary Outcome Measures

1. PAP: Hemoglobin Level [PAP Baseline (Day 1)]

2. PAP: Absolute Change From Baseline in Hemoglobin Level at Week 39 [PAP Baseline (Day 1), Week 39]

   Absolute change = hemoglobin level at Week 39 minus hemoglobin level at baseline.

3. PAP: Percent Change From Baseline in Liver Volume (in MN) at Week 39 [PAP Baseline (Day 1), Week 39]

   Percent change in liver volume = ([liver volume at Week 39 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in MN.

4. PAP: Percent Change From Baseline in Platelet Counts at Week 39 [PAP Baseline (Day 1), Week 39]

   Percent change in platelet count = ([platelet count at Week 39 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.

5. LTTP: Percent Change From Baseline in Spleen Volume (in MN) at Week 234 [PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234]

   Percent change in spleen volume = ([spleen volume at Week 234 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.

6. LTTP: Absolute Change From Baseline in Hemoglobin Level at Week 234 [PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234]

   Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.

7. LTTP: Percent Change From Baseline in Liver Volume (in MN) at Week 234 [PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234]

   Percent change in liver volume = ([liver volume at Week 234 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in MN. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.

8. LTTP: Percent Change From Baseline in Platelet Counts at Week 234 [PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234]

   Percent change in platelet count = ([platelet count at Week 234 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The participant (and/or their parent/legal guardian) was willing and able to provide signed informed consent prior to any study-related procedures to be performed;

• The participant was at least 16 years old at the time of randomization;

• The participant had a confirmed diagnosis of Gaucher disease Type 1;

• Female participants of childbearing potential must had a documented negative pregnancy test prior to dosing. In addition all female participants of childbearing potential must use a medically accepted form of contraception throughout the study.

Exclusion Criteria:

• The participant has had a partial or total splenectomy;

• The participant had received pharmacological chaperones or miglustat within 6 months prior to randomization;

• The participant had received enzyme replacement therapy within 9 months prior to randomization;

• The participant had Type 2 or 3 Gaucher disease or was suspected of having Type 3 Gaucher disease;

• The participant had any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal (GI), pulmonary, neurologic, endocrine, metabolic, (for example, hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illness that might confound the study results, or, on the opinion of the investigator, might preclude participation in the study;

• The participant had tested positive for the human immunodeficiency virus (HIV) antibody, Hepatitis C antibody, or Hepatitis B surface antigen;

• The participant had received an investigational product within 30 days prior to randomization;

• The participant was pregnant or lactating.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF MS Center	San Francisco	California	United States	94143
2	Yale University School of Medicine	New Haven	Connecticut	United States	06510
3	Emory University Medical Genetics	Decatur	Georgia	United States	30033
4	University of Kansas Medical Center, Division of Hematology/Oncology, Dept. of Medicine	Westwood	Kansas	United States	66160
5	New York University School of Medicine, Neurology Department	New York	New York	United States	10016
6	Mount Sinai School of Medicine	New York	New York	United States	10029
7	University hospital "Alexandrovska" Sofia	Sofia		Bulgaria	1431
8	Sir Mortimer B. Davis - Jewish General Hospital	Montreal, Quebec		Canada	H3T 1E2
9	Mount Sinai Hospital and the Samuel Lunenfeld Research Institute	Toronto Ontario		Canada	M5G 1X5
10	Hospital de San Jose	Bogota		Colombia
11	Christian Medical College Hospital	Vellore		India	632004
12	Rabin Medical Center, Beilinson Hospital	Petach Tikvah		Israel	49100
13	Hôtel-Dieu de France University Hospital	Beirut		Lebanon
14	OCA Hospital	Monterrey, Nuevo Leon		Mexico
15	Hematology Research Center of Ministry of Healthcare of the Russian Federation	Moscow		Russian Federation	125167
16	Institut za endokrinologiju	Belgrade		Serbia	11000
17	Hopital La-Rabta	Tunis	TN	Tunisia	1007
18	Royal Free Hospital	London		United Kingdom	NW3 2QG

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Medical Monitor, Genzyme, a Sanofi Company

Study Documents (Full-Text)

None provided.

