A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE)

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00943111
• Collaborator: (none)
• Enrollment: 160
• Locations: 34
• Arms: 2
• Duration (Months): 69
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.1

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 who had reached therapeutic goals with enzyme replacement therapy (ERT).

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

Detailed Description

Gaucher disease is characterized by lysosomal accumulation of glucosylceramide due to impaired glucosylceramide hydrolysis. Gaucher disease type 1, which is the most common form, accounts for greater than (>) 90% of cases and does not involve the central nervous system (CNS). Typical manifestations of Gaucher disease type 1 include splenomegaly, hepatomegaly, thrombocytopenia, anemia, bone disease, and decreased quality of life. The disease manifestations are caused by the accumulation of glucosylceramide (storage material) in macrophages (called Gaucher cells) which have infiltrated the spleen and liver as well as other tissues.

Eliglustat tartrate is a small molecule drug 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 PK of eliglustat tartrate in adult participants with Gaucher disease type 1 who had been stabilized on ERT.

Study Design

• Study Type: Interventional
• Actual Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Multi-Center, Multi-National, Open-Label, Active Comparator Study to Evaluate the Efficacy and Safety of Genz-112638 in Patients With Gaucher Disease Type 1 Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE)
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Investigational Eliglustat tartrate	Drug: Eliglustat tartrate; Primary analysis period (PAP): Eliglustat tartrate capsule 50 milligram (mg) twice daily (BID) orally from Day 1 to Week 4 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 8, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 52. Dose adjustments after Week 4 and Week 8 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was less than (<) 5 nanogram per milliliter [ng/mL] next higher dose was administered whereas if Genz-99067 trough plasma concentration was greater than or equal to (>=) 5 ng/mL same dose was continued. Pharmacokinetic (PK) assessment at Week 2 and 6 were used for dose adjustment after Week 4 and Week 8, respectively. Long-term treatment period (LTTP): Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6.; Other Names: Genz-112638
Active Comparator: Imiglucerase	Drug: Imiglucerase; PAP: Imiglucerase intravenous infusion every other week (q2w) up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change. LTTP: Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was <5 ng/mL the next higher dose was administered whereas if the Genz-99067 trough plasma concentration was >=5 ng/mL the same dose was continued. The PK assessment at Week 54 and Week 58 were used for dose adjustment after Week 56 and Week 60, respectively.; Other Names: Cerezyme®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Remained Stable for 52 Weeks During the Primary Analysis Period [Baseline up to Week 52]

   For a participant to be classified as stable, the participant must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in multiples of normal [MN]). Stable hematological parameters were defined as hemoglobin level did not decrease more than (>) 1.5 gram per deciliter (g/dL) from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume (in MN) did not increase >20% from baseline.

2. Percentage of Participants Who Remained Stable Annually for 4 Years During the LTTP [Week 52 up to week 208]

   For a participant to be classified as stable, the participant must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in MN). Stable hematological parameters were defined as hemoglobin level did not decrease >1.5 g/dL from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume did not increase >20% from baseline.

Secondary Outcome Measures

1. Total T-Scores for Bone Mineral Density [Baseline]

   Images of the spine and bilateral femur were obtained by dual energy X-Ray absorptiometry (DXA) to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score greater than [>]-1), osteopenia (score -2.5 to less than or equal to [<=] -1), and osteoporosis (score <= -2.5).

2. Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52 [Baseline, Week 52]

   Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 52 minus T-score at baseline.

3. Total Z-Scores for Bone Mineral Density [Baseline]

   Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2).

4. Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52 [Baseline, Week 52]

   Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 52 minus Z-score at baseline.

5. Hemoglobin Level [Baseline]

6. Absolute Change From Baseline in Hemoglobin Levels at Week 52 [Baseline, Week 52]

   Absolute change = hemoglobin level at Week 52 minus hemoglobin level at baseline.

7. Percent Change From Baseline in Platelet Counts at Week 52 [Baseline, Week 52]

   Percent change in platelet counts = ([platelet count at Week 52 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.

8. Percent Change From Baseline in Spleen Volume (MN) at Week 52 [Baseline, Week 52]

   Percent change in spleen volume = ([spleen volume at Week 52 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.

