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Clinical Trial Results:
A Phase III, Randomized, Multicenter, Open-Label, Active-Comparator Controlled Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Summary
EudraCT number	2017-004268-36
Trial protocol	DE BE ES NL FR GB IT
Global end of trial date	13 Aug 2020

Results information
Results version number	v1(current)
This version publication date	12 Nov 2021
First version publication date	12 Nov 2021
Other versions

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

APL2-302

ISRCTN number

US NCT number

NCT03500549

WHO universal trial number (UTN)

Sponsor organisation name

Apellis Pharmaceuticals, Inc

Sponsor organisation address

100 5th Avenue, Waltham, Massachusetts, United States, MA 02451

Public contact

Apellis Clinical Trial Information Line, Apellis Pharmaceuticals, Inc, 1 833-284-6361, clinicaltrials@apellis.com

Scientific contact

Apellis Clinical Trial Information Line, Apellis Pharmaceuticals, Inc, 1 833-284-6361, clinicaltrials@apellis.com

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

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

13 Aug 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Aug 2020

Was the trial ended prematurely?

Main objective of the trial

Evaluation of the efficacy and safety of pegcetacoplan (APL-2) compared with those of eculizumab in subjects with paroxysmal nocturnal hemoglobinuria (PNH) who continued to have Hb levels <10.5 grams per deciliter (g/dL) despite treatment with eculizumab (Soliris®).

Protection of trial subjects

This research was carried out in accordance with the protocol, applicable regulations, the ethical principles set forth in the Declaration of Helsinki, and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Harmonised Guideline for Good Clinical Practice E6 Revision 2. An external, independent data monitoring committee (IDMC) assessed the progress and cumulative safety/tolerability data of the study. The IDMC had the responsibility to conduct a thorough safety assessment at regular predefined intervals during the randomized controlled period (RCP) and open-label treatment phases of the study.

Background therapy

Evidence for comparator

PNH is caused by complement-mediated lysis of erythrocyte clones lacking functional CD55 and CD59 on their surface to protect them against this process. These erythrocytes are particularly susceptible to the membrane attack complex (MAC) and have been shown to lyse readily in the presence of complement activation. Eculizumab is a monoclonal anti-C5 antibody that inhibits the formation of the MAC, and has been approved for the treatment of PNH.

Actual start date of recruitment

14 Jun 2018

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 14

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Japan: 10

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

Germany: 11

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

Spain: 2

Country: Number of subjects enrolled

Canada: 4

Country: Number of subjects enrolled

Russian Federation: 2

Country: Number of subjects enrolled

Korea, Republic of: 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

This was a Phase 3, randomized, multicenter, open-label, active-comparator controlled study. The treatment period of the study consisted of 3 parts: a 4-week run-in period, a 16-week RCP, and a 32-week open-label period.

Screening details

Of the 102 subjects screened, 80 subjects met all the inclusion criteria and none of the exclusion criteria and entered the run-in period. Randomization was stratified by the number of packed red blood cell (PRBC) transfusions within the 12 months prior to Day –28 and platelet count at screening.

Period 1 title

Run-in Period (Day -28 to ≤Day 1)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Run-in Period: Pegcetacoplan

Arm description

During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly subcutaneous (SC) doses of pegcetacoplan 1080 milligrams (mg) in addition to their current dosage of eculizumab treatment.

Arm type

Experimental

Investigational medicinal product name

Eculizumab

Investigational medicinal product code

Other name

Soliris

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Dosage of eculizumab treatment continued as prescribed regardless of study visit scheduling or the pegcetacoplan administration schedule (ie, it was not required that eculizumab dosing aligned with pegcetacoplan dosing or study visits).

Investigational medicinal product name

Pegcetacoplan

Investigational medicinal product code

APL2-302

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Pegcetacoplan was administered as a 20 mL SC infusion.

Run-in Period: Eculizumab

Arm description

During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment.

Arm type

Active comparator

Investigational medicinal product name

Eculizumab

Investigational medicinal product code

Other name

Soliris

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Pegcetacoplan

Investigational medicinal product code

APL2-302

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Pegcetacoplan was administered as a 20 mL SC infusion.

Number of subjects in period 1	Run-in Period: Pegcetacoplan	Run-in Period: Eculizumab
Started	41	39
Completed	41	39

Period 2 title

RCP (Day 1 - Week 16)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

RCP: Pegcetacoplan

Arm description

On Day 1, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

Arm type

Experimental

Investigational medicinal product name

Pegcetacoplan

Investigational medicinal product code

APL2-302

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Pegcetacoplan was administered as a 20 mL SC infusion.

RCP: Eculizumab

Arm description

On Day 1, the subjects were randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks up to the end of the RCP (Week 16).

Arm type

Active comparator

Investigational medicinal product name

Eculizumab

Investigational medicinal product code

Other name

Soliris

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 2	RCP: Pegcetacoplan	RCP: Eculizumab
Started	41	39
Completed	38	39
Not completed	3	0
Adverse event, non-fatal	3	-

Period 3 title

Open-label Period (Week 17 to Week 48)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Open-label Period: Continue Pegcetacoplan

Arm description

On Day 1 of the RCP, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

Arm type

Experimental

Investigational medicinal product name

Pegcetacoplan

Investigational medicinal product code

APL2-302

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Pegcetacoplan was administered as a 20 mL SC infusion.

Open-label Period: Crossover to Pegcetacoplan

Arm description

Subjects entered the open-label run-in period where they received pegcetacoplan 1080 mg twice-weekly in addition to eculizumab for 4 weeks (Week 17 to Week 20) before receiving monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

Arm type

Experimental

Investigational medicinal product name

Pegcetacoplan

Investigational medicinal product code

APL2-302

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Pegcetacoplan was administered as a 20 mL SC infusion.

Investigational medicinal product name

Eculizumab

Investigational medicinal product code

Other name

Soliris

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 3	Open-label Period: Continue Pegcetacoplan	Open-label Period: Crossover to Pegcetacoplan
Started	38	39
Completed	35	32
Not completed	3	7
Adverse event, non-fatal	3	7

Baseline characteristics

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Reporting group title

Run-in Period: Pegcetacoplan

Reporting group description

Reporting group title

Run-in Period: Eculizumab

Reporting group description

During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment.

Reporting group values	Run-in Period: Pegcetacoplan	Run-in Period: Eculizumab	Total
Number of subjects	41	39	80
Age categorical
Units: Subjects
<=18 years	0	0	0
Between 18 and 65 years	31	32	63
>=65 years	10	7	17
Gender categorical
Units: Subjects
Female	27	22	49
Male	14	17	31
Ethnicity
Units: Subjects
Hispanic or Latino	2	1	3
Not Hispanic or Latino	29	32	61
Unknown or Not Reported	10	6	16
Race
Units: Subjects
Asian	5	7	12
Black or African American	2	0	2
White	24	25	49
Other	0	1	1
Not Reported	10	6	16
Number of transfusions in the last 12 months prior to Day −28
Units: Subjects
<4	20	16	36
≥4	21	23	44
Platelet count at screening
Units: Subjects
<100,000 (count/ cubic millimeter [mm^3])	12	9	21
≥100,000 (count/ mm^3)	29	30	59

End points

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Reporting group title

Run-in Period: Pegcetacoplan

Reporting group description

Reporting group title

Run-in Period: Eculizumab

Reporting group description

During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment.

