Clinical Trial Results:
A multicenter, single-arm, open-label trial to evaluate efficacy and safety of oral, twice daily iptacopan in adult PNH patients who are naive to complement inhibitor therapy
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Summary
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EudraCT number |
2020-003172-41 |
Trial protocol |
FR CZ IT |
Global end of trial date |
18 Apr 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Apr 2024
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First version publication date |
25 Apr 2024
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Other versions |
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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 |
CLNP023C12301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04820530 | ||
WHO universal trial number (UTN) |
- | ||
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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 |
18 Apr 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 |
18 Apr 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 |
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.
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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 |
19 Jul 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 |
Korea, Republic of: 2
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Country: Number of subjects enrolled |
Malaysia: 3
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Country: Number of subjects enrolled |
Singapore: 1
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Country: Number of subjects enrolled |
China: 20
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
Italy: 2
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Worldwide total number of subjects |
40
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EEA total number of subjects |
10
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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) |
37
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants took part in 12 investigative sites in 8 countries: France(1), United Kingdom(1), Italy(1), Korea, Republic of(1), Singapore(1), China(3), Malaysia(2), Germany(2) | ||||||
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Pre-assignment
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Screening details |
All patients provided written informed consent prior to the start of any study-related activities. Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae infections was required prior to the start of treatment. | ||||||
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Period 1
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Period 1 title |
Core treatment period
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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LNP023 | ||||||
Arm description |
Participants receive LNP023 at a dose of 200 mg b.i.d. orally | ||||||
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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Period 2
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Period 2 title |
Extension treatment period
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Is this the baseline period? |
No | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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LNP023 | ||||||
Arm description |
Participants receive LNP023 at a dose of 200 mg b.i.d. orally | ||||||
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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Baseline characteristics reporting groups
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Reporting group title |
LNP023
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Reporting group description |
Participants receive LNP023 at a dose of 200 mg b.i.d. orally | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
LNP023
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Reporting group description |
Participants receive LNP023 at a dose of 200 mg b.i.d. orally | ||
Reporting group title |
LNP023
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Reporting group description |
Participants receive LNP023 at a dose of 200 mg b.i.d. orally | ||
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End point title |
Marginal Proportion (expressed as percentage) of participants with sustained increase in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of red blood cell transfusions [1] | ||||||||
End point description |
Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels of ≥ 2 g/dL on three out of four measurements between Day 126 and 168 of the core 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 of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), 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. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the primary analysis.
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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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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: 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 |
Marginal proportion (expressed as percentage) of participants who remain free from transfusions | ||||||||
End point description |
Marginal proportion (expressed as percentage) of participants who did not require transfusions between Day 14 and Day 168.
Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), 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.
The 95% CI was obtained using the bootstrap method
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End point type |
Secondary
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End point timeframe |
Between Day 14 and Day 168
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| No statistical analyses for this end point | |||||||||
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End point title |
Percent change from baseline in LDH | ||||||||
End point description |
Percent change from baseline in lactate dehydrogenase (LDH) levels as mean of visits between Day 126 and Day 168.
Percentage change from baseline was analyzed using a mixed model for repeated measures (MMRM) which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline LDH as fixed effects and visit*baseline LDH as interaction.
Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 126 to 168
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from baseline in hemoglobin levels in the core treatment period | ||||||||
End point description |
Change from baseline in hemoglobin levels as mean of visits between Day 126 and Day 168.
In order to factor out the effect of transfusions in this analysis, if a patient had a transfusion during the core treatment period, the hemoglobin (Hb) values during 30 days following the transfusion were excluded and Hb data were imputed.
Change from baseline was analyzed using a mixed model of repeated measures which included age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, and baseline hemoglobin as fixed effects and the interaction between visit and baseline hemoglobin levels.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 126 to 168
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| No statistical analyses for this end point | |||||||||
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End point title |
Marginal proportion (expressed as percentage) 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 between Day 126 and 168 of the core 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 of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), 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. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the analysis.
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End point type |
Secondary
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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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| No statistical analyses for this end point | |||||||||
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End point title |
Change from baseline in absolute reticulocyte count | ||||||||
End point description |
Change from baseline in absolute reticulocyte counts as mean of visits between Day 126 and Day 168.
Change from baseline was analyzed using a MMRM which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline reticulocyte counts as fixed effects and visit*baseline reticulocyte counts as interaction.
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End point type |
Secondary
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End point timeframe |
Baseline and mean of visits between Day 126 and 168
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| No statistical analyses for this end point | |||||||||
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End point title |
Adjusted annualized Major Adverse Vascular Events rate in the core treatment period | ||||||||
End point description |
Adjusted annual rate is carried out using the Wilson method. 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.
