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Clinical Trial Results:
A Phase 1/2, Single-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously Administered ALN-GO1 in Healthy Adult Subjects, and Patients with Primary Hyperoxaluria Type 1

Summary
EudraCT number	2015-004407-23
Trial protocol	GB DE NL
Global end of trial date	23 Jan 2019

Results information
Results version number	v2(current)
This version publication date	07 Feb 2020
First version publication date	21 Aug 2019
Other versions	v1
Version creation reason	Correction of full data set Inclusion of data for a secondary outcome measure.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ALN-GO1-001

ISRCTN number

US NCT number

NCT02706886

WHO universal trial number (UTN)

Sponsor organisation name

Alnylam Pharmaceuticals, Inc.

Sponsor organisation address

300 Third Street, Cambridge, MA, United States, 02142

Public contact

Investor Relations and Corporate Communications, Alnylam Pharmaceuticals Inc, +1 866330 0326, Investors@alnylam.com

Scientific contact

Chief Medical Officer, Alnylam Pharmaceuticals Inc, +1 866330 0326, medinfo@alnylam.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002079-PIP01-16

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Jan 2019

Was the trial ended prematurely?

Main objective of the trial

To evaluate the safety and tolerability of single and multiple ascending doses of lumasiran (ALN-GO1), respectively, in healthy adult subjects and in patients with primary hyperoxaluria type 1 (PH1).

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form (ICF).

Background therapy

Subjects with PH1 were required to continue their individual standard of care regimen.

Evidence for comparator

Actual start date of recruitment

08 Mar 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Israel: 7

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

United Kingdom: 35

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 1

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled at nine sites in Germany, France, the United Kingdom, Israel, and the Netherlands.

Screening details

Fifty-two subjects were enrolled in this study. In Part A, single ascending dose (SAD), 32 healthy adults were dosed and in Part B, multiple ascending doses (MAD), 20 adult and paediatric subjects with PH1 were dosed.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Are arms mutually exclusive

Part A: SAD: Placebo

Arm description

A single dose of matching placebo was administered.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Matching placebo (Sterile saline: 0.9% sodium chloride [NaCl]) was administered subcutaneously (SC) on Day 1.

Part A: SAD: Lumasiran 0.3 mg/kg

Arm description

A single dose of 0.3 mg/kg lumasiran was administered.

Arm type

Experimental

Investigational medicinal product name

Lumasiran

Investigational medicinal product code

Other name

ALN-GO1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Lumasiran was administered SC on Day 1.

Part A: SAD: Lumasiran 1.0 mg/kg

Arm description

A single dose of 1.0 mg/kg lumasiran was administered.

Arm type

Experimental

Investigational medicinal product name

Lumasiran

Investigational medicinal product code

Other name

ALN-GO1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Lumasiran was administered SC on Day 1.

Part A: SAD: Lumasiran 3.0 mg/kg

Arm description

A single dose of 3.0 mg/kg lumasiran was administered.

Arm type

Experimental

Investigational medicinal product name

Lumasiran

Investigational medicinal product code

Other name

ALN-GO1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Lumasiran was administered SC on Day 1.

Part A: SAD: Lumasiran 6.0 mg/kg

Arm description

A single dose of 6.0 mg/kg lumasiran was administered.

Arm type

Experimental

Investigational medicinal product name

Lumasiran

Investigational medicinal product code

Other name

ALN-GO1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Lumasiran was administered SC on Day 1.

Part B: MAD: Placebo

Arm description

Subjects with PH1 were treated with placebo matching one of the lumasiran dosages (one placebo subject for each lumasiran arm) in Part B. At Day 85 these placebo-treated subjects crossed over to their respective Part B lumasiran arms.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Matching placebo (sterile saline: 0.9% sodium chloride [NaCl]) was administered subcutaneously (SC) on Days 1, 29 and 57 for qM and Day 1 for q3M.

Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)

Arm description

Subjects with PH1 were treated with 1.0 mg/kg lumasiran qM.

Arm type

Experimental

Investigational medicinal product name

Lumasiran

Investigational medicinal product code

Other name

ALN-GO1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Lumasiran was administered SC on Days 1, 29 and 57.

Part B: MAD: Lumasiran 3.0 mg/kg qM

Arm description

Subjects with PH1 were treated with 3.0 mg/kg lumasiran qM.

Arm type

Experimental

Investigational medicinal product name

Lumasiran

Investigational medicinal product code

Other name

ALN-GO1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Lumasiran was administered SC on Days 1, 29 and 57.

Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)

Arm description

Subjects with PH1 were treated with 3.0 mg/kg lumasiran q3M.