Reporting group title

RCP: Pegcetacoplan

Reporting group description

On Day 1, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

Reporting group title

RCP: Eculizumab

Reporting group description

On Day 1, the subjects were randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks up to the end of the RCP (Week 16).

Reporting group title

Open-label Period: Continue Pegcetacoplan

Reporting group description

On Day 1 of the RCP, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

Reporting group title

Open-label Period: Crossover to Pegcetacoplan

Reporting group description

Subject analysis set title

Treatment Period: Pegcetacoplan

Subject analysis set type

Full analysis

Subject analysis set description

During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment. On Day 1, the subjects were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

Subject analysis set title

Treatment Period: Eculizumab

Subject analysis set type

Full analysis

Subject analysis set description

During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment. On Day 1, the subjects were randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks up to the end of the RCP (Week 16). Subjects then entered the open-label run-in period where they received pegcetacoplan 1080 mg twice-weekly in addition to eculizumab for 4 weeks (Week 17 to Week 20) before receiving monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days up to the end of the open-label period (Week 48).

Subject analysis set title

Open-label Run-in Period: Crossover to Pegcetacoplan

Subject analysis set type

Full analysis

Subject analysis set description

Subjects in the open-label run-in period received pegcetacoplan 1080 mg twice-weekly in addition to eculizumab for 4 weeks (Week 17 to Week 20).

Primary: Least Squares (LS) Mean Change From Baseline to Week 16 in Hemoglobin (Hb) Level During the RCP

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End point title

Least Squares (LS) Mean Change From Baseline to Week 16 in Hemoglobin (Hb) Level During the RCP

End point description

Baseline was the average of measurements recorded before taking the first dose of pegcetacoplan, which included local and central laboratory values during the screening period. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.

End point type

Primary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: g/dL
least squares mean (standard error)	2.37 ( 0.363 )	-1.47 ( 0.666 )

Pegcetacoplan Versus Eculizumab

Statistical analysis description

The primary endpoint analysis was a between-treatment-group comparison using a mixed effect model for repeated measures (MMRM). The difference between pegcetacoplan and eculizumab LS mean Hb changes from Baseline at Week 16 was calculated along with its 2-sided 95% confidence interval (CI) and associated P-value from the MMRM model for the ITT set, censored for transfusions.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001

Method

MMRM

Parameter type

LS mean difference

Point estimate

3.84

Confidence interval

level

95%

sides

2-sided

lower limit

2.33

upper limit

5.34

Notes
[1] - Superiority was tested at the 5% level. MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Secondary: Percentage of Subjects Who Did Not Require a Transfusion (Transfusion Avoidance) During the RCP

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End point title

Percentage of Subjects Who Did Not Require a Transfusion (Transfusion Avoidance) During the RCP

End point description

Subjects who experienced more than 1 transfusion during the RCP are only counted once. Subjects who did not have a transfusion but withdrew before Week 16 were considered as having a transfusion in the analysis of transfusion avoidance. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Day 1 to Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Percentage of subjects
number (not applicable)	85.4	15.4

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Analysis was based on prespecified non-inferiority margins (NIM) and non-inferiority was achieved if the lower confidence limit or upper confidence limit of the 95% CI of the treatment difference met the prespecified NIM of -20%. Stratified Cochran-Mantel Haenszel (CMH) chi-square test was used for treatment comparison and the 95% CI for difference in percentage between treatments is constructed using the stratified (Miettinen-Nurminen) method.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

< 0.0001

Method

Miettinen-Nurminen

Parameter type

Risk difference (RD)

Point estimate

0.6253

Confidence interval

level

95%

sides

2-sided

lower limit

0.483

upper limit

0.7677

Notes
[2] - Non-inferiority was tested at the 2.5% level.

Secondary: LS Mean Change From Baseline to Week 16 in Absolute Reticulocyte Count (ARC) During the RCP

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End point title

LS Mean Change From Baseline to Week 16 in Absolute Reticulocyte Count (ARC) During the RCP

End point description

Baseline was the average of available measurements recorded from central laboratory before taking the first dose of pegcetacoplan. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: 10^9cells/ liter (L)
least squares mean (standard error)	-135.82 ( 6.543 )	27.79 ( 11.859 )

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Analysis was based on prespecified NIM and non-inferiority was achieved if the lower confidence limit or upper confidence limit of the 95% CI of the treatment difference met the prespecified NIM of 10.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

< 0.0001

Method

MMRM

Parameter type

LS mean difference

Point estimate

-163.61

Confidence interval

level

95%

sides

2-sided

lower limit

-189.91

upper limit

-137.3

Notes
[3] - Non-inferiority was tested at the 2.5% level. MMRM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Secondary: LS Mean Change From Baseline to Week 16 in Lactate Dehydrogenase (LDH) Level During the RCP

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End point title

LS Mean Change From Baseline to Week 16 in Lactate Dehydrogenase (LDH) Level During the RCP

End point description

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Units (U)/L
least squares mean (standard error)	-14.76 ( 42.708 )	-10.12 ( 71.025 )

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

P-value

= 0.9557

Method

MMRM

Parameter type

LS mean difference

Point estimate

-4.63

Confidence interval

level

95%

sides

2-sided

lower limit

-181.3

upper limit

172.04

Notes
[4] - Non-inferiority was tested at the 2.5% level. MMRM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Secondary: LS Mean Change From Baseline to Week 16 in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale Score During the RCP

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End point title

LS Mean Change From Baseline to Week 16 in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale Score During the RCP

End point description

The FACIT-fatigue scale version 4 is a 13-item Likert scaled instrument where the subject was presented with 13 statements and asked to indicate their response as it applied to the past 7 days. The 5 possible responses were 'Not at all' (0), 'A little bit (1), 'Somewhat' (2), 'Quite a bit' (3) and 'Very much' (4). With 13 statements the total score had a range of 0 to 52. A higher score corresponds to a higher quality of life (QoL). Baseline was the last available, nonmissing observation before taking the first dose of pegcetacoplan. Data collected after transfusion is excluded from analysis. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Score on a scale
least squares mean (standard error)	9.22 ( 1.607 )	-2.65 ( 2.821 )

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Non-inferiority was not assessed because of the prespecified hierarchical testing. Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.0005

Method

MMRM

Parameter type

LS mean difference

Point estimate

11.87

Confidence interval

level

95%

sides

2-sided

lower limit

5.49

upper limit

18.25

Notes
[5] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Secondary: Percentage of Subjects Who Achieved a Hb Response in the Absence of Transfusions at Week 16

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End point title

Percentage of Subjects Who Achieved a Hb Response in the Absence of Transfusions at Week 16

End point description

Hb response was defined as an increase of at least 1 g/dL in Hb from Baseline at Week 16. Baseline was the average of measurements recorded before taking the first dose of pegcetacoplan, which included local and central laboratory values during the screening period. Analysis excluded data before the RCP and was censored for transfusions. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Percentage of subjects
number (not applicable)	75.6	0.0

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Stratified CMH chi-square test was used for treatment comparison and the 95% CI for difference in percentage between treatments is constructed using the stratified Miettinen-Nurminen method.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentage]

Point estimate

0.6745

Confidence interval

level

95%

sides

2-sided

lower limit

0.5452

upper limit

0.8039

Secondary: Percentage of Subjects Who Achieved Reticulocyte Normalization in the Absence of Transfusions at Week 16

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End point title

Percentage of Subjects Who Achieved Reticulocyte Normalization in the Absence of Transfusions at Week 16

End point description

Reticulocyte normalization was defined as the ARC being below the upper limit of the gender-specific normal range at Week 16, censored for transfusions. Subjects who received a transfusion between Day 1 and Week 16 or withdrew without providing efficacy data at Week 16 were classified as nonresponders. The ITT set includes all randomized subjects.