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End point type |
Secondary
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End point timeframe |
Between Day 1 and Day 168
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| No statistical analyses for this end point | |||||||||
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End point title |
Adjusted annualized clinical BTH rate in the core treatment period | ||||||||
End point description |
Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events is carried out using the Wilson method. 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.
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End point type |
Secondary
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End point timeframe |
Between Day 1 and Day 168
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from baseline in FACIT-Fatigue score between Day 126 and Day 168 | ||||||||
End point description |
Change from baseline in FACIT-Fatigue scores as mean of visits between Day 126 and Day 168. 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.
Change from baseline was analyzed using a Mixed Model of Repeated Measures (MMRM) which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline FACIT-Fatigue score as fixed effects and visit*baseline FACIT-Fatigue score as interaction.
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End point type |
Secondary
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End point timeframe |
Baseline and mean of visits between Day 126 and Day 168
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| No statistical analyses for this end point | |||||||||
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End point title |
Marginal Proportion (expressed as percentage) of patients not receiving and not requiring RBC transfusions | ||||||||
End point description |
Requiring Red Blood Cells (RBC) transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms).
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End point type |
Other pre-specified
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End point timeframe |
Between Day 14 and Day 336
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of patients meeting hematological response criteria irrespective of RBC transfusions | ||||||||||||
End point description |
Patients with hematological response are those with an increase in Hb from baseline ≥ 2g/dL irrespective of red blood cell (RBC) transfusions and patients achieving Hb ≥ 12g/dL irrespective of RBC transfusions.
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End point type |
Other pre-specified
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End point timeframe |
Baseline, Day 336
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from baseline in LDH at Visit Day 336 | ||||||||
End point description |
Change from baseline in Lactate dehydrogenase (LDH) at Visit Day 336
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End point type |
Other pre-specified
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End point timeframe |
Baseline, Day 336
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| No statistical analyses for this end point | |||||||||
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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.
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End point type |
Other pre-specified
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End point timeframe |
Baseline, Day 336
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from baseline in FACIT-Fatigue score 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.
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End point type |
Other pre-specified
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End point timeframe |
Baseline, Day 336
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from baseline in Hemoglobin levels | ||||||||
End point description |
Change from baseline in Hemoglobin at Visit Day 336
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End point type |
Other pre-specified
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End point timeframe |
Baseline, Day 336
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| No statistical analyses for this end point | |||||||||
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End point title |
Adjusted annualized clinical BTH rate after the start of LNP023 treatment | ||||||||
End point description |
Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events is carried out using the Wilson method. 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.
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End point type |
Other pre-specified
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End point timeframe |
Between Day 1 and Day 336
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| No statistical analyses for this end point | |||||||||
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End point title |
Adjusted annualized Major Adverse Vascular Events rate after the start of LNP023 treatment | ||||||||
End point description |
Adjusted annual rate is carried out using the Wilson method. A Major Adverse Vascular Events (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
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End point type |
Other pre-specified
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End point timeframe |
Between Day 1 and Day 336
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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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 up to 30 days, up to a maximum duration of 48 weeks
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.0
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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17 Aug 2021 |
This amendment was implemented to address several requests from Health Authorities. The amendment provided more flexibility on timing of vaccination against encapsulated bacteria at study entry, and the associated need for prophylactic antibiotic. Additionally, this amendment was also implemented to further assess the hematological response of iptacopan in the study
by adding both a threshold for response rate as well as a Hb stabilization assessment, and to specifically address new requirements regarding SAE reporting in Germany.
Furthermore, due to the use of (high dose) steroids as first line therapy in some countries, reduction of the maximum allowed dose at study entry reduces the risk of tapering down during the Core treatment period. Further updates have been made to certain exclusion criteria, provide new juvenile toxicity animal data, add the possibility for interim safety analyses when study is still ongoing, and add a supplementary estimand that considers use of rescue medication as a treatment failure. |
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23 Nov 2021 |
This amendment was implemented to provide a more comprehensive evaluation of patients’ hematological parameters by the central laboratory, by replacing the abbreviated hematology assessments with full hematology assessments. The amendment was also implemented to add the possibility to use PK-PD data for modeling at the time of an interim safety analysis.
In addition, simplification of the analyses of the PRO have been introduced. A comprehensive analysis of a separate PRO report are documented in a separate statistical analysis plan.
Changes have also been made to provide additional clarity on AE/SAE reporting post-treatment discontinuation and to address new requirements regarding SAE reporting. |
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28 Mar 2022 |
This amendment was implemented to address the request from the Chinese Health Authority (Center for Drug Evaluation) to collect additional historical data in Chinese trial patients. The retrospective data collection of laboratory values for Hb, LDH and absolute reticulocyte count over 6 months before screening for patients from China was intended to support the regulatory
filing in China. |
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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 | |||