Arm type

Experimental

Investigational medicinal product name

Lumasiran

Investigational medicinal product code

Other name

ALN-GO1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Lumasiran was administered SC on Days 1 and 85.

Number of subjects in period 1	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Started	8	6	6	6	6	3	8	8	4
Completed	8	6	6	4	6	3	8	8	4
Not completed	0	0	0	2	0	0	0	0	0
Withdrawal by subject	-	-	-	2	-	-	-	-	-

Baseline characteristics

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Reporting group title

Part A: SAD: Placebo

Reporting group description

A single dose of matching placebo was administered.

Reporting group title

Part A: SAD: Lumasiran 0.3 mg/kg

Reporting group description

A single dose of 0.3 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 1.0 mg/kg

Reporting group description

A single dose of 1.0 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 3.0 mg/kg

Reporting group description

A single dose of 3.0 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 6.0 mg/kg

Reporting group description

A single dose of 6.0 mg/kg lumasiran was administered.

Reporting group title

Part B: MAD: Placebo

Reporting group description

Reporting group title

Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)

Reporting group description

Subjects with PH1 were treated with 1.0 mg/kg lumasiran qM.

Reporting group title

Part B: MAD: Lumasiran 3.0 mg/kg qM

Reporting group description

Subjects with PH1 were treated with 3.0 mg/kg lumasiran qM.

Reporting group title

Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)

Reporting group description

Subjects with PH1 were treated with 3.0 mg/kg lumasiran q3M.

Reporting group values	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)	Total
Number of subjects	8	6	6	6	6	3	8	8	4
Age categorical
Units: Subjects
Age continuous
Safety Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of study drug (lumasiran, placebo), grouped according to actual treatment received.
Units: years
arithmetic mean (standard deviation)	29.8 ± 6.25	28.8 ± 7.36	30.2 ± 7.81	27.3 ± 3.44	28.8 ± 5.46	20.7 ± 19.40	13.3 ± 9.44	14.9 ± 7.47	18.0 ± 17.26	-
Gender categorical
Safety Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of study drug (lumasiran, placebo), grouped according to actual treatment received.
Units: Subjects
Female	5	0	3	3	5	1	7	4	2	29
Male	3	6	3	3	1	2	1	4	2	23

End points

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Reporting group title

Part A: SAD: Placebo

Reporting group description

A single dose of matching placebo was administered.

Reporting group title

Part A: SAD: Lumasiran 0.3 mg/kg

Reporting group description

A single dose of 0.3 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 1.0 mg/kg

Reporting group description

A single dose of 1.0 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 3.0 mg/kg

Reporting group description

A single dose of 3.0 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 6.0 mg/kg

Reporting group description

A single dose of 6.0 mg/kg lumasiran was administered.

Reporting group title

Part B: MAD: Placebo

Reporting group description

Reporting group title

Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)

Reporting group description

Subjects with PH1 were treated with 1.0 mg/kg lumasiran qM.

Reporting group title

Part B: MAD: Lumasiran 3.0 mg/kg qM

Reporting group description

Subjects with PH1 were treated with 3.0 mg/kg lumasiran qM.

Reporting group title

Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)

Reporting group description

Subjects with PH1 were treated with 3.0 mg/kg lumasiran q3M.

Primary: Number of Subjects With Adverse Events (AEs)

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End point title

Number of Subjects With Adverse Events (AEs) ^[1]

End point description

An AE is any untoward medical occurrence in a clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Safety Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of study drug (lumasiran, placebo), grouped according to actual treatment received.

End point type

Primary

End point timeframe

Part A (SAD phase): Up to 405 days; Part B (MAD phase): Up to 546 days

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data were planned to be reported for this safety endpoint.

End point values	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	8	6	6	6	6	3	8	8	4
Units: subjects	5	6	2	6	6	2	8	7	4

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Lumasiran in Plasma

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End point title

Maximum Concentration (Cmax) of Lumasiran in Plasma ^[2]

End point description

Pharmacokinetic (PK) Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of lumasiran and had at least 1 postdose sample for PK parameters and who had evaluable PK data. In each row header within the table n indicates the number of subjects analysed for the specific time point. Here, 9999 = Not Applicable: Data for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.

End point type

Secondary

End point timeframe

Part A (SAD phase): Day 1: predose, 30 minutes (min), 1 hour (h), 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD phase): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Pharmacokinetic (PK) endpoints were only determined in subjects treated with lumasiran.

End point values	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	6	6	6	6	8	8	4
Units: ng/mL
arithmetic mean (standard deviation)
Day 1 (n=6,6,6,6,8,8,4)	39.7940 ± 8.58882	204.3748 ± 111.68091	533.4527 ± 160.11060	1176.1302 ± 199.89797	324.1386 ± 489.71104	582.4515 ± 266.90105	432.2798 ± 245.02660
Day 57 (n=0,0,0,0,8,8,0)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	147.6780 ± 67.97968	701.1708 ± 511.63001	9999 ± 9999
Day 85 (n=0,0,0,0,0,0,3)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	411.5613 ± 174.92146

No statistical analyses for this end point

Secondary: Time to Cmax (tmax) of Lumasiran in Plasma

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End point title

Time to Cmax (tmax) of Lumasiran in Plasma ^[3]

End point description

PK Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of lumasiran and had at least 1 postdose sample for PK parameters and who had evaluable PK data. In each row header within the table n indicates the number of subjects analysed for the specific time point. Here, 9999 = Not Applicable: Data for Part A were collected only on Day 1; Part B on Days 1 and 57 for qM and on Days 1 and 85 for q3M arm groups.

End point type

Secondary

End point timeframe

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK endpoints were only determined in subjects treated with lumasiran.

End point values	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	6	6	6	6	8	8	4
Units: hours
median (full range (min-max))
Day 1 (n=6,6,6,6,8,8,4)	5.0167 (4.000 to 8.017)	1.5000 (0.517 to 8.000)	3.0000 (0.500 to 8.000)	7.0000 (0.500 to 8.067)	3.9917 (0.567 to 5.967)	4.9917 (0.533 to 12.000)	9.0000 (5.783 to 12.017)
Day 57 (n=0,0,0,0,8,8,0)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	3.0417 (0.500 to 6.000)	2.9833 (0.500 to 8.000)	9999 (9999 to 9999)
Day 85 (n=0,0,0,0,0,0,3)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	5.9833 (4.050 to 7.950)

No statistical analyses for this end point

Secondary: Area Under the Concentration-Time Curve from Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma

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End point title

Area Under the Concentration-Time Curve from Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma ^[4]

End point description

End point type

Secondary

End point timeframe

Part A (SAD phase): predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h; Part B (MAD phase): Starting on Days 1, 57, 85, and 141 (q3M only Days 1 and 85): predose, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK endpoints were only determined in subjects treated with lumasiran.

End point values	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	6	6	6	6	8	8	4
Units: h*ng/mL
arithmetic mean (standard deviation)
Day 1 (n=6,6,6,6,8,8,4)	293.5232 ± 96.86989	1899.8119 ± 558.25326	7211.5890 ± 1125.64173	16778.0579 ± 4380.15325	1428.0412 ± 697.85233	7400.2181 ± 2331.89843	6337.9082 ± 3840.03340
Day 57 (n=0,0,0,0,8,8,0)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	1608.1457 ± 708.95156	7959.7873 ± 1726.57675	9999 ± 9999
Day 85 (n=0,0,0,0,0,0,3)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	5136.3462 ± 2757.90139

No statistical analyses for this end point

Secondary: Terminal Half-life (t1/2) of Lumasiran in Plasma

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End point title

Terminal Half-life (t1/2) of Lumasiran in Plasma ^[5]

End point description

End point type

Secondary

End point timeframe

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK endpoints were only determined in subjects treated with lumasiran.

End point values	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	6	6	6	8	8	4
Units: hours
arithmetic mean (standard deviation)
Day 1 (n=2,2,1,4,5,1)	7.0655 ± 0.37379	5.9798 ± 1.52471	3.4683 ± 99999	3.2670 ± 1.52759	5.4574 ± 3.49432	7.8028 ± 99999
Day 57 (n=0,0,0,0,4,4,0)	9999 ± 9999	9999 ± 9999	9999 ± 9999	7.8090 ± 4.52009	5.8356 ± 3.12156	9999 ± 9999
Day 85 (n=0,0,0,0,0,0,1)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	4.6694 ± 99999

No statistical analyses for this end point

Secondary: Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran

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End point title

Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran ^[6]

End point description

End point type

Secondary

End point timeframe

Part A (SAD): Day 1: pooled urine 0-4 h, 4-8 h and 8-24 h; Part B (MAD): Part B (MAD phase): Days 1 and 57 for qM dosing and Days 1 and 85 for q3M dosing: pooled urine 0-4 h, 4-8 h, 8-12 h and 12-24 h

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK endpoints were only determined in subjects treated with lumasiran.

End point values	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	6	6	6	6	8	8	4
Units: percentage of fractional excretion
arithmetic mean (standard deviation)
Day 1 (n=6,6,6,5,7,7,4)	17.4219 ± 2.44129	19.0713 ± 3.88914	21.0472 ± 5.36667	25.7931 ± 3.25937	11.0895 ± 3.74207	11.1877 ± 6.07719	7.1691 ± 2.37465
Day 57 (n=0,0,0,0,8,6,0)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9.4698 ± 4.21949	12.4604 ± 4.02897	9999 ± 9999
Day 85 (n=0,0,0,0,0,0,3)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	13.6938 ± 3.60004

No statistical analyses for this end point

Secondary: Renal Clearance (CLR) of Lumasiran

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End point title

Renal Clearance (CLR) of Lumasiran ^[7]

End point description

End point type

Secondary

End point timeframe

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK endpoints were only determined in subjects treated with lumasiran.