End point type

Secondary

End point timeframe

Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Percentage of subjects
number (not applicable)	78.0	2.6

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Stratified CMH chi-square test was used for treatment comparison and the 95% CI for difference in percentage between treatments is constructed using the stratified Miettinen-Nurminen method.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentage

Point estimate

0.6639

Confidence interval

level

95%

sides

2-sided

lower limit

0.5309

upper limit

0.7968

Secondary: Percentage of Subjects Who Achieved Hb Normalization in the Absence of Transfusions at Week 16

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End point title

Percentage of Subjects Who Achieved Hb Normalization in the Absence of Transfusions at Week 16

End point description

Hb normalization was defined as the Hb level being above the lower limit of the normal range at Week 16, censored for transfusions. Subjects who received a transfusion between Day 1 and Week 16 or withdrew without providing efficacy data at Week 16 are classified as nonnormalization. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Percentage of subjects
number (not applicable)	34.1	0.0

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Stratified CMH chi-square test was used for treatment comparison and the 95% CI for difference in percentage between treatments is constructed using the stratified Miettinen-Nurminen method.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in percentage

Point estimate

0.3043

Confidence interval

level

95%

sides

2-sided

lower limit

0.1493

upper limit

0.4593

Secondary: LS Mean Change From Baseline to Week 16 in Indirect Bilirubin Level During the RCP

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End point title

LS Mean Change From Baseline to Week 16 in Indirect Bilirubin Level During the RCP

End point description

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Micromole (μmol)/L
least squares mean (standard error)	-17.78 ( 2.727 )	4.15 ( 4.477 )

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Analysis was a between-treatment-group comparison using an MMRM. The difference between pegcetacoplan and eculizumab LS mean changes from Baseline at Week 16 was calculated along with its 2-sided 95% CI and associated P-value from the MMRM model for the ITT set, censored for transfusions.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.0002

Method

MMRM

Parameter type

LS mean difference

Point estimate

-21.93

Confidence interval

level

95%

sides

2-sided

lower limit

-32.49

upper limit

-11.36

Notes
[6] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Secondary: LS Mean Change From Baseline to Week 16 in Haptoglobin Level During the RCP

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End point title

LS Mean Change From Baseline to Week 16 in Haptoglobin Level During the RCP

End point description

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: g/L
least squares mean (standard error)	-0.02 ( 0.033 )	0.12 ( 0.063 )

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.0369

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

-0.01

Notes
[7] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Secondary: LS Mean Change From Baseline to Week 16 in Linear Analog Scale Assessment (LASA) Scores During the RCP

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End point title

LS Mean Change From Baseline to Week 16 in Linear Analog Scale Assessment (LASA) Scores During the RCP

End point description

The LASA consists of 3 items, where the respondents were asked to rate their perceived level of functioning. Specific domains included activity level, ability to carry out daily activities, and an item for overall QoL. Their level of functioning was reported on a 0 to 100 scale with 0 indicates "As low as could be" and 100 indicates "As high as could be". The combined score ranged from 0 to 300, with higher scores corresponding to a higher QoL. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Score on a scale
least squares mean (standard error)	49.38 ( 10.189 )	-9.72 ( 18.988 )

Pegcetacoplan Versus Eculizumab

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[8]

P-value

= 0.0069

Method

MMRM

Parameter type

LS mean difference

Point estimate

59.1

Confidence interval

level

95%

sides

2-sided

lower limit

16.88

upper limit

101.32

Notes
[8] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Secondary: LS Mean Change From Baseline to Week 16 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 Scale (QLQ-C30) Scores During the RCP

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End point title

LS Mean Change From Baseline to Week 16 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 Scale (QLQ-C30) Scores During the RCP

End point description

The EORTC QLQ-C30 questionnaire (version 3.0) consists of 30 questions comprised of both multi-item scales and single-item measures to assess overall QoL in subjects. Questions are designated by functional scales, symptom scales, and global subject QoL/overall perceived health status. For the first 28 questions the 4 possible responses are 'Not at all’ (1), ‘A little’ (2), ‘Quite a bit’ (3) and ‘Very much’ (4). For the remaining 2 questions the response is requested on a 7-point scale from 1 (‘Very poor’) to 7 (‘Excellent’). The raw scale scores were linear transformed, producing scale scores that ranged from 0% to 100%. A high scale score represents a higher response level. Hence for the functional scales and the global health status a higher score indicates a better QoL, whilst for the symptom scale scores this is implied by a lower score. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: Score on a scale
least squares mean (standard error)
Global Health Status/QoL	15.91 ( 3.635 )	-2.71 ( 8.515 )
Functional Scales - Physical functioning	16.92 ( 2.081 )	4.06 ( 3.605 )
Functional Scales - Role functioning	15.39 ( 3.930 )	-9.04 ( 6.954 )
Functional Scales - Emotional functioning	7.98 ( 3.366 )	3.86 ( 7.237 )
Functional Scales - Cognitive functioning	5.76 ( 3.258 )	-3.80 ( 6.420 )
Functional Scales - Social functioning	15.08 ( 2.946 )	3.82 ( 6.349 )
Symptom Scales - Fatigue	-22.93 ( 3.321 )	-2.18 ( 6.644 )
Symptom Scales - Nausea and vomiting	-0.34 ( 1.632 )	-0.33 ( 3.876 )
Symptom Scales - Pain	-0.74 ( 4.323 )	2.01 ( 7.841 )
Symptom Scales - Dyspnoea	-20.12 ( 3.488 )	-5.55 ( 7.019 )
Symptom Scales - Insomnia	-9.18 ( 3.955 )	-9.50 ( 7.090 )
Symptom Scales - Appetite loss	-3.76 ( 3.357 )	4.19 ( 7.009 )
Symptom Scales - Constipation	2.98 ( 3.248 )	1.19 ( 8.129 )
Symptom Scales - Diarrhoea	0.31 ( 3.711 )	1.68 ( 8.204 )
Symptom Scales - Financial difficulties	-6.82 ( 3.853 )	0.58 ( 6.297 )

Global Health Status/QoL

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[9]

P-value

= 0.0486

Method

MMRM

Parameter type

LS mean difference

Point estimate

18.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.12

upper limit

37.13

Notes
[9] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Functional Scales - Physical functioning