9. Percent Change From Baseline in Liver Volume (in MN) at Week 52 [Baseline, Week 52]

   Percent change in liver volume = ([liver volume at Week 52 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.

10. Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 208 [Baseline, Week 208]

    Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 208 minus T-score at baseline.

11. Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 208 [Baseline, Week 208]

    Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 208 minus Z-score at baseline.

12. Absolute Change From Baseline in Hemoglobin Levels at Week 208 [Baseline, Week 208]

    Absolute change = hemoglobin level at Week 208 minus hemoglobin level at baseline.

13. Percent Change From Baseline in Platelet Counts at Week 208 [Baseline, Week 208]

    Percent change in platelet counts = ([platelet count at Week 208 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.

14. Percent Change From Baseline in Spleen Volume (in MN) at Week 208 [Baseline, Week 208]

    Percent change in spleen volume = ([spleen volume at Week 208 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.

15. Percent Change From Baseline in Liver Volume (in MN) at Week 208 [Baseline, Week 208]

    Percent change in liver volume = ([liver volume at Week 208 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 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 18 years old at the time of randomization

• The participant had a confirmed diagnosis of Gaucher disease type 1

• The participant had received treatment with ERT for at least 3 years. Within the 9 months prior to randomization, the participant had received a total monthly dose of 30 to 130 Units/kilogram for at least 6 months

• The participant had reached Gaucher disease therapeutic goals prior to randomization

• Female participants of childbearing potential must have 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 had a partial or total splenectomy within 3 years prior to randomization

• The participant had received substrate reduction therapies for Gaucher disease within 6 months prior to randomization

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

• The participant had any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal (GI), pulmonary, neurologic, endocrine, metabolic (e.g. hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may confound the study results or, in the opinion of the Investigator, may 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	Tower Hematology Oncology Medical Group	Beverly Hills	California	United States
2	UCSF MS Center	San Francisco	California	United States
3	University of Colorado Health Science Center - Aurora	Aurora	Colorado	United States
4	Yale University School of Medicine	New Haven	Connecticut	United States
5	Northwest Oncology Hematology Associates PA	Coral Springs	Florida	United States
6	Emory University Medical Genetics	Decatur	Georgia	United States
7	Children's Memorial Hospital	Chicago	Illinois	United States
8	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States
9	Albany Medical Center	Albany	New York	United States
10	North Shore University Medical Center	Manhasset	New York	United States	11030
11	Mount Sinai School of Medicine	New York	New York	United States
12	New York University School of Medicine	New York	New York	United States
13	Duke University Medical Center	Durham	North Carolina	United States
14	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States
15	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States
16	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States
17	O and O Alpan LLC	Springfield	Virginia	United States
18	Hospital General de Agudos J.M Ramos Mejia	Buenos Aires		Argentina
19	Hospital General de Ninos Dr. Ricardo Gutierrez	Buenos Aires		Argentina
20	Royal Perth Hospital	Perth, WA		Australia
21	Hospital de Clinicas da Universidade Federal do Parana	Curitiba		Brazil
22	Instituto de Estadual de Hematologia Arthur de Siqueria Cavalcanti	Rio de Janeiro		Brazil
23	IGEIM	São Paulo		Brazil
24	Mount Sinai Hospital and the Samuel Lunenfeld Research Institute	Toronto Ontario		Canada
25	Abou El Reesh Children's University Hospital (El Mounira), Faculty of Medicine (Kasr Al-Aini), Cairo University Hospitals, El Mounira, Cairo, Egypt	Cairo		Egypt
26	Hôpital Beaujon	Clichy		France
27	Charité Universitätsmedizin Berlin	Berlin		Germany
28	Asklepios Klinik St. Georg	Hamburg		Germany
29	Katholische Kliniken Oberhausen gem. GmbH	Oberhausen		Germany
30	Azienda Ospedaliero Universitaria Careggi	Firenze		Italy
31	Azienda Ospedialiero-Universitaria S. Maria Della Misericordia	Udine		Italy
32	Hematology Research Center of Ministry of Healthcare of the Russian Federation	Moscow		Russian Federation
33	Hospital University Miguel Servet	Zaragoza		Spain
34	Cambridge University Hosptials, Addenbrookes Hospital	Cambridge		United Kingdom