More Information

Publications

• Kamath RS, Lukina E, Watman N, Dragosky M, Pastores GM, Arreguin EA, Rosenbaum H, Zimran A, Aguzzi R, Puga AC, Norfleet AM, Peterschmitt MJ, Rosenthal DI. Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat. Skeletal Radiol. 2014 Oct;43(10):1353-60. doi: 10.1007/s00256-014-1891-9. Epub 2014 May 10.
• Lukina E, Watman N, Arreguin EA, Banikazemi M, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Rosenthal DI, Kaper M, Singh T, Puga AC, Bonate PL, Peterschmitt MJ. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 2010 Aug 12;116(6):893-9. doi: 10.1182/blood-2010-03-273151. Epub 2010 May 3.
• Lukina E, Watman N, Arreguin EA, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Kamath RS, Rosenthal DI, Kaper M, Singh T, Puga AC, Peterschmitt MJ. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood. 2010 Nov 18;116(20):4095-8. doi: 10.1182/blood-2010-06-293902. Epub 2010 Aug 16. Erratum in: Blood. 2011 May 19;117(20):5551.
• Lukina E, Watman N, Dragosky M, Pastores GM, Arreguin EA, Rosenbaum H, Zimran A, Angell J, Ross L, Puga AC, Peterschmitt JM. Eliglustat, an investigational oral therapy for Gaucher disease type 1: Phase 2 trial results after 4 years of treatment. Blood Cells Mol Dis. 2014 Dec;53(4):274-6. doi: 10.1016/j.bcmd.2014.04.002. Epub 2014 May 15.
• McEachern KA, Fung J, Komarnitsky S, Siegel CS, Chuang WL, Hutto E, Shayman JA, Grabowski GA, Aerts JM, Cheng SH, Copeland DP, Marshall J. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab. 2007 Jul;91(3):259-67. Epub 2007 May 16.
• Peterschmitt MJ, Burke A, Blankstein L, Smith SE, Puga AC, Kramer WG, Harris JA, Mathews D, Bonate PL. Safety, tolerability, and pharmacokinetics of eliglustat tartrate (Genz-112638) after single doses, multiple doses, and food in healthy volunteers. J Clin Pharmacol. 2011 May;51(5):695-705. doi: 10.1177/0091270010372387. Epub 2010 Sep 23.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00891202
• Other Study ID Numbers: GZGD02507; 2008-005222-37; EFC12813
• First Posted: May 1, 2009
• Last Update Posted: Mar 3, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Genzyme, a Sanofi Company: Gaucher,; beta-glucosidase,; acid ß-glucosidase,; glucocerebrosidase,; glucosylceramide,; D-glucosyl-N-acylsphingosine glucohydrolase,; substrate reduction therapy
• Additional relevant MeSH terms: Gaucher Disease; Eliglustat

Study Results

Participant Flow

Recruitment Details	A total of 72 participants were screened between 5 November 2009 and 29 July 2011, of which 32 participants were screen failure. Overall 40 participants were enrolled and the study was conducted across 18 centers in 12 countries.
Pre-assignment Detail	The 40 participants who met inclusion criteria received placebo or Genz-112638 (eliglustat tartrate) during 39 weeks primary analysis period (PAP). After Week 39 of the PAP, all participants who remained in the study received eliglustat tartrate in the long-term treatment period (LTTP) for up to Week 312.

Arm/Group Title	PAP: Eliglustat	PAP: Placebo	LTTP: Eliglustat (Originally on Eliglustat)	LTTP: Eliglustat (Originally on Placebo)
Arm/Group Description	Eliglustat tartrate capsule as a single 50 milligram (mg) dose on Day 1 followed by eliglustat tartrate 50 mg capsule twice daily (BID) from Day 2 to Week 4, and then either eliglustat tartrate 50 mg capsule BID (in participants who had a Genz-99067 [active moiety of eliglustat tartrate in plasma] trough plasma concentration greater than or equal to [>=] 5 nanogram per milliliter [ng/mL]) or eliglustat tartrate 100 mg capsule BID (in participants who had a Genz-99067 trough plasma concentration less than [<] 5 ng/mL), up to Week 39. The pharmacokinetic (PK) assessment at Week 2 was used for dose adjustment after Week 4.	Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39.	Participants of the eliglustat arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate capsule 50 mg BID orally from Day 1 (post Week 39) until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.	Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline of LTTP for this arm. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.
Period Title: PAP (Up To Week 39)
STARTED	20	20	0	0
COMPLETED	19	20	0	0
NOT COMPLETED	1	0	0	0
Period Title: PAP (Up To Week 39)
STARTED	0	0	19	20
COMPLETED	0	0	12	15
NOT COMPLETED	0	0	7	5