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.0023

Method

MMRM

Parameter type

LS mean difference

Point estimate

12.86

Confidence interval

level

95%

sides

2-sided

lower limit

4.86

upper limit

20.86

Notes
[10] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Functional Scales - Role functioning

Statistical analysis description

Comparison groups

RCP: Eculizumab v RCP: Pegcetacoplan

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

= 0.0027

Method

MMRM

Parameter type

LS mean difference

Point estimate

24.43

Confidence interval

level

95%

sides

2-sided

lower limit

8.84

upper limit

40.01

Notes
[11] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Functional Scales - Emotional functioning

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.6013

Method

MMRM

Parameter type

LS mean difference

Point estimate

4.11

Confidence interval

level

95%

sides

2-sided

lower limit

-11.58

upper limit

19.8

Notes
[12] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Functional Scales - Cognitive functioning

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

= 0.1792

Method

MMRM

Parameter type

LS mean difference

Point estimate

9.56

Confidence interval

level

95%

sides

2-sided

lower limit

-4.52

upper limit

23.64

Notes
[13] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Functional Scales - Social functioning

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.1039

Method

MMRM

Parameter type

LS mean difference

Point estimate

11.27

Confidence interval

level

95%

sides

2-sided

lower limit

-2.38

upper limit

24.92

Notes
[14] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Fatigue

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

= 0.0062

Method

MMRM

Parameter type

LS mean difference

Point estimate

-20.74

Confidence interval

level

95%

sides

2-sided

lower limit

-35.29

upper limit

-6.19

Notes
[15] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Nausea and vomiting

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

= 0.9975

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-8.38

upper limit

8.35

Notes
[16] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Pain

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.7554

Method

MMRM

Parameter type

LS mean difference

Point estimate

-2.76

Confidence interval

level

95%

sides

2-sided

lower limit

-20.36

upper limit

14.85

Notes
[17] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Dyspnoea

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.062

Method

MMRM

Parameter type

LS mean difference

Point estimate

-14.57

Confidence interval

level

95%

sides

2-sided

lower limit

-29.9

upper limit

0.76

Notes
[18] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Insomnia

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

= 0.9686

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-15.67

upper limit

16.3

Notes
[19] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Appetite loss

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

= 0.3002

Method

MMRM

Parameter type

LS mean difference

Point estimate

-7.95

Confidence interval

level

95%

sides

2-sided

lower limit

-23.23

upper limit

7.33

Notes
[20] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Constipation

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

= 0.8374

Method

MMRM

Parameter type

LS mean difference

Point estimate

1.79

Confidence interval

level

95%

sides

2-sided

lower limit

-15.7

upper limit

19.29

Notes
[21] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Diarrhoea

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.8775

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.38

Confidence interval

level

95%

sides

2-sided

lower limit

-19.28

upper limit

16.52

Notes
[22] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Symptom Scales - Financial difficulties

Statistical analysis description

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.3066

Method

MMRM

Parameter type

LS mean difference

Point estimate

-7.4

Confidence interval

level

95%

sides

2-sided

lower limit

-21.76

upper limit

6.95

Notes
[23] - MRMM includes treatment + baseline value + analysis visit + strata + analysis visit × treatment, where strata is the combination of randomization stratification factors.

Secondary: Total Number of PRBC Units Transfused During the RCP

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End point title

Total Number of PRBC Units Transfused During the RCP

End point description

Subjects who withdrew during the RCP before Week 16 will have their number of units of PRBC estimated from the duration they were in the study. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Day 1 to Week 16

End point values	RCP: Pegcetacoplan	RCP: Eculizumab
Number of subjects analysed	41	39
Units: PRBC Units
number (not applicable)	26	198

Pegcetacoplan versus Eculizumab

Statistical analysis description

Wilcoxon rank-sum test P-value for the comparison between treatments is based on median using stratified non-parametric analysis. The 95% CI is constructed using Hodges-Lehmann Estimation of Location Shift.

Comparison groups

RCP: Pegcetacoplan v RCP: Eculizumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Wilcoxon rank-sum test

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Mean Change From Baseline to Week 48 in Hb Level During the Treatment Period

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End point title

Mean Change From Baseline to Week 48 in Hb Level During the Treatment Period

End point description

End point type

Secondary

End point timeframe

Baseline and Week 48

End point values	Treatment Period: Pegcetacoplan	Treatment Period: Eculizumab
Number of subjects analysed	33	30
Units: g/dL
arithmetic mean (standard deviation)	2.47 ( 1.72 )	2.93 ( 2.09 )

No statistical analyses for this end point

Secondary: Mean Change From Week 17 to Week 48 in Hb Level During the Open-label Period

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End point title

Mean Change From Week 17 to Week 48 in Hb Level During the Open-label Period

End point description

End point type

Secondary

End point timeframe

Week 17 and Week 48

End point values	Open-label Period: Continue Pegcetacoplan	Open-label Period: Crossover to Pegcetacoplan
Number of subjects analysed	33	29
Units: g/dL
arithmetic mean (standard deviation)	-0.16 ( 1.154 )	2.89 ( 2.078 )

No statistical analyses for this end point

Secondary: Mean Change From Baseline to Week 48 in ARC During the Treatment Period

Top of page

End point title

Mean Change From Baseline to Week 48 in ARC During the Treatment Period

End point description

End point type

Secondary

End point timeframe

Baseline and Week 48

End point values	Treatment Period: Pegcetacoplan	Treatment Period: Eculizumab
Number of subjects analysed	31	29
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-135.64 ( 67.90 )	-128.22 ( 59.60 )

No statistical analyses for this end point

Secondary: Mean Change From Week 17 to Week 48 in ARC During the Open-label Period

Top of page

End point title

Mean Change From Week 17 to Week 48 in ARC During the Open-label Period

End point description

End point type

Secondary

End point timeframe

Week 17 and Week 48

End point values	Open-label Period: Continue Pegcetacoplan	Open-label Period: Crossover to Pegcetacoplan
Number of subjects analysed	31	29
Units: 10^9 cells/L
arithmetic mean (standard deviation)	-6.50 ( 26.471 )	-121.15 ( 70.969 )

No statistical analyses for this end point

Secondary: Mean Change From Baseline to Week 48 in LDH Level During the Treatment Period

Top of page

End point title

Mean Change From Baseline to Week 48 in LDH Level During the Treatment Period

End point description

End point type

Secondary

End point timeframe

Baseline and Week 48

End point values	Treatment Period: Pegcetacoplan	Treatment Period: Eculizumab
Number of subjects analysed	33	30
Units: U/L
arithmetic mean (standard deviation)	-41.53 ( 153.68 )	-105.27 ( 315.59 )

No statistical analyses for this end point

Secondary: Mean Change From Week 17 to Week 48 in LDH Level During the Open-label Period

Top of page

End point title

Mean Change From Week 17 to Week 48 in LDH Level During the Open-label Period

End point description

End point type

Secondary

End point timeframe

Week 17 and Week 48

End point values	Open-label Period: Continue Pegcetacoplan	Open-label Period: Crossover to Pegcetacoplan
Number of subjects analysed	33	28
Units: U/L
arithmetic mean (standard deviation)	8.03 ( 129.285 )	-46.84 ( 292.607 )

