Clinical Trial Results:
A randomized, multicenter, active-comparator controlled, open-label trial to evaluate efficacy and safety of oral, twice daily LNP023 in adult patients with PNH and residual anemia, despite treatment with an intravenous anti-C5 antibody.
Summary
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EudraCT number |
2019-004665-40 |
Trial protocol |
FR DE HU CZ NL IT |
Global end of trial date |
06 Mar 2023
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Results information
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Results version number |
v2(current) |
This version publication date |
21 Mar 2024
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First version publication date |
05 Oct 2023
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Other versions |
v1 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CLNP023C12302
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04558918 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
Novartis Campus, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office , Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
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Scientific contact |
Clinical Disclosure Office , Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Mar 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Mar 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to demonstrate superiority of iptacopan compared to anti-C5 antibody
treatment in the proportion of patients achieving hematological response. Two hematological responder endpoints were defined as primary endpoints:
• Increase from baseline Hb levels ≥ 2 g/dL (assessed between Day 126 and Day 168) in the absence of RBC transfusion between Day 14 and Day 168.
• Hb levels ≥ 12 g/dL (assessed between Day 126 and Day 168) in the absence of RBC transfusion between Day 14 and Day 168.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Jan 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Brazil: 4
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Country: Number of subjects enrolled |
Czechia: 1
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Country: Number of subjects enrolled |
France: 15
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Country: Number of subjects enrolled |
Germany: 20
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Country: Number of subjects enrolled |
United Kingdom: 11
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Country: Number of subjects enrolled |
Italy: 17
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Country: Number of subjects enrolled |
Japan: 9
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Country: Number of subjects enrolled |
Korea, Republic of: 1
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Country: Number of subjects enrolled |
Netherlands: 4
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
Taiwan: 3
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Country: Number of subjects enrolled |
United States: 8
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Worldwide total number of subjects |
97
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EEA total number of subjects |
61
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
71
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From 65 to 84 years |
26
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants took part in 39 investigative sites in 12 countries: Netherlands(1), Germany(5), France(3), Japan(7), Korea, Republic of(1), Italy(7), Spain(3), Taiwan(2), United Kingdom(2), Czech Republic(1), United States(5), Brazil(2) | |||||||||
Pre-assignment
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Screening details |
Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae infections was required prior to the start of treatment, if the patient had not been previously vaccinated, or if a booster was required. | |||||||||
Period 1
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Period 1 title |
Randomized treatment period
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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LNP023 200mg b.i.d. | |||||||||
Arm description |
Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
ptacopan
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Investigational medicinal product code |
LNP023
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
LNP023 200mg b.i.d.
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Arm title
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Anti-C5 antibody | |||||||||
Arm description |
In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Ravulizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Ravulizumab 300mg/30mL intravenousinfusion
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Investigational medicinal product name |
Eculizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Eculizumab 300
mg/30mLconcentrate
solution forinfusion
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Period 2
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Period 2 title |
Extension treatment period
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Is this the baseline period? |
No | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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LNP023 200mg b.i.d. | |||||||||
Arm description |
Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Iptacopan
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Investigational medicinal product code |
LNP023
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
LNP023 200mg b.i.d.
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Arm title
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Anti-C5 antibody | |||||||||
Arm description |
In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d. | |||||||||
Arm type |
No intervention | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Of the 97 patients completing the Randomized Treatment Period, 95 entered the treatment extension period. One patient, initially randomized to anti-C5, did not enter the extension period. |
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Baseline characteristics reporting groups
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Reporting group title |
LNP023 200mg b.i.d.
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Reporting group description |
Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Anti-C5 antibody
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Reporting group description |
In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Combined full analysis set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Includes all patients randomized to LNP023 200 mg b.i.d and all patientsrandomized to anti-C5 treatment and who switched to LNP023 in the treatment extension period.
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Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
includes all patients to whom study treatment has been assigned by randomization
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End points reporting groups
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Reporting group title |
LNP023 200mg b.i.d.
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Reporting group description |
Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d. | ||
Reporting group title |
Anti-C5 antibody
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Reporting group description |
In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d. | ||
Reporting group title |
LNP023 200mg b.i.d.