Baseline Characteristics

Arm/Group Title	PAP: Eliglustat	PAP: Placebo	Total
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50 mg or 100 mg capsule BID orally up to Week 39.	Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39.	Total of all reporting groups
Overall Participants	20	20	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.6 (11.55)	32.1 (11.26)	31.8 (11.26)
Gender (Count of Participants)
Female	12 60%	8 40%	20 50%
Male	8 40%	12 60%	20 50%
Race/Ethnicity, Customized (participants) [Number]
Race: White	19 95%	20 100%	39 97.5%
Race: Asian	1 5%	0 0%	1 2.5%
Ethnicity: Not Hispanic or Latino	18 90%	20 100%	38 95%
Ethnicity: Hispanic or Latino	2 10%	0 0%	2 5%
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	23.3 (2.74)	23.4 (3.54)	23.4 (3.13)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	64.8 (11.74)	68.6 (17.17)	66.7 (14.65)
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	166.2 (9.91)	170.0 (12.02)	168.1 (11.05)

Outcome Measures

1. Primary Outcome

Title	PAP: Percent Change From Baseline in Spleen Volume (in Multiples of Normal [MN]) at Week 39 of the Primary Analysis Period With Eliglustat Tartrate Treatment as Compared to Placebo
Description	Percent change in spleen volume = ([spleen volume at Week 39 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.
Time Frame	PAP Baseline (Day 1), Week 39

Outcome Measure Data

Analysis Population Description

FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).

Arm/Group Title	PAP: Eliglustat	PAP: Placebo
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50 mg or 100 mg capsule BID orally up to Week 39.	Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39.
Measure Participants	20	20
Least Squares Mean (Standard Error) [percent change]	-27.77 (2.37)	2.26 (2.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PAP: Eliglustat, PAP: Placebo
	Comments	Analysis was performed using analysis of covariance (ANCOVA) model fitted with treatment and baseline spleen severity (low spleen severity: spleen volume less than or equal to [<=] 20 multiples of normal spleen volume, high spleen severity: spleen volume greater than [>] 20 multiples of normal spleen volume).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-30.03
	Confidence Interval	(2-Sided) 95%; -36.82 to -23.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.35
	Estimation Comments

2. Secondary Outcome

Title	PAP: Hemoglobin Level
Time Frame	PAP Baseline (Day 1)

Outcome Measure Data

Analysis Population Description

FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).

Arm/Group Title	PAP: Eliglustat	PAP: Placebo
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50 mg or 100 mg capsule BID orally up to Week 39.	Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39.
Measure Participants	20	20
Mean (Standard Deviation) [gram per deciliter (g/dL)]	12.05 (1.816)	12.75 (1.629)

3. Secondary Outcome

Title	PAP: Absolute Change From Baseline in Hemoglobin Level at Week 39
Description	Absolute change = hemoglobin level at Week 39 minus hemoglobin level at baseline.
Time Frame	PAP Baseline (Day 1), Week 39

Outcome Measure Data

Analysis Population Description

FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).

Arm/Group Title	PAP: Eliglustat	PAP: Placebo
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50 mg or 100 mg capsule BID orally up to Week 39.	Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39.
Measure Participants	20	20
Least Squares Mean (Standard Error) [g/dL]	0.69 (0.23)	-0.54 (0.23)

4. Secondary Outcome

Title	PAP: Percent Change From Baseline in Liver Volume (in MN) at Week 39
Description	Percent change in liver volume = ([liver volume at Week 39 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in MN.
Time Frame	PAP Baseline (Day 1), Week 39

Outcome Measure Data

Analysis Population Description

FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).

Arm/Group Title	PAP: Eliglustat	PAP: Placebo
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50 mg or 100 mg capsule BID orally up to Week 39.	Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39.
Measure Participants	20	20
Least Squares Mean (Standard Error) [percent change]	-5.20 (1.64)	1.44 (1.64)

5. Secondary Outcome

Title	PAP: Percent Change From Baseline in Platelet Counts at Week 39
Description	Percent change in platelet count = ([platelet count at Week 39 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.
Time Frame	PAP Baseline (Day 1), Week 39

Outcome Measure Data

Analysis Population Description

FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).

Arm/Group Title	PAP: Eliglustat	PAP: Placebo
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50 mg or 100 mg capsule BID orally up to Week 39.	Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39.
Measure Participants	20	20
Least Squares Mean (Standard Error) [percent change]	32.00 (5.95)	-9.06 (5.95)

6. Secondary Outcome

Title	LTTP: Percent Change From Baseline in Spleen Volume (in MN) at Week 234
Description	Percent change in spleen volume = ([spleen volume at Week 234 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.
Time Frame	PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population for LTTP included all participants who received at least 1 dose of eliglustat in LTTP period. Number of participants analyzed= participants evaluable for this outcome measure and had available data for baseline and Week 234 spleen volume assessment.