No statistical analyses for this end point

Secondary: Mean Change From Baseline to Week 48 in FACIT-fatigue Scale Score During the Treatment Period

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End point title

Mean Change From Baseline to Week 48 in FACIT-fatigue Scale Score During the Treatment Period

End point description

The FACIT-fatigue scale version 4 is a 13-item Likert scaled instrument where the subject was presented with 13 statements and asked to indicate their response as it applied to the past 7 days. The 5 possible responses were 'Not at all' (0), 'A little bit (1), 'Somewhat' (2), 'Quite a bit' (3) and 'Very much' (4). With 13 statements the total score had a range of 0 to 52. A higher score corresponds to a higher QoL. Baseline was the last available, nonmissing observation before taking the first dose of pegcetacoplan. Data collected after transfusion is excluded from analysis. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline and Week 48

End point values	Treatment Period: Pegcetacoplan	Treatment Period: Eculizumab
Number of subjects analysed	30	29
Units: Score on a scale
arithmetic mean (standard deviation)	10.14 ( 9.06 )	9.62 ( 10.34 )

No statistical analyses for this end point

Secondary: Mean Change From Week 17 to Week 48 in FACIT-fatigue Scale Score During the Open-label Period

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End point title

Mean Change From Week 17 to Week 48 in FACIT-fatigue Scale Score During the Open-label Period

End point description

The FACIT-fatigue scale is a 13 item Likert scaled instrument where the subject was presented with 13 statements and asked to indicate their response as it applied to the past 7 days. The 5 possible responses were 'Not at all' (0), 'A little bit (1), 'Somewhat' (2), 'Quite a bit' (3) and 'Very much' (4). With 13 statements the total score had a range of 0 to 52. Higher score corresponds to a higher QoL. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Week 17 and Week 48

End point values	Open-label Period: Continue Pegcetacoplan	Open-label Period: Crossover to Pegcetacoplan
Number of subjects analysed	30	26
Units: Score on a scale
arithmetic mean (standard deviation)	1.28 ( 7.805 )	10.19 ( 10.973 )

No statistical analyses for this end point

Secondary: Mean Change From Baseline to Week 48 in LASA Scores During the Treatment Period

Top of page

End point title

Mean Change From Baseline to Week 48 in LASA Scores During the Treatment Period

End point description

End point type

Secondary

End point timeframe

Baseline and Week 48

End point values	Treatment Period: Pegcetacoplan	Treatment Period: Eculizumab
Number of subjects analysed	29	29
Units: Score on a scale
arithmetic mean (standard deviation)	58.66 ( 51.16 )	56.52 ( 65.55 )

No statistical analyses for this end point

Secondary: Mean Change From Week 17 to Week 48 in LASA Scores During the Open-label Period

Top of page

End point title

Mean Change From Week 17 to Week 48 in LASA Scores During the Open-label Period

End point description

End point type

Secondary

End point timeframe

Week 17 and Week 48

End point values	Open-label Period: Continue Pegcetacoplan	Open-label Period: Crossover to Pegcetacoplan
Number of subjects analysed	30	26
Units: Score on a scale
arithmetic mean (standard deviation)	13.13 ( 46.296 )	62.92 ( 60.053 )

No statistical analyses for this end point

Secondary: Mean Change From Baseline to Week 48 in QLQ-C30 Scores During the Treatment Period

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End point title

Mean Change From Baseline to Week 48 in QLQ-C30 Scores During the Treatment Period

End point description

End point type

Secondary

End point timeframe

Baseline and Week 48

End point values	Treatment Period: Pegcetacoplan	Treatment Period: Eculizumab
Number of subjects analysed	30	28
Units: Score on a scale
arithmetic mean (standard deviation)
Global Health Status/QoL	18.89 ( 17.635 )	13.99 ( 22.912 )
Functional Scales - Physical functioning	15.33 ( 15.278 )	10.80 ( 17.765 )
Functional Scales - Role functioning	16.67 ( 27.334 )	20.11 ( 27.595 )
Functional Scales - Emotional functioning	10.28 ( 18.657 )	5.36 ( 17.005 )
Functional Scales - Cognitive functioning	7.78 ( 23.462 )	0.00 ( 18.703 )
Functional Scales - Social functioning	16.11 ( 24.166 )	14.88 ( 22.379 )
Symptom Scales - Fatigue	-21.48 ( 26.733 )	-23.75 ( 29.506 )
Symptom Scales - Nausea and vomiting	-2.22 ( 11.357 )	0.00 ( 4.454 )
Symptom Scales - Pain	0.56 ( 27.849 )	3.45 ( 20.596 )
Symptom Scales - Dyspnoea	-17.78 ( 29.985 )	-27.59 ( 33.415 )
Symptom Scales - Insomnia	-6.67 ( 25.371 )	0.00 ( 28.172 )
Symptom Scales - Appetite loss	-7.78 ( 14.339 )	-3.45 ( 22.440 )
Symptom Scales - Constipation	-1.11 ( 22.289 )	-2.38 ( 8.742 )
Symptom Scales - Diarrhoea	1.11 ( 29.664 )	5.95 ( 15.853 )
Symptom Scales - Financial difficulties	-15.56 ( 24.343 )	-8.33 ( 19.510 )

No statistical analyses for this end point

Secondary: Mean Change From Week 17 to Week 48 in QLQ-C30 Scores During the Open-label Period

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End point title

Mean Change From Week 17 to Week 48 in QLQ-C30 Scores During the Open-label Period

End point description

End point type

Secondary

End point timeframe

Week 17 and Week 48

End point values	Open-label Period: Continue Pegcetacoplan	Open-label Period: Crossover to Pegcetacoplan
Number of subjects analysed	30	26
Units: Score on a scale
arithmetic mean (standard deviation)
Global Health Status/QoL	7.22 ( 19.664 )	23.08 ( 22.149 )
Functional Scales - Physical functioning	0.89 ( 10.168 )	11.03 ( 17.173 )
Functional Scales - Role functioning	5.00 ( 20.599 )	19.87 ( 22.617 )
Functional Scales - Emotional functioning	-2.22 ( 27.328 )	1.92 ( 13.806 )
Functional Scales - Cognitive functioning	-2.78 ( 16.999 )	2.56 ( 24.355 )
Functional Scales - Social functioning	3.89 ( 18.919 )	12.18 ( 23.361 )
Symptom Scales - Fatigue	-2.96 ( 20.824 )	-23.08 ( 28.790 )
Symptom Scales - Nausea and vomiting	-2.22 ( 5.762 )	-4.49 ( 12.072 )
Symptom Scales - Pain	-2.78 ( 23.195 )	-5.77 ( 21.051 )
Symptom Scales - Dyspnoea	3.33 ( 25.295 )	-19.23 ( 28.555 )
Symptom Scales - Insomnia	8.89 ( 23.050 )	-5.13 ( 27.797 )
Symptom Scales - Appetite loss	-8.89 ( 26.164 )	-5.13 ( 22.494 )
Symptom Scales - Constipation	-1.11 ( 20.498 )	-1.28 ( 11.473 )
Symptom Scales - Diarrhoea	-4.44 ( 28.679 )	3.85 ( 27.206 )
Symptom Scales - Financial difficulties	-2.22 ( 12.172 )	-2.56 ( 16.119 )

No statistical analyses for this end point

Secondary: Total Number of PRBC Units Transfused During the Open-Label Period

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End point title

Total Number of PRBC Units Transfused During the Open-Label Period

End point description

Number of units of PRBC transfused to subjects in the open-label period are reported. The ITT set included all randomized subjects.

