A Study of Alirocumab in Participants With Autosomal Dominant Hypercholesterolemia (ADH) and Gain-of-Function Mutations (GOFm) of the Proprotein Convertase Subtilisin Kexin 9 (PCSK9) Gene or Loss-of-Function Mutations (LOFm) of the Apolipoprotein (Apo) B Gene

• Sponsor: Regeneron Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01604824
• Collaborator: Sanofi (Industry)
• Enrollment: 23
• Locations: 4
• Arms: 4
• Actual Duration (Months): 65.1
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of the study is to assess the pharmacodynamic (PD) effect of alirocumab on serum low density lipoprotein cholesterol (LDL-C) during 14 weeks of subcutaneous (SC) administered alirocumab in patients with autosomal dominant hypercholesterolemia (ADH) and gain-of-function mutation (GOFm) in 1 or both alleles of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or with loss-of-function mutation (LOFm) in 1 or more alleles of the apolipoprotein (ApoB) gene.

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia	Drug: Alirocumab; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Pilot Study With a Randomized Double-Blind Treatment Phase to Evaluate the Pharmacodynamics and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia and Gain-of-Function Mutations in 1 or Both Alleles of the PCSK9 Gene or Loss-of-Function Mutations in 1 or More Alleles of the Loss-of-Function Mutations B Gene
• Actual Study Start Date: Feb 22, 2012
• Actual Primary Completion Date: Jun 2, 2014
• Actual Study Completion Date: Jul 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GOFm PCSK9 (Cohort 1): Alirocumab From Day 1 Participants with gain-of-function mutation (GOFm) in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (Cohort 1): Alirocumab 150 mg subcutaneous (SC) injection at Week 0 (Day 1), Week 2 (Day 15), Week 4, 6 and 10 (matching placebo at Week 8, 12 and 14) during the double-blind period (Group A). Afterwards, participants have the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Drug: Alirocumab; SC injection in the abdomen; Other Names: Praluent® REGN727 SAR236553 ; Drug: Placebo; SC injection in the abdomen
Experimental: GOFm PCSK9 (Cohort 1): Alirocumab From Day 15 Participants with gain-of-function mutation (GOFm) in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (Cohort 1): Alirocumab 150 mg subcutaneous (SC) injection at Week 2 (Day 15), Week 4, 6, 8 and 12 ([matching placebo at Week 0 (Day 1), 10 and 14]) during the double-blind period (Group B). Afterwards, participants have the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Drug: Alirocumab; SC injection in the abdomen; Other Names: Praluent® REGN727 SAR236553 ; Drug: Placebo; SC injection in the abdomen
Experimental: GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 1 Participants with gain-of-function mutation (GOFm) in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or loss-of-function mutation (LOFm) in the apolipoprotein (Apo) B gene (Cohort 2): Alirocumab 150 mg subcutaneous (SC) injection at Week 0 (Day 1), Week 2 (Day 15), Week 4, 6 and 10 (matching placebo at Week 8, 12 and 14) during the double-blind period (Group C). Afterwards, participants have the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Drug: Alirocumab; SC injection in the abdomen; Other Names: Praluent® REGN727 SAR236553 ; Drug: Placebo; SC injection in the abdomen
Experimental: GOFm PCSK9 or LOFm ApoB (Cohort 2): Alirocumab from Day 15 Participants with gain-of-function mutation (GOFm) in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or loss-of-function mutation (LOFm) in apolipoprotein (Apo) B gene (Cohort 2): Alirocumab 150 mg subcutaneous (SC) injection at Week 2 (Day 15), Week 4, 6, 8 and 12 ([matching placebo at Week 0 (Day 1), 10 and 14]) during the double-blind period (Group D). Afterwards, participants have the possibility to continue in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Drug: Alirocumab; SC injection in the abdomen; Other Names: Praluent® REGN727 SAR236553 ; Drug: Placebo; SC injection in the abdomen

Outcome Measures

Primary Outcome Measures

1. Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15 [Baseline to Day 15]

   By day 15, participants in groups A and C had received 1 subcutaneous (SC) dose of 150 mg alirocumab and participants in group B and D had received 1 SC dose of placebo. [Baseline adjusted least squares (LS) means and standard errors were obtained using analysis of covariance (ANCOVA) model specifying the treatment arm as the fixed effect and the baseline measured LDL-C value as a covariate.]