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.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT00943111
• Other Study ID Numbers: GZGD02607; 2008-005223-28; EFC12812
• First Posted: Jul 22, 2009
• Last Update Posted: Nov 25, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Genzyme, a Sanofi Company: Gaucher disease,; Genz-112638,; 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 209 participants were screened, of which 46 participants were screen failure and 3 participants withdrew prior to randomization. A total of 160 participants were enrolled in this study.
Pre-assignment Detail	All enrolled participants received eliglustat or imiglucerase in 52 week primary analysis period (PAP). After 52-weeks PAP, all participants who remained on-study, received eliglustat in the long-term treatment period (LTTP) for up to 5 years.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP	Eliglustat: LTTP
Arm/Group Description	Eliglustat tartrate (Genz-112638) capsule 50 milligram (mg) twice daily (BID) orally from Day 1 to Week 4 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 8, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 52. The dose adjustments after Week 4 and Week 8 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was less than [<] 5 nanogram per milliliter [ng/mL] the next higher dose was administered whereas if the Genz-99067 trough plasma concentration was greater than or equal to [>=] 5 ng/mL the same dose was continued. The pharmacokinetic (PK) assessment at Week 2 and Week 6 were used for dose adjustment after Week 4 and Week 8, respectively.	Imiglucerase (Cerezyme®) intravenous infusion every other week (q2w) up to Week 52 in doses equivalent to participant's past enzyme replacement therapy (ERT) dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.	Participants from both the arms of PAP who completed PAP were included in this arm of LTTP. Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was <5 ng/mL next higher dose was administered whereas if the Genz-99067 trough plasma concentration was >=5 ng/mL the same dose was continued. PK assessment at Week 54 and Week 58 were used for dose adjustment after Week 56 and Week 60, respectively.
Period Title: 52-Weeks Primary Analysis Period
STARTED	106	54	0
Treated	106	53	0
COMPLETED	104	52	0
NOT COMPLETED	2	2	0
Period Title: 52-Weeks Primary Analysis Period
STARTED	0	0	152
COMPLETED	0	0	77
NOT COMPLETED	0	0	75

Baseline Characteristics

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP	Total
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.	Total of all reporting groups
Overall Participants	106	53	159
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.6 (14.17)	37.5 (14.92)	37.5 (14.37)
Sex: Female, Male (Count of Participants)
Female	59 55.7%	28 52.8%	87 54.7%
Male	47 44.3%	25 47.2%	72 45.3%
Race/Ethnicity, Customized (participants) [Number]
Race: White	98 92.5%	48 90.6%	146 91.8%
Race: Black or African American	6 5.7%	4 7.5%	10 6.3%
Race: Asian	1 0.9%	1 1.9%	2 1.3%
Race: White/American Indian	1 0.9%	0 0%	1 0.6%
Ethnicity: Hispanic or Latino	42 39.6%	19 35.8%	61 38.4%
Ethnicity: Not Hispanic or Latino	64 60.4%	34 64.2%	98 61.6%
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	25.2 (5.24)	24.5 (4.51)	24.9 (5.01)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	70.8 (16.82)	67.8 (14.44)	69.8 (16.08)
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	167.6 (9.92)	166.2 (9.56)	167.1 (9.79)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Remained Stable for 52 Weeks During the Primary Analysis Period
Description	For a participant to be classified as stable, the participant must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in multiples of normal [MN]). Stable hematological parameters were defined as hemoglobin level did not decrease more than (>) 1.5 gram per deciliter (g/dL) from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume (in MN) did not increase >20% from baseline.
Time Frame	Baseline up to Week 52