End point type

Secondary

End point timeframe

Week 17 to Week 48

End point values	Open-label Period: Continue Pegcetacoplan	Open-label Period: Crossover to Pegcetacoplan	Open-label Run-in Period: Crossover to Pegcetacoplan
Number of subjects analysed	38	39	38
Units: PRBC Units
number (not applicable)	68	110	14

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Day -28 to Week 54, a maximum of approximately 58 weeks

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Run-in Periods: Pegcetacoplan + Eculizumab

Reporting group description

During the 4-week run-in period (Day –28 to ≤Day 1) all subjects received twice-weekly SC doses of pegcetacoplan 1080 mg in addition to their current dosage of eculizumab treatment. During the 4-week open-label run-in period (Week 17 to Week 20) subjects randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks during the RCP also received twice-weekly SC doses of pegcetacoplan 1080 mg.

Reporting group title

Open-label Period: Pegcetacoplan

Reporting group description

The subjects who were randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days during the RCP continued to receive monotherapy with pegcetacoplan until the end of the open-label period (Week 17 to Week 48). Subjects randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks during the RCP received monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days after the open-label run-in period, up to the end of the open-label period (Week 20 to Week 48).

Reporting group title

RCP: Eculizumab

Reporting group description

Subjects randomized to receive monotherapy with their pre-screening stable dose of eculizumab via intravenous infusion every 2 weeks during the RCP.

Reporting group title

RCP: Pegcetacoplan

Reporting group description

Subjects randomized to receive monotherapy with SC infusions of pegcetacoplan 1080 mg twice-weekly or every 3 days during the RCP.