Secondary Outcome Measures

1. Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15 [Baseline to Day 15]

   Baseline adjusted LS means and standard errors were obtained using the same ANCOVA model as for primary endpoint specifying the treatment arm as the fixed effect and the parameter value as a covariate.

2. Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15 [Baseline to Day 15]

3. Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15 [Baseline to Day 15]

4. Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15 [Baseline to Day 15]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Inclusion criteria include, but are not limited to the following:

1. Between the ages of 18 and 70 years, inclusive

2. A history of molecularly confirmed PCSK9 GOFm for cohort 1 and a history of molecularly confirmed PCSK9 GOFm or ApoB LOFm

3. Plasma LDL-Cholesterol levels ≥70 mg/dL at the screening visit on a lipid-lowering therapy (LLT) regimen stable for at least 28 days

Exclusion Criteria:

Exclusion criteria include, but are not limited to the following:

1. Serum triglycerides >350 mg/dL at the screening visit

2. Known to be positive for human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus

3. Pregnant or breast-feeding women.

4. Sexually active man or woman of childbearing potential who is unwilling to practice adequate contraception during the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Salt Lake City	Utah	United States
2		Lille	Cedex	France
3		Nantes	Cedex	France
4		Paris		France

Sponsors and Collaborators

• Regeneron Pharmaceuticals
• Sanofi

Investigators

• Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Circ Cardiovasc Genet. 2015 Dec;8(6):823-31. doi: 10.1161/CIRCGENETICS.115.001129. Epub 2015 Sep 15

Publications

None provided.

• Responsible Party: Regeneron Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01604824
• Other Study ID Numbers: R727-CL-1018
• First Posted: May 24, 2012
• Last Update Posted: Jun 17, 2020
• Last Verified: Jun 1, 2020

• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hyperlipoproteinemia Type II; Hypercholesterolemia

Study Results

Participant Flow

Recruitment Details	This study was conducted at 4 sites, 3 in France & 1 in the United States. Twenty-eight participants were screened between Feb 2012 & Apr 2013. A total of 23 participants were enrolled: 13 in cohort 1 & 10 in cohort 2. Recruitment for cohort 2 occurred after the un-blinding of cohort 1 & analyses of the double-blind study data for cohort 1.
Pre-assignment Detail	Eligible participants entered a 2-wk, single-blind, placebo run-in period. Participants in cohort 1 were randomized in a 1:1 ratio (group A or B); Participants in cohort 2 were also randomized in a 1:1 ratio (group C or D).

Arm/Group Title	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)	PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)	PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)	PCSK9 GOFm (Cohort 1: Group A and Group B)	PCSK9 GOFm/ApoB LOFm (Cohort 2: Group C and Group D)
Arm/Group Description	Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC, Q2W for an additional 3 years.	Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
Period Title: Double-blind (DB) Period
STARTED	6	7	5	5	0	0
Completed DB Period (Day 99)	6	7	5	5	0	0
Completed DB Follow-up (Day 155)	6	7	5	5	0	0
COMPLETED	6	7	5	5	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Double-blind (DB) Period
STARTED	0	0	0	0	13	10
Started Open-label Extension Period	0	0	0	0	11	10
Completed Study	0	0	0	0	10	10
COMPLETED	0	0	0	0	10	10
NOT COMPLETED	0	0	0	0	3	0