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP included participants who were at least 80% compliant with treatment during PAP, had no major protocol deviations, and did not exhibit hematological decline as a result of medically determined etiologies other than Gaucher disease.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	99	47
Number (95% Confidence Interval) [percentage of participants]	84.8 80%	93.6 176.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eliglustat: PAP, Imiglucerase: PAP
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size for study was based on expected stability rates of 95% for the Imiglucerase group and 85% for the Eliglustat group, power of 85%, a one-sided significance level of 0.025, a non-inferiority margin of 25%, and a 20% non-evaluable/drop-out rate. Eliglustat was declared non-inferior to Imiglucerase if the lower-bound of the 95% confidence interval for the difference was within the non-inferiority margin of 25%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage Stable
	Estimated Value	-8.8
	Confidence Interval	(2-Sided) 95%; -17.6 to 4.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Percentage of Participants Who Remained Stable Annually for 4 Years During the LTTP
Description	For a participant to be classified as stable, the participant must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in MN). Stable hematological parameters were defined as hemoglobin level did not decrease >1.5 g/dL from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume did not increase >20% from baseline.
Time Frame	Week 52 up to week 208

Outcome Measure Data

Analysis Population Description

FAS population for LTTP: included all participants who received at least 1 dose of eliglustat in the extension study period. Number of participants analyzed=participants at risk at specified time-points. Here 'n' signifies number of participants with available data for specified time-points.

Arm/Group Title	Eliglustat: LTTP
Arm/Group Description	Participants from both the arms of PAP who completed PAP were included in this arm of LTTP. Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.
Measure Participants	152
Year 1 (n=127)	83.6 78.9%
Year 2 (n= 115)	75.65 71.4%
Year 3 (n= 92)	60.53 57.1%
Year 4 (n= 41)	26.97 25.4%

3. Secondary Outcome

Title	Total T-Scores for Bone Mineral Density
Description	Images of the spine and bilateral femur were obtained by dual energy X-Ray absorptiometry (DXA) to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score greater than [>]-1), osteopenia (score -2.5 to less than or equal to [<=] -1), and osteoporosis (score <= -2.5).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with baseline T-score assessment. Here, 'n' signifies participants with baseline T-score assessment for specified bone area.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	81	38
Lumbar Spine T-Score (n=81, 38)	-0.56 (1.309)	-0.33 (1.169)
Femur T-Score (n=80, 37)	-0.11 (1.080)	-0.47 (1.293)

4. Secondary Outcome

Title	Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52
Description	Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 52 minus T-score at baseline.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with both baseline and Week 52 T-score assessment. Here, 'n' signifies participants with both baseline and Week 52 T-score assessment for specified bone area. Eliglustat participants switching to imiglucerase were excluded.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	81	38
Change in Lumbar Spine T-Score (n=81, 38)	0.04 (0.03)	0.03 (0.05)
Change in Femur T-Score (n=80, 37)	0.00 (0.02)	-0.03 (0.03)

5. Secondary Outcome

Title	Total Z-Scores for Bone Mineral Density
Description	Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2).
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with baseline Z-score assessment. Here, 'n' signifies participants with baseline Z-score assessment for specified bone area.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	94	45
Lumbar Spine Z-Score (n=94, 45)	-0.35 (1.260)	-0.14 (1.108)
Femur Z-Score (n=93, 44)	0.09 (1.020)	-0.18 (1.122)

6. Secondary Outcome

Title	Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52
Description	Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 52 minus Z-score at baseline.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with both baseline and Week 52 Z-score assessment. Here, 'n' signifies participants with both baseline and Week 52 Z-score assessment for specified bone area. Eliglustat participants switching to imiglucerase were excluded.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	94	45
Change in Lumbar Spine Z-Score (n=94, 45)	0.06 (0.03)	0.06 (0.04)
Change in Femur Z-Score (n=93, 44)	0.03 (0.02)	0.02 (0.02)

7. Secondary Outcome

Title	Hemoglobin Level
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with baseline hemoglobin assessment.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	98	47
Mean (Standard Deviation) [gram per deciliter (g/dL)]	13.592 (1.2467)	13.797 (1.2234)

8. Secondary Outcome

Title	Absolute Change From Baseline in Hemoglobin Levels at Week 52
Description	Absolute change = hemoglobin level at Week 52 minus hemoglobin level at baseline.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with both baseline and Week 52 hemoglobin assessment. Eliglustat participants switching to imiglucerase were excluded.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	98	47
Least Squares Mean (Standard Error) [g/dL]	-0.22 (0.07)	0.05 (0.10)