End point values	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	6	6	6	6	8	8	4
Units: Liter/hour (L/h)
arithmetic mean (standard deviation)
Day 1 (n=1,5,6,5,6,6,4)	8.7817 ± 99999	5.4906 ± 2.07402	5.8211 ± 1.31377	6.3417 ± 1.15497	2.2612 ± 1.17616	2.3818 ± 1.13067	2.0564 ± 1.20600
Day 57 (n=0,0,0,0,7,6,0)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	1.9610 ± 1.11228	2.5150 ± 0.80386	9999 ± 9999
Day 85 (n=0,0,0,0,0,0,3)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	3.3663 ± 1.18371

No statistical analyses for this end point

Secondary: Baseline Plasma Glycolate Concentration

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End point title

Baseline Plasma Glycolate Concentration ^[8]

End point description

Pharmacodynamic (PD) Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments. Due to a quality issue with the plasma glycolate assay at the testing laboratory the data for Part B could not be calculated.

End point type

Secondary

End point timeframe

Part A (SAD phase): Baseline, Part B (MAD phase): Baseline

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Plasma glycolate concentration was only calculated for Part A.

End point values	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg
Number of subjects analysed	8	6	6	6	6
Units: umol/L
arithmetic mean (standard deviation)	5.1 ± 1.73	5.3 ± 1.51	5.7 ± 1.97	6.2 ± 2.56	4.8 ± 1.72

No statistical analyses for this end point

Secondary: Percentage Change from Baseline in Plasma Glycolate Concentration

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End point title

Percentage Change from Baseline in Plasma Glycolate Concentration ^[9]

End point description

PD Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments. Due to a quality issue with the plasma glycolate assay at the testing laboratory the data for Part B could not be calculated. In each row header within the table n indicates the number of subjects analysed for the specific time point.

End point type

Secondary

End point timeframe

Part A (SAD phase): Days 15, 29, 57 and 85; Part B (MAD phase): Days 15, 29, 57, 85

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Plasma glycolate concentration was only calculated for Part A.

End point values	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg
Number of subjects analysed	8	6	6	6	6
Units: percentage change from baseline
arithmetic mean (standard deviation)
Day 15 (n=8,6,6,6,6)	18.3 ± 67.19	58.3 ± 55.29	48.5 ± 82.99	56.4 ± 28.50	59.5 ± 49.00
Day 29 (n=8,6,6,6,6)	22.4 ± 46.83	32.9 ± 57.67	70.6 ± 82.74	146.4 ± 81.99	390.1 ± 270.40
Day 57 (n=8,6,6,6,6)	126.7 ± 242.68	66.3 ± 38.07	109.8 ± 124.29	230.1 ± 180.36	730.4 ± 439.54
Day 85 (n=8,6,6,5,6)	31.2 ± 131.04	15.6 ± 100.54	40.7 ± 110.75	196.2 ± 152.41	731.3 ± 375.02

No statistical analyses for this end point

Secondary: Baseline Spot Urine Glycolate:Creatinine Ratio in Part A

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End point title

Baseline Spot Urine Glycolate:Creatinine Ratio in Part A ^[10]

End point description

End point type

Secondary

End point timeframe

Part A (SAD phase): Baseline

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only measured in Part A.

End point values	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg
Number of subjects analysed	8	6	6	6	6
Units: mg/g
arithmetic mean (standard deviation)	12.4 ± 4.63	15.7 ± 4.27	15.7 ± 3.14	13.0 ± 3.52	14.8 ± 4.31

No statistical analyses for this end point

Secondary: Percentage Change from Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A

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End point title

Percentage Change from Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A ^[11]

End point description

End point type

Secondary

End point timeframe

Part A (SAD phase): Days 29 and 57

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only measured in Part A.

End point values	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg
Number of subjects analysed	8	6	6	6	6
Units: percentage change from baseline
arithmetic mean (standard deviation)
Day 29 (=8,6,6,6,6)	8.1 ± 43.42	32.5 ± 22.6	82.9 ± 65.00	109.1 ± 66.51	210.5 ± 199.30
Day 57 (n=8,6,6,6,6)	73.8 ± 108.9	38.0 ± 50.62	47.8 ± 41.03	215.0 ± 178.72	310.7 ± 94.51

No statistical analyses for this end point

Secondary: Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B

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End point title

Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B ^[12]

End point description

End point type

Secondary

End point timeframe

Part B (MAD): Baseline

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only measured in Part B.