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Reporting group description |
Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d. | ||
Reporting group title |
Anti-C5 antibody
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Reporting group description |
In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d. | ||
Subject analysis set title |
Combined full analysis set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Includes all patients randomized to LNP023 200 mg b.i.d and all patientsrandomized to anti-C5 treatment and who switched to LNP023 in the treatment extension period.
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Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
includes all patients to whom study treatment has been assigned by randomization
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End point title |
Marginal proportion (expressed as percentages) of participants with sustained increase in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of red blood cell transfusions | ||||||||||||
End point description |
Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels ≥ 2 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms).
The term ‘marginal proportion’ can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
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End point type |
Primary
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End point timeframe |
Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
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Statistical analysis title |
Increase in hemoglobin levels | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
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Number of subjects included in analysis |
97
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Difference in marginal proportion | ||||||||||||
Point estimate |
80.2
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
71.2 | ||||||||||||
upper limit |
87.6 | ||||||||||||
Statistical analysis title |
Increase in hemoglobin levels | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
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Number of subjects included in analysis |
97
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [1] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
338.25
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
25.07 | ||||||||||||
upper limit |
4564.14 | ||||||||||||
Notes [1] - two sided unadjusted p-value |
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End point title |
Marginal proportion (expressed as percentages) of participants with sustained hemoglobin levels of ≥ 12 g/dL in the absence of red blood cell transfusions | ||||||||||||
End point description |
Sustained hemoglobin levels (responder) is defined as hemoglobin levels ≥ 12 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms).
The term ‘marginal proportion’ can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
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End point type |
Primary
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End point timeframe |
Hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
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Statistical analysis title |
Increase in hemoglobin levels | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
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Number of subjects included in analysis |
97
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Diff. in marginal proportion | ||||||||||||
Point estimate |
67
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
56.4 | ||||||||||||
upper limit |
76.9 | ||||||||||||
Statistical analysis title |
Increase in hemoglobin levels | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
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Number of subjects included in analysis |
97
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
495.74
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
24.41 | ||||||||||||
upper limit |
10066.53 | ||||||||||||
Notes [2] - two sided unadjusted p-value |
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End point title |
Percentage of patients meeting hematological response criterion after the start of LNP023 treatment [3] | ||||||||||||||||||
End point description |
Patients with hematological response are those with ≥ 2g/dL increase in hemoglobin from baseline regardless of transfusions and patients with Hb ≥ 12g/dL regardless of transfusions.
Patients in the LNP023-LNP023 group received iptacopan from Day 1 to Day 336 (48 weeks) while patients in the anti-C5 antibody-LNP023 group received iptacopan from Day 169 to Day 336 (treatment extension period - 24 weeks).
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End point type |
Primary
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End point timeframe |
Up to 48 weeks
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Notes [3] - 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: No statistical analysis was planned for this primary outcome. |
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No statistical analyses for this end point |
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End point title |
Change from baseline in Hemoglobin at Visit Day 336 | ||||||||||||
End point description |
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
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End point type |
Primary
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End point timeframe |
Baseline, Day 336
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Statistical analysis title |
Change from baseline in hemoglobin at day 336 | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
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Number of subjects included in analysis |
89
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Adjusted mean difference | ||||||||||||
Point estimate |
-0.01
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.53 | ||||||||||||
upper limit |
0.51 |
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End point title |
Number of patients not requiring RBC transfusions after the start of LNP023 treatment [4] | |||||||||||||||
End point description |
Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms).
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
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End point type |
Primary
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End point timeframe |
Up to 48 weeks
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Notes [4] - 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: No statistical analysis was planned for this primary outcome. |
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No statistical analyses for this end point |
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End point title |
Change from baseline in FACIT-Fatigue questionnaire at Day 336 | ||||||||||||
End point description |
The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best.
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
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End point type |
Primary
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End point timeframe |
Baseline, Day 336
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Statistical analysis title |
Analysis of FACIT Fatigue scores at day 336 | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
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Number of subjects included in analysis |
81
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Adjusted mean difference | ||||||||||||
Point estimate |
-1.17
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-4.01 | ||||||||||||
upper limit |
1.68 |
|
|||||||||
End point title |
Adjusted annualized clinical BTH rate after the start of LNP023 treatment [5] | ||||||||
End point description |
This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set.
Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs & symptoms, in presence of laboratory evidence of intravascular hemolysis.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Up to 336 Days
|
||||||||
Notes [5] - 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: No statistical analysis was planned for this primary outcome. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Adjusted annualized Major Adverse Vascular Events rate after the start of LNP023 treatment [6] | ||||||||
End point description |
This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set.
Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd‐Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other.
A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Up to 336 Days
|
||||||||
Notes [6] - 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: No statistical analysis was planned for this primary outcome. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in absolute reticulocyte count in the randomized treatment period | ||||||||||||
End point description |
Change from baseline in absolute reticulocyte count as mean of visits between Day 126 and Day 168
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and mean of visits between Day 126 and 168
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of absolute reticulocyte counts | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
97
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [7] | ||||||||||||
Method |
Mixed Model of Repeated Measures (MMRM) | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-116.15
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-132.04 | ||||||||||||
upper limit |
-100.26 | ||||||||||||
Notes [7] - two sided unadjusted p-value |
|
|||||||||||||
End point title |
Ratio to baseline in log-transformed LDH in the randomized treatment period | ||||||||||||
End point description |
Average of the Lactate dehydrogenase (LDH) log transformed ratio to baseline in each treatment estimated between Day 126 and Day 168.The log transformation used refers to the natural log (base of e).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and mean of visits between Day 126 and 168
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of LDH log-transformed ratio to baseline | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
97
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.8361 [8] | ||||||||||||
Method |
Mixed Model of Repeated Measures (MMRM) | ||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
0.99
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.89 | ||||||||||||
upper limit |
1.1 | ||||||||||||
Notes [8] - two sided unadjusted p-value |
|
|||||||||||||
End point title |
Adjusted annualized Major Adverse Vascular Events rate in the randomized treatment period | ||||||||||||
End point description |
Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd‐Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other.
A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Between Day 1 and Day 168
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Rate of MAVEs | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
97
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.31731 [9] | ||||||||||||
Method |
Poisson model | ||||||||||||
Parameter type |
rate difference | ||||||||||||
Point estimate |
0.03
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.03 | ||||||||||||
upper limit |
0.1 | ||||||||||||
Notes [9] - two sided unadjusted p-value |
|
|||||||||||||
End point title |
Marginal proportion (expressed as percentages) of participants who remain free from transfusions | ||||||||||||
End point description |
Marginal proportion (expressed as percentages) of participants who did not require transfusions between Day 14 and Day 168. Requiring red blood cell transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term ‘marginal proportion’ can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Between Day 14 and Day 168
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of transfusion avoidance | ||||||||||||
Statistical analysis description |
logistic regression model
|
||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
97
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Diff. in marginal proportion | ||||||||||||
Point estimate |
68.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
51.4 | ||||||||||||
upper limit |
83.9 | ||||||||||||
Statistical analysis title |
Analysis of transfusion avoidance | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
97
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [10] | ||||||||||||
Method |
Conditional logistic regression | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
108.41
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
17.25 | ||||||||||||
upper limit |
681.24 | ||||||||||||
Notes [10] - two sided unadjusted p-value |
|
|||||||||||||
End point title |
Change from baseline in FACIT-Fatigue questionnaire in the Randomized Treatment Period | ||||||||||||
End point description |
The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, mean of visits between Day 126 and Day 168
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of FACIT Fatigue scores | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
95
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [11] | ||||||||||||
Method |
Mixed Model of Repeated Measures (MMRM) | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
8.29
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
5.28 | ||||||||||||
upper limit |
11.29 | ||||||||||||
Notes [11] - two sided unadjusted p-value |
|
|||||||||||||
End point title |
Change from baseline in hemoglobin between Day 126 and 168 | ||||||||||||
End point description |
Change from baseline in hemoglobin levels as mean of visits between Day 126 and Day 168.