9. Secondary Outcome

Title	Percent Change From Baseline in Platelet Counts at Week 52
Description	Percent change in platelet counts = ([platelet count at Week 52 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with both baseline and Week 52 platelet assessment. Eliglustat participants switching to imiglucerase were excluded.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	98	47
Least Squares Mean (Standard Error) [percent change]	3.93 (1.71)	2.63 (2.47)

10. Secondary Outcome

Title	Percent Change From Baseline in Spleen Volume (MN) at Week 52
Description	Percent change in spleen volume = ([spleen volume at Week 52 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with both baseline and Week 52 spleen volume assessment. Eliglustat participants switching to imiglucerase were excluded.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	70	39
Least Squares Mean (Standard Error) [percent change]	-6.05 (1.57)	-3.22 (2.13)

11. Secondary Outcome

Title	Percent Change From Baseline in Liver Volume (in MN) at Week 52
Description	Percent change in liver volume = ([liver volume at Week 52 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.
Time Frame	Baseline, Week 52

Outcome Measure Data

Analysis Population Description

Per protocol population for PAP. Number of participants analyzed = participants with both baseline and Week 52 liver volume assessment. Eliglustat participants switching to imiglucerase were excluded.

Arm/Group Title	Eliglustat: PAP	Imiglucerase: PAP
Arm/Group Description	Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52.	Imiglucerase intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change.
Measure Participants	98	47
Least Squares Mean (Standard Error) [percent change]	1.99 (0.94)	3.13 (1.36)

12. Secondary Outcome

Title	Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 208
Description	Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 208 minus T-score at baseline.
Time Frame	Baseline, Week 208

Outcome Measure Data

Analysis Population Description

Number of participants analyzed = participants with both baseline and Week 208 T-score assessment.

Arm/Group Title	Eliglustat: LTTP
Arm/Group Description	Participants from both the arms of PAP who completed PAP were included in this arm of LTTP. Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.
Measure Participants	36
Total Spine	0.22 (0.405)
Total Femur	-0.03 (0.345)

13. Secondary Outcome

Title	Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 208
Description	Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 208 minus Z-score at baseline.
Time Frame	Baseline, Week 208

Outcome Measure Data

Analysis Population Description

FAS population for LTTP. Number of participants analyzed = participants with both baseline and Week 208 Z-score assessment. Here, 'n' signifies participants with both baseline and Week 208 Z-score assessment for specified bone area.

Arm/Group Title	Eliglustat: LTTP
Arm/Group Description	Participants from both the arms of PAP who completed PAP were included in this arm of LTTP. Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.
Measure Participants	42
Total Spine	0.29 (0.358)
Total Femur	0.03 (0.381)

14. Secondary Outcome

Title	Absolute Change From Baseline in Hemoglobin Levels at Week 208
Description	Absolute change = hemoglobin level at Week 208 minus hemoglobin level at baseline.
Time Frame	Baseline, Week 208

Outcome Measure Data

Analysis Population Description

FAS population for LTTP. Number of participants analyzed = participants with both baseline and Week 208 hemoglobin assessment.

Arm/Group Title	Eliglustat: LTTP
Arm/Group Description	Participants from both the arms of PAP who completed PAP were included in this arm of LTTP. Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.
Measure Participants	45
Mean (Standard Deviation) [g/dL]	0.297 (0.7472)

15. Secondary Outcome

Title	Percent Change From Baseline in Platelet Counts at Week 208
Description	Percent change in platelet counts = ([platelet count at Week 208 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.
Time Frame	Baseline, Week 208

Outcome Measure Data

Analysis Population Description

FAS population for LTTP. Number of participants analyzed = participants with both baseline and Week 208 platelet assessment.

Arm/Group Title	Eliglustat: LTTP
Arm/Group Description	Participants from both the arms of PAP who completed PAP were included in this arm of LTTP. Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.
Measure Participants	45
Mean (Standard Deviation) [percent change]	6.990 (20.4382)

16. Secondary Outcome

Title	Percent Change From Baseline in Spleen Volume (in MN) at Week 208
Description	Percent change in spleen volume = ([spleen volume at Week 208 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.
Time Frame	Baseline, Week 208

Outcome Measure Data

Analysis Population Description

FAS population for LTTP. Number of participants analyzed = participants with both baseline and Week 208 spleen volume assessment.