End point values	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	3	8	8	4
Units: mmol/24h/1.73m^2
arithmetic mean (standard deviation)	1.96 ± 0.321	1.73 ± 0.696	1.84 ± 0.621	1.30 ± 0.350

No statistical analyses for this end point

Secondary: Percentage Change from Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B

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End point title

Percentage Change from Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B ^[13]

End point description

PD Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments. In each row header within the table n indicates the number of subjects analysed for the specific time point. 9999 = Not Applicable as data for the Part B placebo arm were only collected up to Day 85. 99999 = SD was not calculated for arms with data for 1 subject.

End point type

Secondary

End point timeframe

Part B (MAD): 24 hour urine collections on Days 29, 57, 85, 113, 141, 169, 197

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only measured in Part B.

End point values	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	3	8	8	4
Units: percentage change from baseline
arithmetic mean (standard deviation)
Day 29 (n=1,7,7,4)	-2.4 ± 99999	-41.1 ± 24.76	-57.5 ± 10.84	-49.2 ± 5.40
Day 57 (n=2,7,8,4)	-27.8 ± 47.11	-49.7 ± 20.08	-72.5 ± 10.70	-49.1 ± 5.82
Day 85 (n=1,8,7,3)	9.1 ± 99999	-65.6 ± 16.64	-68.4 ± 10.60	-53.3 ± 3.66
Day 113 (n=0,7,6,4)	9999 ± 9999	-61.4 ± 12.24	-78.1 ± 7.80	-59.1 ± 20.75
Day 141 (n=0,7,7,2)	9999 ± 9999	-64.6 ± 13.55	-73.5 ± 8.11	-68.4 ± 3.21
Day 169 (n=0,8,7,3)	9999 ± 9999	-61.6 ± 14.19	-69.3 ± 9.61	-48.7 ± 14.19
Day 197 (n=0,6,7,4)	9999 ± 9999	-63.8 ± 13.85	-71.2 ± 11.70	-52.7 ± 6.38

No statistical analyses for this end point

Secondary: Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days

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End point title

Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days ^[14]

End point description

End point type

Secondary

End point timeframe

Part B (MAD): Baseline

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only measured in Part B.

End point values	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	3	7	7	3
Units: mg/g
arithmetic mean (standard deviation)	193 ± 117.2	241 ± 85.6	289 ± 146.0	281 ± 139.0

No statistical analyses for this end point

Secondary: Percentage Change from Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days

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End point title

Percentage Change from Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days ^[15]

End point description

End point type

Secondary

End point timeframe

Part B (MAD): 24 hour urine collections on Days 29, 57 and 85.

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only measured in Part B.

End point values	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	3	7	7	3
Units: percentage change from baseline
arithmetic mean (standard deviation)
Day 29 (n=3,7,7,3)	-15.1 ± 6.47	53.1 ± 42.18	31.4 ± 35.99	33.0 ± 36.37
Day 57 (n=3,7,7,3)	-13.8 ± 29.02	82.3 ± 40.12	42.3 ± 57.56	81.8 ± 35.66
Day 85 (n=3,7,7,2)	-23.0 ± 10.45	71.0 ± 55.62	43.7 ± 62.15	42.0 ± 20.86

No statistical analyses for this end point

Secondary: Baseline Creatinine Clearance Corrected for BSA in Part B

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End point title

Baseline Creatinine Clearance Corrected for BSA in Part B ^[16]

End point description

End point type

Secondary

End point timeframe

Part B (MAD): Baseline

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only measured in Part B.

End point values	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	3	8	8	4
Units: mL/min/1.73 m^2
arithmetic mean (standard deviation)	64.389 ± 19.8024	108.149 ± 44.1783	86.268 ± 22.1226	88.251 ± 30.0118

No statistical analyses for this end point

Secondary: Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B

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End point title

Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B ^[17]

End point description

PD Analysis Set in Part B consisted of all patients with PH1 who received at least 1 dose of study drug (lumasiran, placebo) and had at least 1 postdose blood and/or urine sample available that was evaluable for PD assessments. 9999 = Not Applicable as zero subjects were evaluated for this time point. 99999 = SD was not calculated for arms with data for 1 subject.

End point type

Secondary

End point timeframe

Part B (MAD): Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365, 393, 421, 449

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only measured in Part B.