Baseline Characteristics

Arm/Group Title	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)	PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)	PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)	Total
Arm/Group Description	Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Total of all reporting groups
Overall Participants	6	7	5	5	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.3 (14.72)	46.4 (13.24)	45.6 (3.21)	42.0 (10.84)	44.2 (11.15)
Age, Customized (Number) [Number]
In utero	0 0%	0 0%	0 0%	0 0%	0 0%
Preterm newborn infants (gestational age < 37 wks)	0 0%	0 0%	0 0%	0 0%	0 0%
Newborns (0-27 days)	0 0%	0 0%	0 0%	0 0%	0 0%
Infants and toddlers (28 days-23 months)	0 0%	0 0%	0 0%	0 0%	0 0%
Children (2-11 years)	0 0%	0 0%	0 0%	0 0%	0 0%
Adolescents (12-17 years)	0 0%	0 0%	0 0%	0 0%	0 0%
Adults (18-64 years)	6 100%	7 100%	5 100%	5 100%	23 100%
From 65-84 years	0 0%	0 0%	0 0%	0 0%	0 0%
85 years and over	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	4 66.7%	5 71.4%	4 80%	2 40%	15 65.2%
Male	2 33.3%	2 28.6%	1 20%	3 60%	8 34.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	6 100%	7 100%	5 100%	5 100%	23 100%
Race (NIH/OMB) (Count of Participants)
White	5 83.3%	6 85.7%	5 100%	5 100%	21 91.3%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Other: Indian Ocean Islander	0 0%	1 14.3%	0 0%	0 0%	1 4.3%
Other: Mauritius	1 16.7%	0 0%	0 0%	0 0%	1 4.3%
Measured Low-Density Lipoprotein Cholesterol (LDL-C) (milligrams per deciliter (mg/dL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per deciliter (mg/dL)]	108.8 (33.84)	144.3 (68.39)	187.4 (98.12)	151.0 (82.70)	145.9 (72.82)
Total Cholesterol (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	181.3 (41.89)	216.3 (78.61)	249.8 (86.68)	226.0 (77.80)	216.6 (71.84)
Non-high-density lipoprotein cholesterol (Non-HDL-C) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	124.3 (49.00)	165.9 (75.59)	189.4 (93.43)	163.4 (86.88)	159.6 (74.97)
Apolipoprotein (Apo) B100 (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	89.2 (27.29)	101.0 (15.77)	129.4 (58.27)	103.6 (42.83)	104.7 (37.38)
Apolipoprotein (Apo) A1 (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	136.3 (29.75)	131.4 (30.02)	154.0 (10.98)	154.8 (20.36)	142.7 (25.65)

Outcome Measures

1. Primary Outcome

Title	Percent Change in Measured Serum Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 15
Description	By day 15, participants in groups A and C had received 1 subcutaneous (SC) dose of 150 mg alirocumab and participants in group B and D had received 1 SC dose of placebo. [Baseline adjusted least squares (LS) means and standard errors were obtained using analysis of covariance (ANCOVA) model specifying the treatment arm as the fixed effect and the baseline measured LDL-C value as a covariate.]
Time Frame	Baseline to Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)	PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)	PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
Arm/Group Description	Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
Measure Participants	6	7	5	5
Least Squares Mean (Standard Error) [percent change]	-62.48 (8.217)	-8.77 (7.575)	-48.21 (7.660)	-4.93 (7.660)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A), PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0009
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-53.72
	Confidence Interval	(2-Sided) 95%; -79.31 to -28.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.486
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C), PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0056
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-43.28
	Confidence Interval	(2-Sided) 95%; -69.21 to 17.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.965
	Estimation Comments