Arm/Group Title	Eliglustat: LTTP
Arm/Group Description	Participants from both the arms of PAP who completed PAP were included in this arm of LTTP. Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.
Measure Participants	33
Mean (Standard Deviation) [percent change]	-14.768 (17.9435)

17. Secondary Outcome

Title	Percent Change From Baseline in Liver Volume (in MN) at Week 208
Description	Percent change in liver volume = ([liver volume at Week 208 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.
Time Frame	Baseline, Week 208

Outcome Measure Data

Analysis Population Description

FAS population for LTTP. Number of participants analyzed = participants with both baseline and Week 208 liver volume assessment.

Arm/Group Title	Eliglustat: LTTP
Arm/Group Description	Participants from both the arms of PAP who completed PAP were included in this arm of LTTP. Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6. Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.
Measure Participants	46
Mean (Standard Deviation) [percent change]	-2.345 (12.8795)

Adverse Events

Time Frame	From signature of informed consent up to 30-37 days after the last dose of treatment (last dose = up to Week 104)
Adverse Event Reporting Description	Safety set included all participants who received at least 1 dose of study drug (Eliglustat or Imiglucerase). In the event a single participant experienced both serious and non-serious forms of same adverse events (AE), individual was included in numerator (number of participants affected) of each AE table.
Arm/Group Title	Eliglustat		Imiglucerase
Arm/Group Description	PAP: Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50, 100 or 150 mg capsule BID orally up to Week 52. Dose adjustments after Week 4 and Week 8 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. LTTP: Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6.		PAP: Imiglucerase (Cerezyme®) intravenous infusion q2w up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change. LTTP: Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations.
All Cause Mortality
	Eliglustat		Imiglucerase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Eliglustat		Imiglucerase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/106 (17%)		7/53 (13.2%)
Blood and lymphatic system disorders
Polycythaemia	0/106 (0%)		1/53 (1.9%)
Cardiac disorders
Acute myocardial infarction	0/106 (0%)		1/53 (1.9%)
Myocardial infarction	0/106 (0%)		1/53 (1.9%)
Gastrointestinal disorders
Colitis ischaemic	1/106 (0.9%)		0/53 (0%)
Diarrhoea	1/106 (0.9%)		0/53 (0%)
Intestinal obstruction	1/106 (0.9%)		0/53 (0%)
General disorders
Device malfunction	1/106 (0.9%)		0/53 (0%)
Pain	1/106 (0.9%)		0/53 (0%)
Pyrexia	1/106 (0.9%)		0/53 (0%)
Hepatobiliary disorders
Biliary colic	1/106 (0.9%)		0/53 (0%)
Cholecystitis	1/106 (0.9%)		0/53 (0%)
Infections and infestations
Appendicitis	1/106 (0.9%)		0/53 (0%)
Diverticulitis	1/106 (0.9%)		0/53 (0%)
Injury, poisoning and procedural complications
Injury	0/106 (0%)		1/53 (1.9%)
Joint dislocation	1/106 (0.9%)		0/53 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign ovarian tumour	0/106 (0%)		1/53 (1.9%)