End point values	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg once every 3 months (q3M)
Number of subjects analysed	2	8	8	4
Units: percentage change from baseline
arithmetic mean (standard deviation)
Day 29 (n=1,7,7,4)	9.019 ± 99999	-6.672 ± 11.9614	-0.624 ± 15.1771	2.748 ± 5.6858
Day 57 (n=2,7,8,4)	20.184 ± 23.5572	-8.426 ± 19.7271	4.505 ± 35.2457	37.030 ± 56.1210
Day 85 (n=1,8,7,2)	-5.945 ± 99999	-13.536 ± 22.8679	-3.720 ± 22.6231	-6.113 ± 43.5441
Day 113 (n=0,7,6,4)	9999 ± 9999	-14.424 ± 24.1107	3.444 ± 29.6749	7.570 ± 40.5928
Day 141 (n=0,7,7,2)	9999 ± 9999	-8.804 ± 27.4802	9.315 ± 27.5044	-30.691 ± 12.8912
Day 169 (n=0,8,7,1)	9999 ± 9999	-19.796 ± 31.7492	-8.544 ± 14.8481	20.210 ± 99999
Day 197 (n=0,6,7,4)	9999 ± 9999	-8.546 ± 13.5672	-13.513 ± 25.0560	28.857 ± 22.1891
Day 225 (n=0,6,8,3)	9999 ± 9999	-18.221 ± 14.2322	29.013 ± 53.5563	-14.964 ± 9.9130
Day 253 (n=0,6,7,0)	9999 ± 9999	-5.140 ± 19.2839	10.232 ± 24.4929	9999 ± 9999
Day 281 (n=0,6,6,0)	9999 ± 9999	-14.283 ± 22.6126	5.841 ± 13.0381	9999 ± 9999
Day 309 (n=0,5,4,0)	9999 ± 9999	-0.403 ± 34.6839	8.441 ± 11.5329	9999 ± 9999
Day 337 (n=0,4,4,0)	9999 ± 9999	-5.168 ± 31.0756	8.688 ± 24.2094	9999 ± 9999
Day 365 (n=0,2,2,0)	9999 ± 9999	2.268 ± 33.7565	9.201 ± 14.4856	9999 ± 9999
Day 393 (n=0,3,2,0)	9999 ± 9999	-11.942 ± 45.3027	-4.484 ± 12.6320	9999 ± 9999
Day 421 (n=0,3,2,0)	9999 ± 9999	7.610 ± 11.2195	-6.498 ± 12.9022	9999 ± 9999
Day 449 (n=0,0,2,0)	9999 ± 9999	9999 ± 9999	-15.093 ± 10.3705	9999 ± 9999

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Part A (SAD phase): Up to 405 days; Part B (MAD phase): Up to 546 days

Adverse event reporting additional description

Safety Analysis Set consisted of all healthy subjects and patients who received at least 1 dose of study drug (lumasiran, placebo), grouped according to actual treatment received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Part A: SAD: Placebo

Reporting group description

A single dose of matching placebo was administered.

Reporting group title

Part A: SAD: Lumasiran 0.3 mg/kg

Reporting group description

A single dose of 0.3 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 1.0 mg/kg

Reporting group description

A single dose of 1.0 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 3.0 mg/kg

Reporting group description

A single dose of 3.0 mg/kg lumasiran was administered.

Reporting group title

Part A: SAD: Lumasiran 6.0 mg/kg

Reporting group description

A single dose of 6.0 mg/kg lumasiran was administered.

Reporting group title

Part B: MAD: Placebo

Reporting group description

Subjects with PH1 were treated with placebo matching one of the lumasiran dosages (one placebo subject for each lumasiran arm). After 85 days these subjects crossed over to the lumasiran groups.

Reporting group title

Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)

Reporting group description

Subjects with PH1 were treated with 1.0 mg/kg lumasiran qM for 197 days.

Reporting group title

Part B: MAD: Lumasiran 3.0 mg/kg qM

Reporting group description

Subjects with PH1 were treated with 3.0 mg/kg lumasiran qM for 197 days.

Reporting group title

Part B: MAD: Lumasiran 3.0 mg/kg q3M

Reporting group description

Subjects with PH1 were treated with 3.0 mg/kg lumasiran q3M for 197 days.