Arm/Group Title	LTTP: Eliglustat (Originally on Eliglustat)	LTTP: Eliglustat (Originally on Placebo)
Arm/Group Description	Participants of the eliglustat arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate capsule 50 mg BID orally from Day 1 (post Week 39) until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.	Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline of LTTP for this arm. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.
Measure Participants	7	6
Mean (Standard Deviation) [percent change]	-66.9 (8.45)	-64.0 (6.43)

7. Secondary Outcome

Title	LTTP: Absolute Change From Baseline in Hemoglobin Level at Week 234
Description	Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.
Time Frame	PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234

Outcome Measure Data

Analysis Population Description

ITT population for LTTP included all participants who received at least 1 dose of eliglustat in LTTP period. Number of participants analyzed=participants evaluable for this outcome measure and had available data for baseline and Week 234 hemoglobin level assessment.

Arm/Group Title	LTTP: Eliglustat (Originally on Eliglustat)	LTTP: Eliglustat (Originally on Placebo)
Arm/Group Description	Participants of the eliglustat arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate capsule 50 mg BID orally from Day 1 (post Week 39) until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.	Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline of LTTP for this arm. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.
Measure Participants	7	5
Mean (Standard Deviation) [g/dL]	1.1 (0.65)	1.9 (1.88)

8. Secondary Outcome

Title	LTTP: Percent Change From Baseline in Liver Volume (in MN) at Week 234
Description	Percent change in liver volume = ([liver volume at Week 234 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in MN. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.
Time Frame	PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234

Outcome Measure Data

Analysis Population Description

ITT population for LTTP included all participants who received at least 1 dose of eliglustat in LTTP period. Number of participants analyzed=participants evaluable for this outcome measure and had available data for baseline and Week 234 liver volume assessment.

Arm/Group Title	LTTP: Eliglustat (Originally on Eliglustat)	LTTP: Eliglustat (Originally on Placebo)
Arm/Group Description	Participants of the eliglustat arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate capsule 50 mg BID orally from Day 1 (post Week 39) until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.	Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline of LTTP for this arm. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.
Measure Participants	7	6
Mean (Standard Deviation) [percent change]	-24.3 (11.21)	-22.4 (10.77)

9. Secondary Outcome

Title	LTTP: Percent Change From Baseline in Platelet Counts at Week 234
Description	Percent change in platelet count = ([platelet count at Week 234 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.
Time Frame	PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234

Outcome Measure Data

Analysis Population Description

ITT population for LTTP included all participants who received at least 1 dose of eliglustat in LTTP period. Number of participants analyzed=participants evaluable for this outcome measure and had available data for baseline and Week 234 platelet count assessment.

Arm/Group Title	LTTP: Eliglustat (Originally on Eliglustat)	LTTP: Eliglustat (Originally on Placebo)
Arm/Group Description	Participants of the eliglustat arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate capsule 50 mg BID orally from Day 1 (post Week 39) until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.	Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline of LTTP for this arm. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.
Measure Participants	7	5
Mean (Standard Deviation) [percent change]	77.3 (28.17)	100.1 (80.69)