Metastatic renal cell carcinoma	0/106 (0%)		1/53 (1.9%)
Pancreatic carcinoma metastatic	0/106 (0%)		1/53 (1.9%)
Uterine leiomyoma	1/106 (0.9%)		0/53 (0%)
Nervous system disorders
Neuropathy peripheral	1/106 (0.9%)		0/53 (0%)
Syncope	3/106 (2.8%)		0/53 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/106 (0.9%)		0/53 (0%)
Nasal septum deviation	1/106 (0.9%)		0/53 (0%)
Surgical and medical procedures
Mammoplasty	1/106 (0.9%)		0/53 (0%)
Other (Not Including Serious) Adverse Events
	Eliglustat		Imiglucerase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	91/106 (85.8%)		38/53 (71.7%)
Cardiac disorders
Palpitations	8/106 (7.5%)		3/53 (5.7%)
Gastrointestinal disorders
Abdominal pain	14/106 (13.2%)		6/53 (11.3%)
Abdominal pain lower	6/106 (5.7%)		0/53 (0%)
Abdominal pain upper	26/106 (24.5%)		3/53 (5.7%)
Constipation	10/106 (9.4%)		6/53 (11.3%)
Diarrhoea	20/106 (18.9%)		2/53 (3.8%)
Dyspepsia	15/106 (14.2%)		4/53 (7.5%)
Gastritis	6/106 (5.7%)		5/53 (9.4%)
Gastrooesophageal reflux disease	13/106 (12.3%)		2/53 (3.8%)
Nausea	18/106 (17%)		7/53 (13.2%)
Toothache	7/106 (6.6%)		3/53 (5.7%)
Vomiting	10/106 (9.4%)		0/53 (0%)
General disorders
Asthenia	10/106 (9.4%)		1/53 (1.9%)
Chest pain	9/106 (8.5%)		1/53 (1.9%)
Fatigue	20/106 (18.9%)		7/53 (13.2%)
Pain	6/106 (5.7%)		3/53 (5.7%)
Peripheral swelling	6/106 (5.7%)		1/53 (1.9%)
Pyrexia	2/106 (1.9%)		3/53 (5.7%)
Hepatobiliary disorders
Hepatomegaly	5/106 (4.7%)		3/53 (5.7%)
Infections and infestations
Bronchitis	8/106 (7.5%)		2/53 (3.8%)
Gastroenteritis	11/106 (10.4%)		2/53 (3.8%)
Influenza	20/106 (18.9%)		6/53 (11.3%)
Nasopharyngitis	28/106 (26.4%)		10/53 (18.9%)
Sinusitis	20/106 (18.9%)		3/53 (5.7%)
Upper respiratory tract infection	21/106 (19.8%)		7/53 (13.2%)
Urinary tract infection	16/106 (15.1%)		3/53 (5.7%)
Injury, poisoning and procedural complications
Contusion	7/106 (6.6%)		2/53 (3.8%)
Laceration	7/106 (6.6%)		1/53 (1.9%)
Ligament sprain	8/106 (7.5%)		0/53 (0%)
Limb injury	6/106 (5.7%)		0/53 (0%)
Investigations
Blood creatine phosphokinase increased	16/106 (15.1%)		3/53 (5.7%)
Mean cell volume abnormal	0/106 (0%)		3/53 (5.7%)
Nerve conduction studies abnormal	7/106 (6.6%)		3/53 (5.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	38/106 (35.8%)		13/53 (24.5%)
Back pain	23/106 (21.7%)		6/53 (11.3%)
Bone pain	9/106 (8.5%)		3/53 (5.7%)
Muscle spasms	6/106 (5.7%)		1/53 (1.9%)
Musculoskeletal pain	8/106 (7.5%)		3/53 (5.7%)
Myalgia	6/106 (5.7%)		2/53 (3.8%)
Pain in extremity	21/106 (19.8%)		5/53 (9.4%)
Nervous system disorders
Dizziness	18/106 (17%)		4/53 (7.5%)
Headache	26/106 (24.5%)		9/53 (17%)
Hypoaesthesia	6/106 (5.7%)		1/53 (1.9%)
Paraesthesia	7/106 (6.6%)		1/53 (1.9%)
Psychiatric disorders
Anxiety	10/106 (9.4%)		1/53 (1.9%)
Depression	3/106 (2.8%)		3/53 (5.7%)
Respiratory, thoracic and mediastinal disorders
Cough	11/106 (10.4%)		2/53 (3.8%)
Epistaxis	7/106 (6.6%)		1/53 (1.9%)
Oropharyngeal pain	7/106 (6.6%)		3/53 (5.7%)
Skin and subcutaneous tissue disorders
Dry skin	5/106 (4.7%)		4/53 (7.5%)
Vascular disorders
Hypertension	6/106 (5.7%)		1/53 (1.9%)

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.