2. Secondary Outcome

Title	Percent Change in Apolipoprotein (Apo) B100 From Baseline to Day 15
Description	Baseline adjusted LS means and standard errors were obtained using the same ANCOVA model as for primary endpoint specifying the treatment arm as the fixed effect and the parameter value as a covariate.
Time Frame	Baseline to Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)	PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)	PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
Arm/Group Description	Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
Measure Participants	6	7	5	5
Least Squares Mean (Standard Error) [percent change]	-53.33 (8.678)	-3.78 (8.008)	-47.73 (7.547)	-3.09 (7.547)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A), PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)
	Comments	LS means (SE), mean difference, 95% CI, and p-values were derived from ANCOVA with treatment group as factor and baseline as covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0021
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-49.55
	Confidence Interval	(2-Sided) 95%; -76.39 to -22.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.050
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C), PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
	Comments	LS means (SE), mean difference, 95% CI, and p-values were derived from ANCOVA with treatment group as factor and baseline as covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0045
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-44.64
	Confidence Interval	(2-Sided) 95%; -70.36 to 18.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.876
	Estimation Comments

3. Secondary Outcome

Title	Percent Change in Non High-Density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Day 15
Time Frame	Baseline to Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)	PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)	PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
Arm/Group Description	Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
Measure Participants	6	7	5	5
Least Squares Mean (Standard Error) [percent change]	-56.87 (8.217)	-7.50 (7.575)	-44.40 (7.357)	-4.04 (7.357)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A), PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0016
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-49.37
	Confidence Interval	(2-Sided) 95%; -74.96 to -23.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.487
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C), PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0063
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-40.36
	Confidence Interval	(2-Sided) 95%; -65.12 to 15.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.471
	Estimation Comments

4. Secondary Outcome

Title	Percent Change in Total Cholesterol (Total-C) From Baseline to Day 15
Time Frame	Baseline to Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)	PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)	PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
Arm/Group Description	Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
Measure Participants	6	7	5	5
Least Squares Mean (Standard Error) [percent change]	-36.94 (5.203)	-6.18 (4.802)	-29.40 (4.422)	-7.18 (4.422)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A), PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0017
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-30.75
	Confidence Interval	(2-Sided) 95%; -46.85 to -14.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.224
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C), PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0096
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-22.23
	Confidence Interval	(2-Sided) 95%; -37.11 to -7.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.294
	Estimation Comments

5. Secondary Outcome

Title	Percent Change in Apolipoprotein (Apo) B100/ ApoA-1 Ratio From Baseline to Day 15
Time Frame	Baseline to Day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)	PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)	PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
Arm/Group Description	Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.	Participants with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
Measure Participants	6	7	5	5
Least Squares Mean (Standard Error) [percent change]	-55.26 (7.188)	-5.53 (6.647)	-48.34 (8.090)	0.99 (8.090)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A), PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0005
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-49.72
	Confidence Interval	(2-Sided) 95%; -71.71 to -27.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.867
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C), PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2: Group D)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0037
	Comments	Threshold for significance ≤ 0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-49.33
	Confidence Interval	(2-Sided) 95%; -76.63 to -22.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.545
	Estimation Comments

Adverse Events

Time Frame	From the screening visit after the last alirocumab injection in the open-label period + 70 days through the end of study
Adverse Event Reporting Description	Observation periods for safety analyses: Pretreatment: screening to before 1st injection of alirocumab; Double-blind (DB) treatment-emergent (TE): after 1st through last in DB+70 days; Interim: after last in DB+70 days prior to 1st in open-label (OL). OL TE: after 1st through last in OL+70 days. Post: after last in OL+70 days through end of study.
Arm/Group Title	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)		PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)		PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)		PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2:Group D)		OLE Period: PCSK9 GOFm (Cohort 1) Group A & Group B		OLE Period: PCSK9 GOFm/ ApoB LOFm (Cohort 2) Group C & Group D
Arm/Group Description	Participants with a gain-of-function mutation (GOFm) in the PCSK9 gene (Cohort 1: Group A) received 150 mg alirocumab subcutaneously (SC) on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.		Participants with a GOFm in PCSK9 gene (Cohort 1: Group B) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.		Participants with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2: Group C) received 150 mg alirocumab SC on days 1, 15, 29, 43, and 71 and matching placebo SC on days 57, 85, and 99. Participants who continued in an open-label extension period received 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.		Subjects with a GOFm in PCSK9 gene or LOFm in Apo B gene (Cohort 2: Group D) received 150 mg alirocumab SC on days 15, 29, 43, 57, and 85 and matching placebo SC on days 1, 71, and 99 during the double-blind period. Afterwards, subjects continued in an open-label extension period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.		Subjects with a GOFm in PCSK9 gene (Cohort 1): alirocumab 150 mg subcutaneous (SC) injection at Week 0 (Day 1), Week 2 (Day 15), Weeks 4, 6 and 10 (matching placebo at Week 8, 12 and 14) during the double-blind period (Group A) or at Week 2 (Day 15), Weeks 4, 6, 8 and 12 (matching placebo at Week 0 [Day 1], Weeks 10 and 14) during the double-blind period (Group B). Afterwards, subjects continued in an OLE period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.		Subjects with a GOFm in the PCSK9 gene or a LOFm in the Apo B gene (Cohort 2): alirocumab 150 mg SC injection at Week 0 (Day 1), Week 2 (Day 15), Weeks 4, 6 and 10 (matching placebo at Weeks 8, 12 and 14) during the double-blind period (Group C) or at Week 2 (Day 15), Weeks 4, 6, 8 and 12 (matching placebo at Week 0 [Day 1], 10 and 14) during the double-blind period (Group D). Afterwards, subjects continued in an OLE period with 150 mg alirocumab SC twice per week (Q2W) for an additional 3 years.
All Cause Mortality
	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)		PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)		PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)		PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2:Group D)		OLE Period: PCSK9 GOFm (Cohort 1) Group A & Group B		OLE Period: PCSK9 GOFm/ ApoB LOFm (Cohort 2) Group C & Group D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/7 (0%)		0/5 (0%)		0/5 (0%)		0/11 (0%)		0/10 (0%)
Serious Adverse Events
	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)		PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)		PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)		PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2:Group D)		OLE Period: PCSK9 GOFm (Cohort 1) Group A & Group B		OLE Period: PCSK9 GOFm/ ApoB LOFm (Cohort 2) Group C & Group D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		0/7 (0%)		0/5 (0%)		0/5 (0%)		3/11 (27.3%)		0/10 (0%)
Cardiac disorders
Angina unstable	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Myocardial ischaemia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Gastrointestinal disorders
Salivary gland disorder	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
General disorders
Chest pain	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Metabolism and nutrition disorders
Obesity	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Other (Not Including Serious) Adverse Events
	PCSK9 GOFm: Alirocumab From Day 1 (Cohort 1: Group A)		PCSK9 GOFm: Alirocumab From Day 15 (Cohort 1: Group B)		PCSK9 GOFm/ApoB LOFm: Alirocumab From Day1 (Cohort 2: Group C)		PCSK9GOFm/ApoB LOFm: Alirocumab From Day 15(Cohort 2:Group D)		OLE Period: PCSK9 GOFm (Cohort 1) Group A & Group B		OLE Period: PCSK9 GOFm/ ApoB LOFm (Cohort 2) Group C & Group D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/7 (85.7%)		5/5 (100%)		4/5 (80%)		10/11 (90.9%)		9/10 (90%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Cardiac disorders
Angina pectoris	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	3	0/10 (0%)	0
Angina unstable	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	2	0/10 (0%)	0
Prinzmetal angina	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Ear and labyrinth disorders
Vertigo	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	1/10 (10%)	1
Ear pruritus	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Endocrine disorders
Thyroid mass	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Eye disorders
Dry eye	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Ocular hyperaemia	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/10 (0%)	0
Abdominal distension	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/10 (0%)	0
Abdominal pain	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Haemorrhoids	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Constipation	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Aphthous ulcer	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Diarrhoea	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	2	0/10 (0%)	0
Dyspesia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Functional gastrointestinal disorder	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Gastritis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	1/10 (10%)	1
Nausea	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
General disorders
Chest pain	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	1	0/10 (0%)	0
Asthenia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	3	0/10 (0%)	0