Adverse Events

Time Frame	Adverse Events (AEs) were collected from the signature of the Informed Consent Form through the follow-up period (30-37 days after the last visit, which was Week 312).
Adverse Event Reporting Description	Reported AEs are treatment-emergent that is AEs that developed/worsened during the 'on treatment period' (first dose of eliglustat to end of follow-up period).
Arm/Group Title	Eliglustat		Placebo
Arm/Group Description	PAP: Eliglustat tartrate capsule 50 mg orally on Day 1 followed by eliglustat tartrate 50 mg capsule BID from Day 2 to Week 4, then either eliglustat tartrate 50 mg capsule BID(participants with Genz-99067 trough plasma concentration>=5 ng/mL) or eliglustat tartrate 100 mg capsule BID(participants with Genz-99067 trough plasma concentration<5 ng/mL), up to Week 39. PK assessment at Week 2 used for dose adjustment after Week 4. LTTP: Participants of the eliglustat arm in PAP who completed PAP were included in LTTP & received eliglustat tartrate capsule 50 mg BID orally from Day 1(post Week 39) until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 & Week 47 were based on Genz-99067 trough plasma concentrations(if trough plasma concentration<5 ng/mL: next higher dose administered;if>=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.		PAP: Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39. LTTP: Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline for LTTP. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration <5 ng/mL: next higher dose administered; if >=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.
All Cause Mortality
	Eliglustat		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Eliglustat		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/20 (10%)		3/20 (15%)
Cardiac disorders
Atrioventricular block	1/20 (5%)		0/20 (0%)
Atrioventricular block second degree	1/20 (5%)		0/20 (0%)
Ventricular tachycardia	1/20 (5%)		0/20 (0%)
Hepatobiliary disorders
Biliary colic	0/20 (0%)		1/20 (5%)
Infections and infestations
Appendicitis	0/20 (0%)		2/20 (10%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/20 (5%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Eliglustat		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/20 (85%)		14/20 (70%)
Blood and lymphatic system disorders
Iron deficiency anaemia	2/20 (10%)		1/20 (5%)
Cardiac disorders
Palpitations	0/20 (0%)		3/20 (15%)
Eye disorders
Eye irritation	2/20 (10%)		0/20 (0%)
Gastrointestinal disorders
Abdominal distension	3/20 (15%)		0/20 (0%)
Abdominal pain	4/20 (20%)		2/20 (10%)
Abdominal pain upper	1/20 (5%)		4/20 (20%)
Diarrhoea	5/20 (25%)		1/20 (5%)
Dry mouth	0/20 (0%)		2/20 (10%)
Dyspepsia	4/20 (20%)		2/20 (10%)
Gastritis	2/20 (10%)		1/20 (5%)
Gastrooesophageal reflux disease	1/20 (5%)		4/20 (20%)
Nausea	3/20 (15%)		2/20 (10%)
Toothache	2/20 (10%)		1/20 (5%)
Vomiting	1/20 (5%)		2/20 (10%)
General disorders
Asthenia	3/20 (15%)		1/20 (5%)
Fatigue	2/20 (10%)		2/20 (10%)
Oedema peripheral	2/20 (10%)		0/20 (0%)
Pyrexia	2/20 (10%)		2/20 (10%)
Immune system disorders
Seasonal allergy	1/20 (5%)		2/20 (10%)
Infections and infestations
Bronchitis	2/20 (10%)		1/20 (5%)
Gastroenteritis	1/20 (5%)		3/20 (15%)
Hordeolum	0/20 (0%)		2/20 (10%)
Nasopharyngitis	5/20 (25%)		2/20 (10%)
Otitis media	2/20 (10%)		0/20 (0%)
Sinusitis	3/20 (15%)		2/20 (10%)
Tonsillitis	2/20 (10%)		1/20 (5%)
Upper respiratory tract infection	4/20 (20%)		3/20 (15%)
Urinary tract infection	2/20 (10%)		1/20 (5%)
Injury, poisoning and procedural complications
Contusion	2/20 (10%)		0/20 (0%)
Ligament sprain	0/20 (0%)		2/20 (10%)
Thermal burn	0/20 (0%)		2/20 (10%)
Investigations
Blood creatine phosphokinase increased	1/20 (5%)		2/20 (10%)
Bone density decreased	0/20 (0%)		2/20 (10%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/20 (55%)		4/20 (20%)
Back pain	5/20 (25%)		2/20 (10%)
Bone pain	2/20 (10%)		2/20 (10%)
Joint stiffness	2/20 (10%)		0/20 (0%)
Musculoskeletal pain	1/20 (5%)		2/20 (10%)
Myalgia	2/20 (10%)		0/20 (0%)
Pain in extremity	4/20 (20%)		4/20 (20%)
Nervous system disorders
Dizziness	1/20 (5%)		3/20 (15%)
Headache	11/20 (55%)		7/20 (35%)
Migraine	3/20 (15%)		0/20 (0%)
Psychiatric disorders
Anxiety	2/20 (10%)		2/20 (10%)
Renal and urinary disorders
Proteinuria	2/20 (10%)		0/20 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	2/20 (10%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/20 (10%)		1/20 (5%)
Epistaxis	2/20 (10%)		1/20 (5%)
Nasal congestion	2/20 (10%)		0/20 (0%)
Nasal obstruction	2/20 (10%)		0/20 (0%)
Oropharyngeal pain	2/20 (10%)		1/20 (5%)
Rhinorrhoea	2/20 (10%)		0/20 (0%)
Skin and subcutaneous tissue disorders
Acne	2/20 (10%)		1/20 (5%)
Alopecia	2/20 (10%)		0/20 (0%)
Rash	0/20 (0%)		3/20 (15%)
Skin lesion	1/20 (5%)		2/20 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.