Serious adverse events	Run-in Periods: Pegcetacoplan + Eculizumab	Open-label Period: Pegcetacoplan	RCP: Eculizumab	RCP: Pegcetacoplan
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 80 (5.00%)	18 / 77 (23.38%)	5 / 39 (12.82%)	7 / 41 (17.07%)
number of deaths (all causes)	0	1	0	0
number of deaths resulting from adverse events	0	1	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	1 / 39 (2.56%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergy to immunoglobulin therapy
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity pneumonitis
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Facial paralysis
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Haemolysis
subjects affected / exposed	1 / 80 (1.25%)	5 / 77 (6.49%)	1 / 39 (2.56%)	2 / 41 (4.88%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytopenia
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	1 / 39 (2.56%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	1 / 39 (2.56%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedematous pancreatitis
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatocellular injury
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	1 / 39 (2.56%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	1 / 39 (2.56%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	1 / 39 (2.56%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Haematoma muscle
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 80 (0.00%)	2 / 77 (2.60%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural sepsis
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 80 (2.50%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 80 (1.25%)	0 / 77 (0.00%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Run-in Periods: Pegcetacoplan + Eculizumab	Open-label Period: Pegcetacoplan	RCP: Eculizumab	RCP: Pegcetacoplan
Total subjects affected by non serious adverse events
subjects affected / exposed	71 / 80 (88.75%)	71 / 77 (92.21%)	36 / 39 (92.31%)	36 / 41 (87.80%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 80 (0.00%)	3 / 77 (3.90%)	1 / 39 (2.56%)	3 / 41 (7.32%)
occurrences all number	0	4	1	3
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	33 / 80 (41.25%)	9 / 77 (11.69%)	0 / 39 (0.00%)	7 / 41 (17.07%)
occurrences all number	75	127	0	44
Fatigue
subjects affected / exposed	5 / 80 (6.25%)	8 / 77 (10.39%)	6 / 39 (15.38%)	2 / 41 (4.88%)
occurrences all number	5	11	7	2
Pyrexia
subjects affected / exposed	6 / 80 (7.50%)	6 / 77 (7.79%)	1 / 39 (2.56%)	1 / 41 (2.44%)
occurrences all number	6	9	1	1
Injection site pruritus
subjects affected / exposed	12 / 80 (15.00%)	5 / 77 (6.49%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences all number	14	7	0	1
Asthenia
subjects affected / exposed	1 / 80 (1.25%)	4 / 77 (5.19%)	5 / 39 (12.82%)	3 / 41 (7.32%)
occurrences all number	1	4	7	3
Injection site bruising
subjects affected / exposed	2 / 80 (2.50%)	3 / 77 (3.90%)	0 / 39 (0.00%)	2 / 41 (4.88%)
occurrences all number	3	7	0	2
Injection site induration
subjects affected / exposed	5 / 80 (6.25%)	5 / 77 (6.49%)	0 / 39 (0.00%)	3 / 41 (7.32%)
occurrences all number	12	27	0	8
Injection site reaction
subjects affected / exposed	8 / 80 (10.00%)	2 / 77 (2.60%)	0 / 39 (0.00%)	4 / 41 (9.76%)
occurrences all number	26	8	0	56
Injection site swelling
subjects affected / exposed	10 / 80 (12.50%)	1 / 77 (1.30%)	0 / 39 (0.00%)	4 / 41 (9.76%)
occurrences all number	18	4	0	6
Injection site pain
subjects affected / exposed	6 / 80 (7.50%)	4 / 77 (5.19%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences all number	13	68	0	9
Vaccination site pain
subjects affected / exposed	3 / 80 (3.75%)	0 / 77 (0.00%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences all number	3	0	2	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 80 (2.50%)	9 / 77 (11.69%)	1 / 39 (2.56%)	1 / 41 (2.44%)
occurrences all number	2	9	1	1
Oropharyngeal pain
subjects affected / exposed	0 / 80 (0.00%)	6 / 77 (7.79%)	3 / 39 (7.69%)	0 / 41 (0.00%)
occurrences all number	0	7	3	0
Dyspnoea
subjects affected / exposed	4 / 80 (5.00%)	2 / 77 (2.60%)	3 / 39 (7.69%)	1 / 41 (2.44%)
occurrences all number	4	2	4	1
Psychiatric disorders
Anxiety
subjects affected / exposed	2 / 80 (2.50%)	4 / 77 (5.19%)	2 / 39 (5.13%)	1 / 41 (2.44%)
occurrences all number	2	5	2	1
Insomnia
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences all number	0	1	2	0
Injury, poisoning and procedural complications
Vaccination complication
subjects affected / exposed	2 / 80 (2.50%)	2 / 77 (2.60%)	0 / 39 (0.00%)	2 / 41 (4.88%)
occurrences all number	3	2	0	2
Contusion
subjects affected / exposed	3 / 80 (3.75%)	4 / 77 (5.19%)	0 / 39 (0.00%)	1 / 41 (2.44%)
occurrences all number	3	4	0	1
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 80 (1.25%)	1 / 77 (1.30%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences all number	2	1	2	0
Nervous system disorders
Headache
subjects affected / exposed	10 / 80 (12.50%)	8 / 77 (10.39%)	9 / 39 (23.08%)	2 / 41 (4.88%)
occurrences all number	12	13	10	2
Dizziness
subjects affected / exposed	3 / 80 (3.75%)	3 / 77 (3.90%)	5 / 39 (12.82%)	1 / 41 (2.44%)
occurrences all number	3	3	5	1
Lethargy
subjects affected / exposed	0 / 80 (0.00%)	0 / 77 (0.00%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences all number	0	0	2	0
Blood and lymphatic system disorders
Haemolysis
subjects affected / exposed	1 / 80 (1.25%)	13 / 77 (16.88%)	9 / 39 (23.08%)	4 / 41 (9.76%)
occurrences all number	1	14	14	4
Thrombocytopenia
subjects affected / exposed	2 / 80 (2.50%)	3 / 77 (3.90%)	0 / 39 (0.00%)	2 / 41 (4.88%)
occurrences all number	2	5	0	2
Anaemia
subjects affected / exposed	1 / 80 (1.25%)	2 / 77 (2.60%)	5 / 39 (12.82%)	0 / 41 (0.00%)
occurrences all number	1	2	5	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	10 / 80 (12.50%)	11 / 77 (14.29%)	2 / 39 (5.13%)	9 / 41 (21.95%)
occurrences all number	11	15	2	9
Abdominal pain
subjects affected / exposed	2 / 80 (2.50%)	3 / 77 (3.90%)	3 / 39 (7.69%)	4 / 41 (9.76%)
occurrences all number	2	3	3	4
Abdominal distension
subjects affected / exposed	1 / 80 (1.25%)	4 / 77 (5.19%)	1 / 39 (2.56%)	0 / 41 (0.00%)
occurrences all number	1	4	1	0
Nausea
subjects affected / exposed	7 / 80 (8.75%)	2 / 77 (2.60%)	2 / 39 (5.13%)	2 / 41 (4.88%)
occurrences all number	8	4	2	2
Vomiting
subjects affected / exposed	1 / 80 (1.25%)	3 / 77 (3.90%)	4 / 39 (10.26%)	0 / 41 (0.00%)
occurrences all number	1	3	4	0
Abdominal discomfort
subjects affected / exposed	2 / 80 (2.50%)	0 / 77 (0.00%)	2 / 39 (5.13%)	2 / 41 (4.88%)
occurrences all number	2	0	2	2
Constipation
subjects affected / exposed	1 / 80 (1.25%)	2 / 77 (2.60%)	3 / 39 (7.69%)	0 / 41 (0.00%)
occurrences all number	1	2	3	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 80 (0.00%)	3 / 77 (3.90%)	2 / 39 (5.13%)	1 / 41 (2.44%)
occurrences all number	0	3	2	1
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 80 (0.00%)	3 / 77 (3.90%)	0 / 39 (0.00%)	2 / 41 (4.88%)
occurrences all number	0	3	0	2
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 80 (0.00%)	4 / 77 (5.19%)	0 / 39 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	4	0	0
Chromaturia
subjects affected / exposed	3 / 80 (3.75%)	2 / 77 (2.60%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences all number	3	2	3	0
Haemoglobinuria
subjects affected / exposed	0 / 80 (0.00%)	1 / 77 (1.30%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences all number	0	1	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 80 (2.50%)	6 / 77 (7.79%)	2 / 39 (5.13%)	2 / 41 (4.88%)
occurrences all number	2	7	2	2
Pain in extremity
subjects affected / exposed	3 / 80 (3.75%)	5 / 77 (6.49%)	2 / 39 (5.13%)	2 / 41 (4.88%)
occurrences all number	3	6	2	5
Back pain
subjects affected / exposed	3 / 80 (3.75%)	2 / 77 (2.60%)	4 / 39 (10.26%)	3 / 41 (7.32%)
occurrences all number	3	2	4	4
Myalgia
subjects affected / exposed	3 / 80 (3.75%)	4 / 77 (5.19%)	1 / 39 (2.56%)	1 / 41 (2.44%)
occurrences all number	3	4	3	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 80 (5.00%)	12 / 77 (15.58%)	2 / 39 (5.13%)	3 / 41 (7.32%)
occurrences all number	5	13	2	3
Upper respiratory tract infection
subjects affected / exposed	0 / 80 (0.00%)	7 / 77 (9.09%)	1 / 39 (2.56%)	1 / 41 (2.44%)
occurrences all number	0	8	1	1
Urinary tract infection
subjects affected / exposed	1 / 80 (1.25%)	7 / 77 (9.09%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences all number	1	7	2	0
Oral herpes
subjects affected / exposed	1 / 80 (1.25%)	6 / 77 (7.79%)	0 / 39 (0.00%)	2 / 41 (4.88%)
occurrences all number	1	7	0	2
Sinusitis
subjects affected / exposed	1 / 80 (1.25%)	3 / 77 (3.90%)	2 / 39 (5.13%)	1 / 41 (2.44%)
occurrences all number	1	3	2	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 80 (0.00%)	2 / 77 (2.60%)	2 / 39 (5.13%)	0 / 41 (0.00%)
occurrences all number	0	2	2	0

More information

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Were there any global substantial amendments to the protocol? Yes

21 Aug 2018

Protocol amendment 1 included the following changes: - Allowed subjects to proceed to Visit 2 at any time (rather than waiting at least 2 weeks) after confirmation of study eligibility. - Clarified the appropriate 6-hour postdose pharmacokinetics sample window: ±30 minutes. - End of trial was defined as follows: The end of the trial is defined as when the last subject either completes their Week 48 visit and enrolls in the long-term safety extension (LTSE) study, or, should a subject elect not to enter the LTSE study, when the last subject completes their exit visit at Week 60. - Clarified that during the 4-week run-in period (Week - 4 to Day -1), Visit 5 (Day 1), and through the course of the study, pegcetacoplan administration and study visits should be conducted and scheduled independently of each subject’s regular eculizumab administration schedule. - Inclusion Criterion #13: added to require that subjects have a body mass index (BMI) ≤40 in order to qualify for study entry. - Inclusion Criterion #5: updated eligibility of ARC >1.0× upper limit of normal (ULN) at screening visit (from previous requirement of >1.5× ULN). - LDH isoenzymes and erythropoietin were added to the serum chemistry panel.

13 Dec 2018

Protocol amendment 2 included the following changes: - Screening window extended to up to 8 weeks (Week - 12) - Clarified that use of silica reagents in coagulation panels was to be avoided. - Added emphasis that subjects should be instructed to take pegcetacoplan treatment as prescribed and should contact the investigator immediately for guidance in the event of any missed doses. - Allowed administration of eculizumab at home. - Clarified that there was no requirement for eculizumab to be administered on the day of a study visit. - Clarified that subjects administer pegcetacoplan at the study site through the run-in period and on Day 1. After that, every effort should be made to ensure that the subject’s pegcetacoplan dosing schedule aligned with study visit days. If not possible, dosing should occur according to the dosing schedule and not the visit schedule, as there was no requirement for subjects to administer pegcetacoplan at the study site. - Noted that if a screening visit was more than 28 days before dosing, the hematology panel should be repeated.