Inflammation	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Oedema peripheral	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Hepatobiliary disorders
Hepatic steatosis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Immune system disorders
Hypersensitivity	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Infections and infestations
Herpes zoster	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/10 (0%)	0
Gastroenteritis	2/6 (33.3%)	2	1/7 (14.3%)	1	1/5 (20%)	1	0/5 (0%)	0	0/11 (0%)	0	1/10 (10%)	2
Influenza	0/6 (0%)	0	0/7 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Lower respiratory tract infection	1/6 (16.7%)	2	0/7 (0%)	0	1/5 (20%)	1	1/5 (20%)	1	0/11 (0%)	0	1/10 (10%)	1
Nasopharyngitis	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Oral herpes	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	1/5 (20%)	1	1/11 (9.1%)	4	1/10 (10%)	1
Pneumonia	0/6 (0%)	0	0/7 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Rhinitis	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	2	0/10 (0%)	0
Upper respiratory tract infection	1/6 (16.7%)	1	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	2/10 (20%)	2
Viral upper respiratory tract infection	2/6 (33.3%)	3	1/7 (14.3%)	1	2/5 (40%)	4	1/5 (20%)	1	4/11 (36.4%)	6	2/10 (20%)	2
Cystitis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Diverticulitis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	2	0/10 (0%)	0
Ear infection	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Fungal skin infection	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Infectious mononucleosis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Kidney infection	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Localised infection	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Otitis externa	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Pharyngitis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Sialoadenitis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Tooth abscess	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Tooth infection	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Urinary tract infection	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	2	0/10 (0%)	0
Vulvovaginal mycotic infection	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Injury, poisoning and procedural complications
Cardiac procedure complication	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Joint dislocation	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Ligament sprain	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Muscle strain	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Investigations
Blood bilirubin increased	0/6 (0%)	0	0/7 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Haemoglobin decreased	0/6 (0%)	0	0/7 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Blood creatine phosphokinase increased	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Cardiac murmur	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Nitrite urine present	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
White blood cells urine positive	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Metabolism and nutrition disorders
Gout	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Hyperuricaemia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Vitamin B complex deficiency	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Vitamin D deficiency	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	2	0/10 (0%)	0
Musculoskeletal pain	0/6 (0%)	0	0/7 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Back pain	1/6 (16.7%)	1	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Pain in extremity	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Myalgia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Muscle spasms	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Neck pain	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Tendonitis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour benign	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Squamous cell carcinoma of skin	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Nervous system disorders
Headache	0/6 (0%)	0	2/7 (28.6%)	3	0/5 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	0/10 (0%)	0
Migraine	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Neuropathy peripheral	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Paraesthesia	1/6 (16.7%)	1	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Sciatica	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Amnesia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Diabetic neuropathy	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Nerve compression	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Somnolence	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Syncope	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Psychiatric disorders
Anxiety	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	1/10 (10%)	1
Renal and urinary disorders
Nephrolithiasis	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	1/10 (10%)	1
Urinary retention	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	2/11 (18.2%)	2	0/10 (0%)	0
Oropharyngeal pain	1/6 (16.7%)	2	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Hypoxia	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Pleural effusion	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Skin and subcutaneous tissue disorders
Eczema	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Acne	0/6 (0%)	0	1/7 (14.3%)	1	1/5 (20%)	1	1/5 (20%)	1	1/11 (9.1%)	1	0/10 (0%)	0
Rash	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/11 (0%)	0	1/10 (10%)	1
Dermatitis allergic	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Peau d'orange	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Vascular disorders
Raynaud's phenomenon	1/6 (16.7%)	1	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/11 (0%)	0	0/10 (0%)	0
Diabetic vascular disorder	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0
Peripheral vascular disorder	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The investigator has the right to independently publish study results from the investigator's site after a multi-center publication, or a defined period after the completion of the study by all sites. The investigator must provide the sponsor a copy of any such publication derived from the study for review and comment in advance of any submission, and delay publication, if requested, to allow the Sponsor to preserve its proprietary rights.