Serious adverse events	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg q3M
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	3 / 8 (37.50%)	0 / 4 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Part A: SAD: Placebo	Part A: SAD: Lumasiran 0.3 mg/kg	Part A: SAD: Lumasiran 1.0 mg/kg	Part A: SAD: Lumasiran 3.0 mg/kg	Part A: SAD: Lumasiran 6.0 mg/kg	Part B: MAD: Placebo	Part B: MAD: Lumasiran 1.0 mg/kg once monthly (qM)	Part B: MAD: Lumasiran 3.0 mg/kg qM	Part B: MAD: Lumasiran 3.0 mg/kg q3M
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 8 (62.50%)	6 / 6 (100.00%)	3 / 6 (50.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	2 / 3 (66.67%)	7 / 8 (87.50%)	7 / 8 (87.50%)	4 / 4 (100.00%)
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	2	0
Injection site pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 6 (66.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	4	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	1	1	1	1
Axillary pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Influenza like illness
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Injection site bruising
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Injection site discolouration
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Injection site erythema
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Injection site pruritus
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Injection site swelling
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Social circumstances
Caffeine consumption
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Nasal discomfort
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0
Cough
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	2	2	0
Rhinitis allergic
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Psychiatric disorders
Alcoholic hangover
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	2	0	1	0	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	3	0	2	0	0	0	0	0
Blood phosphorus decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	2
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Head injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Laceration
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Tendon injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Arthropod bite
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Soft tissue injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Congenital, familial and genetic disorders
Atrial septal defect
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Cardiac disorders
Tricuspid valve incompetence
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 8 (12.50%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)	3 / 6 (50.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)
occurrences all number	1	1	2	1	3	0	2	7	0
Presyncope
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0
Migraine
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Lethargy
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Blood and lymphatic system disorders
Lymph node pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Eye swelling
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Visual impairment
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	3 / 8 (37.50%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1	0	0	1	3	1
Diarrhoea
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Faeces soft
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Flatulence
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Constipation
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Vomiting
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	1	0	1	1
Abdominal pain upper
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Teething
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Toothache
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Skin and subcutaneous tissue disorders
Papule
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Rash follicular
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Skin texture abnormal
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Blister
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Rash
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	3 / 8 (37.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0
Dysuria
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Myalgia
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0
Arthralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Groin pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Infections and infestations
Gastroenteritis
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	2	0	0	0	0
Influenza
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	3 / 8 (37.50%)	1 / 6 (16.67%)	1 / 6 (16.67%)	4 / 6 (66.67%)	4 / 6 (66.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 4 (50.00%)
occurrences all number	3	2	1	4	4	0	0	0	2
Periodontitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Tonsillitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	1	0	1	0	0
Urinary tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0
Viral pharyngitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0	0	1	0	0	0
Body tinea
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Dermatitis infected
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Rhinitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	3 / 8 (37.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	1	4	0
Urinary tract infection bacterial
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Urinary tract infection staphylococcal
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Pharyngitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Gout
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	5
Overweight
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Increased appetite
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

01 Jul 2016

1. Provided starting dose of lumasiran (1.0 mg/kg) for SC administration every 28 days to PH1 patients in Part B, based on preliminary data from Part A in healthy volunteers. 2. Added cohort progression/escalation and suspension/stopping rules pertaining to AEs. For Part B only, 3. Clarified details regarding collection and evaluation of urinary oxalate and glycolate measurements. 4. Specified that on days when a blood sample for vitamin B6 should be collected, patients should be instructed to not take vitamin B6 before the blood sample is collected and the study drug is administered. 5. Removed 28-day window from the schedule of assessment for the Day 85 study visit to indicate that this visit must occur on the scheduled day. 6. Clarified that additional cohorts may be enrolled at higher, lower, or intermediate dose levels, but will not exceed the maximum administered dose of 6.0 mg/kg. For Parts A and B, 7. Specified that plasma samples, in addition to urine samples, are collected for assessment of pharmacodynamic (PD) assessments.

21 Sep 2016

1. For Parts A and B, subjects were to be followed until PD recovery occurred (until plasma glycolate decreased to a level that was no more than 20% above baseline or until plasma glycolate was below upper limit of normal (ULN </=14 micromol/L). 2. For Part B, subjects with PH1 were to be followed until urinary oxalate increased to a level above 80% of baseline. 3. For Part B, blood samples for anti-drug antibodies (ADA) analysis were added at final dosing/end of treatment (EOT) visit, at 28 days after final lumasiran dose, and every 56 days for remainder of follow-up periods. 4. Language added to indicate confirmed positive ADA samples are tested for cross-reactivity with DNA and nucleic acids. 5. For Part B, pharmacokinetic (PK) sampling times adjusted to capture full PK profile and relieve burden on subject. Clinic visits added at Day 3, Day 58, and Day 59, accordingly. For subjects initially receiving placebo, clinic visits added at Day 87, Day 142, and Day 143. 6. Clarified that liver function tests (LFTs) would be reviewed locally and confirmed by central laboratory prior to study drug administration.

09 Dec 2016

1. To further define cardiac function requirements and monitoring for all Part B subjects, based on safety review committee (SRC) recommendations. 2. Added echocardiogram (ECG) and troponin I assessments and exclusion criterion of left ventricular ejection fraction <55% and troponin I >ULN at screening. 3. Increased maximum blood volume to align with cardiac monitoring evaluations. 4. Aligned wording describing resumption of dosing requirements after dose suspension rule had been met.

27 Jun 2017

1. Shortened the Part B follow-up period so that subjects could transition to open-label extension study earlier, provided that urinary oxalate was >ULN and subjects met at least 1 specific PD recovery criterion: o One 24-hour urinary oxalate value was >80% of baseline. o Two 24-hour urinary oxalate values above the midpoint between baseline and nadir 24-hour urinary oxalate values. o At least 12 months from time of final dose. 2. Increased the number of optional cohorts and sample size in Part B in order to further explore optimal dose. 3. Schedule of Assessments to allow for once every 3 months dosing in Part B was added. 4. Statistical Methods section updated to account for possibility of once every 3 months dosing regimen. 5. Section about the SRC aligned with recent changes to SRC charter regarding frequency of safety data reviews.

14 Feb 2018

1. Extended the allowable time window (from 1 to 2 hours) to conduct predose assessments (i.e., vital signs, 12-lead ECGs, physical examinations, blood and urine sample collections) when scheduled at the same time points for Part B. 2. Shortened the follow-up period from up to 1 year to 12 weeks after final lumasiran dose, without requiring protocol-defined thresholds for urinary oxalate levels for subjects who planned to enroll in the extension study for continued dosing. 3. Added new text to permit the Investigator, following completion of the 12-week follow-up period and per SRC approval, to discontinue safety and PD follow-up for subjects who did not enroll in the open-label extension study, and who had not yet met the PD recovery criteria. 4. Redefined the definition for uncontrolled hypertension in paediatric patients. 5. Clarified that blood samples for pyridoxine (vitamin B6) were required only for subjects receiving therapeutic pyridoxine.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
31 Oct 2016	The study was temporarily halted, with a pause in start of enrollment of patients for Part B of the study. This was to allow a recommendation from a scheduled Safety Review Committee to be incorporated in the protocol, at which point study screening resumed	15 Dec 2016

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1/2, Single-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously Administered ALN-GO1 in Healthy Adult Subjects, and Patients with Primary Hyperoxaluria Type 1

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Adverse Events (AEs)

Primary: Number of Subjects With Adverse Events (AEs)

Secondary: Maximum Concentration (Cmax) of Lumasiran in Plasma

Secondary: Maximum Concentration (Cmax) of Lumasiran in Plasma

Secondary: Time to Cmax (tmax) of Lumasiran in Plasma

Secondary: Time to Cmax (tmax) of Lumasiran in Plasma

Secondary: Area Under the Concentration-Time Curve from Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma

Secondary: Area Under the Concentration-Time Curve from Time 0 to Time of Last Measurable Concentration (AUC0-last) of Lumasiran in Plasma

Secondary: Terminal Half-life (t1/2) of Lumasiran in Plasma

Secondary: Terminal Half-life (t1/2) of Lumasiran in Plasma

Secondary: Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran

Secondary: Fraction Excreted in Urine in 24 Hours (Fe0-24) of Lumasiran

Secondary: Renal Clearance (CLR) of Lumasiran

Secondary: Renal Clearance (CLR) of Lumasiran

Secondary: Baseline Plasma Glycolate Concentration

Secondary: Baseline Plasma Glycolate Concentration

Secondary: Percentage Change from Baseline in Plasma Glycolate Concentration

Secondary: Percentage Change from Baseline in Plasma Glycolate Concentration

Secondary: Baseline Spot Urine Glycolate:Creatinine Ratio in Part A

Secondary: Baseline Spot Urine Glycolate:Creatinine Ratio in Part A

Secondary: Percentage Change from Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A

Secondary: Percentage Change from Baseline in Spot Urine Glycolate:Creatinine Ratio in Part A

Secondary: Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B

Secondary: Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B

Secondary: Percentage Change from Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B

Secondary: Percentage Change from Baseline of 24 Hour Urine Oxalate Corrected for BSA in Part B

Secondary: Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days

Secondary: Baseline 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days

Secondary: Percentage Change from Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days

Secondary: Percentage Change from Baseline of 24 Hour Urine Glycolate:Creatinine Ratio in Part B - Initial 85 Days

Secondary: Baseline Creatinine Clearance Corrected for BSA in Part B

Secondary: Baseline Creatinine Clearance Corrected for BSA in Part B

Secondary: Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B

Secondary: Percentage Change From Baseline of Creatinine Clearance Corrected for BSA in Part B

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1/2, Single-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose Safety, Tolerability, Pharmacokinetic and Pharmacodynamics Study of Subcutaneously Administered ALN-GO1 in Healthy Adult Subjects, and Patients with Primary Hyperoxaluria Type 1