08 Feb 2019

Protocol amendment 3 included the following changes: - Re-arranged secondary endpoints into key secondary and secondary endpoints. The classification of “tertiary endpoints” was removed and former tertiary endpoints were reclassified as secondary endpoints. The duration of when the endpoint was being assessed was specified within some endpoint descriptions for clarity. - Modified randomization stratification factors as follows: 1. Number of PRBC transfusions within the 12 months prior to Day -28 (<4; ≥4) 2. Platelet count at screening (<100,000; ≥100,000). - The study diagram and descriptions of the study were modified to remove references to the wash-out period. - Modified Inclusion Criterion #13: excluded subjects with Class 2 or greater obesity (subjects with a BMI ≥35.0 kg/m^2).

16 Aug 2019

Protocol amendment 4 included the following changes: - Clarified S. pneumoniae vaccination requirements. - Clarified that during the screening period (from up to Week -12 to Week -4), clinical laboratory tests (eg, hematology, coagulation, serum chemistry, flow cytometry, urinalysis) could be repeated with written approval from the sponsor (including the assigned medical monitor), with no requirement to designate the subject as a screen failure. - Dose adjustment was updated to mandate dose escalation to 1080 mg every third day upon the first instance of LDH >2× ULN, rather than requiring LDH to be elevated on 2 consecutive occasions at least 1 week apart. - Clarified subject transfusion history collection requirements.

06 May 2020

As a result of the COVID-19 global pandemic, Apellis issued an Urgent Safety Measure to safeguard the rights, welfare, and safety of APL2-302 study subjects and investigative site staff. Protocol amendment 5 included the following changes: - Added clarifying language to indicate that a dose adjustment can occur for subjects receiving pegcetacoplan monotherapy if LDH is >2 × ULN “on 1 occasion.”. - Terminology updated to reflect current language regarding antidrug antibody assessments, pegcetacoplan peptide antibodies, or anti-pegcetacoplan antibodies. - The “Unknown” category of relationship between adverse events and serious adverse events to study treatment was removed. - Severity of events definitions were updated. - Appendix 6 added to reflect changes made as a result of the COVID-19 pandemic.

Were there any global interruptions to the trial? No

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 III, Randomized, Multicenter, Open-Label, Active-Comparator Controlled Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Least Squares (LS) Mean Change From Baseline to Week 16 in Hemoglobin (Hb) Level During the RCP

Primary: Least Squares (LS) Mean Change From Baseline to Week 16 in Hemoglobin (Hb) Level During the RCP

Secondary: Percentage of Subjects Who Did Not Require a Transfusion (Transfusion Avoidance) During the RCP

Secondary: Percentage of Subjects Who Did Not Require a Transfusion (Transfusion Avoidance) During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Absolute Reticulocyte Count (ARC) During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Absolute Reticulocyte Count (ARC) During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Lactate Dehydrogenase (LDH) Level During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Lactate Dehydrogenase (LDH) Level During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale Score During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale Score During the RCP

Secondary: Percentage of Subjects Who Achieved a Hb Response in the Absence of Transfusions at Week 16

Secondary: Percentage of Subjects Who Achieved a Hb Response in the Absence of Transfusions at Week 16

Secondary: Percentage of Subjects Who Achieved Reticulocyte Normalization in the Absence of Transfusions at Week 16

Secondary: Percentage of Subjects Who Achieved Reticulocyte Normalization in the Absence of Transfusions at Week 16

Secondary: Percentage of Subjects Who Achieved Hb Normalization in the Absence of Transfusions at Week 16

Secondary: Percentage of Subjects Who Achieved Hb Normalization in the Absence of Transfusions at Week 16

Secondary: LS Mean Change From Baseline to Week 16 in Indirect Bilirubin Level During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Indirect Bilirubin Level During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Haptoglobin Level During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Haptoglobin Level During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Linear Analog Scale Assessment (LASA) Scores During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in Linear Analog Scale Assessment (LASA) Scores During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 Scale (QLQ-C30) Scores During the RCP

Secondary: LS Mean Change From Baseline to Week 16 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 Scale (QLQ-C30) Scores During the RCP

Secondary: Total Number of PRBC Units Transfused During the RCP

Secondary: Total Number of PRBC Units Transfused During the RCP

Secondary: Mean Change From Baseline to Week 48 in Hb Level During the Treatment Period

Secondary: Mean Change From Baseline to Week 48 in Hb Level During the Treatment Period

Secondary: Mean Change From Week 17 to Week 48 in Hb Level During the Open-label Period

Secondary: Mean Change From Week 17 to Week 48 in Hb Level During the Open-label Period

Secondary: Mean Change From Baseline to Week 48 in ARC During the Treatment Period

Secondary: Mean Change From Baseline to Week 48 in ARC During the Treatment Period

Secondary: Mean Change From Week 17 to Week 48 in ARC During the Open-label Period

Secondary: Mean Change From Week 17 to Week 48 in ARC During the Open-label Period

Secondary: Mean Change From Baseline to Week 48 in LDH Level During the Treatment Period

Secondary: Mean Change From Baseline to Week 48 in LDH Level During the Treatment Period

Secondary: Mean Change From Week 17 to Week 48 in LDH Level During the Open-label Period

Secondary: Mean Change From Week 17 to Week 48 in LDH Level During the Open-label Period

Secondary: Mean Change From Baseline to Week 48 in FACIT-fatigue Scale Score During the Treatment Period

Secondary: Mean Change From Baseline to Week 48 in FACIT-fatigue Scale Score During the Treatment Period

Secondary: Mean Change From Week 17 to Week 48 in FACIT-fatigue Scale Score During the Open-label Period

Secondary: Mean Change From Week 17 to Week 48 in FACIT-fatigue Scale Score During the Open-label Period

Secondary: Mean Change From Baseline to Week 48 in LASA Scores During the Treatment Period

Secondary: Mean Change From Baseline to Week 48 in LASA Scores During the Treatment Period

Secondary: Mean Change From Week 17 to Week 48 in LASA Scores During the Open-label Period

Secondary: Mean Change From Week 17 to Week 48 in LASA Scores During the Open-label Period

Secondary: Mean Change From Baseline to Week 48 in QLQ-C30 Scores During the Treatment Period

Secondary: Mean Change From Baseline to Week 48 in QLQ-C30 Scores During the Treatment Period

Secondary: Mean Change From Week 17 to Week 48 in QLQ-C30 Scores During the Open-label Period

Secondary: Mean Change From Week 17 to Week 48 in QLQ-C30 Scores During the Open-label Period

Secondary: Total Number of PRBC Units Transfused During the Open-Label Period

Secondary: Total Number of PRBC Units Transfused During the Open-Label Period

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase III, Randomized, Multicenter, Open-Label, Active-Comparator Controlled Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)