For this analysis, in order to factor out the effect of transfusions, if a patient had a transfusion during the randomized treatment period, then the hemoglobin values 30 days following the transfusion were excluded and hemoglobin data were imputed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and mean of visits between Day 126 and 168
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of hemoglobin levels | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
97
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [12] | ||||||||||||
Method |
Mixed Model of Repeated Measures (MMRM) | ||||||||||||
Parameter type |
Adjusted mean diff. | ||||||||||||
Point estimate |
3.66
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
3.2 | ||||||||||||
upper limit |
4.12 | ||||||||||||
Notes [12] - two sided unadjusted p-value |
|
|||||||||||||
End point title |
Adjusted annualized clinical BTH rate in the randomized treatment period | ||||||||||||
End point description |
Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model.
A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.
The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs & symptoms, in presence of laboratory evidence of intravascular hemolysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Between Day 1 and Day 168
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Adjusted annualized BTH rate | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
97
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.01183 [13] | ||||||||||||
Method |
Negative binomial model | ||||||||||||
Parameter type |
Rate ratio | ||||||||||||
Point estimate |
0.1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.02 | ||||||||||||
upper limit |
0.61 | ||||||||||||
Notes [13] - two sided unadjusted p-value |
|||||||||||||
Statistical analysis title |
Adjusted annualized BTH rate | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
97
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
Method |
|||||||||||||
Parameter type |
Rate difference | ||||||||||||
Point estimate |
-0.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.24 | ||||||||||||
upper limit |
0.04 |
|
|||||||||||||
End point title |
Change from baseline in absolute reticulocyte count at Day 336 | ||||||||||||
End point description |
Change from baseline in absolute reticulocyte count at visit Day 336.
Patients randomized to anti-C5 antibody were switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline and Day 336
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of absolute reticulocyte count | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
87
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Adjusted mean difference | ||||||||||||
Point estimate |
1.69
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-16.86 | ||||||||||||
upper limit |
20.23 |
|
|||||||||||||
End point title |
Ratio to baseline in log-transformed LDH at Visit Day 336 | ||||||||||||
End point description |
Average of the Lactate dehydrogenase (LDH) log transformed ratio to baseline at visit Day 336.The log transformation used refers to the natural log (base of e).
Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline and Day 336
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of LDH at visit Day 336 | ||||||||||||
Comparison groups |
LNP023 200mg b.i.d. v Anti-C5 antibody
|
||||||||||||
Number of subjects included in analysis |
94
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Geometric mean ratio | ||||||||||||
Point estimate |
1.12
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.97 | ||||||||||||
upper limit |
1.3 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse events of LNP023 group were reported from first dose of study treatment until the end of study treatment plus 30 days, up to a maximum duration of 48 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Adverse events of anti-C5 antibody were reported from the date of first administration of anti-C5 study treatment in the randomized treatment period to the date of the last actual administration of anti-C5 antibody in the randomized treatment period.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
|
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Reporting groups
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Reporting group title |
LNP023 200mg b.i.d.
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Reporting group description |
LNP023 200mg b.i.d. (Randomized treatment period) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Any LNP023 200mg b.i.d.
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
LNP023 200mg b.i.d.
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Reporting group description |
LNP023 200mg b.i.d. (Randomized treatment period + extension treatment period) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Anti-C5 antibody
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Reporting group description |
Anti-C5 antibody (Randomized treatment period) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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09 Mar 2021 |
This amendment was implemented to add a sub-study for patient interviews to further explore
the clinical meaningfulness of the effects with PROs (specifically the FACIT-Fatigue), to address contraception periods following anti-C5 antibody treatment discontinuation, to provide more clarity to certain inclusion/exclusion criteria, concomitant therapy, and prohibited medication, to ensure consistency throughout the protocol, as well as to clarify aspects related to the COVID-19 pandemic. |
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02 Nov 2021 |
This amendment was implemented to add a supplementary estimand considering the use of rescue therapy as treatment failure. Changes were also implemented to provide a more comprehensive evaluation of patients’ hematology parameters by the central laboratory, by replacing the abbreviated hematology assessments with full hematology assessments. Clarifications were made in the statistical analysis section. In addition, simplification of the analyses of the PRO have been introduced.
Other changes included new juvenile toxicity animal data, updated exclusion criterion on ravulizumab dose, further clarification on severe kidney disease (by adding eGFR < 30 mL/min/1.73 m2), and additional clarity of AE/SAE reporting post-treatment discontinuation, and new requirements regarding SAE reporting. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |