Paroxysmal Nocturnal Hemoglobinuria
Conditions
Keywords
Paroxysmal Nocturnal Hemoglobinuria, iptacopan, single arm open-label, Hb≥10 g/dL in response to anti-C5 antibody, switch to iptacopan, PNH, LNP023
Brief summary
The purpose of the study was to find out if iptacopan is effective and safe in adult patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who switched from their current standard of care treatment (eculizumab or ravulizumab) to study treatment, iptacopan/LNP023.
Detailed description
This was a multicenter, single-arm, open label trial, with iptacopan treatment for 24 weeks in adult PNH patients. This study was comprised of two periods: * A Screening period lasting up to 8 weeks. * A 24-week open-label, iptacopan Treatment period. After completion of the treatment period, participants who continued to benefit from the iptacopan treatment based on the study doctor's evaluation were able to join the Roll-over extension study (CLNP023C12001B).
Interventions
DRUGIptacopan
Treatment with iptacopan at a dose of 200 mg b.i.d. will start on the first day (Day 1) and continue for 24 weeks.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A multicenter, single arm, open-label trial to evaluate efficacy and safety of oral, twice daily iptacopan in adult PNH patients who have Hb≥10 g/dL in response to anti-C5 antibody and switch to iptacopan
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent must be obtained prior to participation in the study. * Male and female participants ≥ 18 years of age, at the time of ICF signatures and with a diagnosis of PNH confirmed by treating physician. * Stable regimen (dose and intervals) of anti-C5 antibody treatment (either eculizumab or ravulizumab) for at least 6 months prior to screening * Mean hemoglobin level ≥10 g/dL * Vaccination against Neisseria meningitidis and S. pneumoniae infection are required prior to the start of iptacopan treatment. * If not received previously, vaccination against Haemophilus influenzae infections is recommended, if available and according to local regulations. * Ability to communicate well with the investigator, to understand and comply with the requirements of the study * Other protocol -defined inclusion criteria may apply at the end.
Exclusion criteria
* Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment * Patients requiring red blood cell transfusion in the 6 months prior to screening or during screening * History of stem cell transplantation or any solid organ transplantation * Active systemic bacterial, viral (incl. COVID-19) or fungal infection within 14 days prior to study drug administration * Presence of fever ≥ 38.0 °C (100.4 °F) within 7 days prior to study drug administration * Human immunodeficiency virus (HIV) infection (known history of HIV or test positive for HIV antibody at Screening) * A history of recurrent invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus * Unstable medical condition including, but not limited to, myocardial ischemia, active gastrointestinal bleeding, coexisting chronic anemia unrelated to PNH, or unstable thrombotic event not amenable to active treatment as judged by the investigator at Screening. * History of cancer of any part of the body within the past 5 years, * Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial. * Any medical condition deemed likely to interfere with the patient's participation in the study * Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hb Levels as Mean of Visits Between Day 126 and Day 168 Compared to Baseline Tested for Non-inferiority | Baseline, Day 126 to Day 168 | Change in hemoglobin (Hb) levels as mean of visits between Day 126 and Day 168 compared to baseline. Baseline is defined as as the mean of three Hb assessments conducted at the central laboratory: two during screening and the third on Day 1. The estimation of change from baseline in Hb levels was handled by the hypothetical strategy where participants were assumed as if they did not receive RBC transfusions while on treatment (RBC transfusions were expected to be rare). Assuming that participants had stable Hb levels at study entry, the mean change from baseline in Hb level between Day 126 and Day 168 was expected to be unchanged should participants have continued on anti-C5 treatment. Non-inferiority of iptacopan was therefore tested by the null hypothesis (H0) against the alternate hypothesis (H1) comparing the mean change from baseline in Hb level in iptacopan between Day 126 and Day 168 (μ) to -1 g/dL: H0: μ \<= -1, H1: μ \> -1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Hematological Responders to Iptacopan Treatment | Day 126 to Day 168 | Response defined as Hb ≥12 g/dL assessed between visits Day 126 and Day 168 in the absence of RBC transfusions, on three out of four measurements taken at the visits occurring in last six weeks |
| Proportion of Participants Who Remain Free From Transfusions | Day 1 to Day 168 | Number of participants with absence of administration of packed RBC transfusions between Day 1 and Day 168 |
| Change From Baseline in Absolute Reticulocytes Count (ARC) Levels | Baseline, Day 126 to Day 168 | Change from baseline in ARC levels as mean of visits between Day 126 and Day 168 |
| Percentage Change From Baseline in Lactate Dehydrogenase (LDH) Levels | Baseline, Day 126 to Day 168 | Percentage change from baseline in LDH levels as mean of visits between Day 126 and Day 168 |
| Change in Hb Levels as Mean of Visits Between Day 126 and Day 168 Compared to Baseline Tested for Superiority | Baseline, Day 126 to Day 168 | Change in hemoglobin (Hb) levels as mean of visits between Day 126 and Day 168 compared to baseline. Baseline is defined as as the mean of three Hb assessments conducted at the central laboratory: two during screening and the third on Day 1. |
| Change From Baseline in Fatigue Score Using FACIT-F Questionnaire | Baseline, Day 84 and Day 168 | Change from baseline in patient-reported scores for the functional assessment of chronic illness therapy - Fatigue (FACIT-F) collected at Day 84 and Day 168. The FACIT-F is a 13-item questionnaire that assesses self-reported fatigue and its impact upon 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. |
| Percentage of Patients Who Had Breakthrough Hemolysis (BTH) Event | Up to 168 Days | Wilson method is used to calculate the confidence interval for the proportion of patients who had events. 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 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. |
| Percentage of Patients Who Had Major Adverse Vascular Events (MAVEs) | Up to 168 Days | 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. |
| Change From Baseline in Treatment Satisfaction Score Using TSQM-9 Questionnaire | Baseline, Day 84 and Day 168 | Difference in scores of the Treatment Satisfaction Questionnaire for Medication(TSQM-9) between baseline and Day 84 and Day 168 assessed after switching from SoC (anti-C5) to iptacopan. TSQM-9 is a patient reported outcomes measure that was designed to assess patients' satisfaction with medication across three domains of effectiveness, convenience and global satisfaction. The TSQM-9 contains 3 questions in each domain. Domain scores range from 0 - 100 with higher scores representing better outcomes for the domain. |
Countries
France, Germany, Italy, South Korea, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 23 centers; 9 in United States, 4 in Germany, 3 in France, 2 in the United Kingdom, 2 in Italy and one each in Spain, Turkey and Republic of Korea enrolled participants.
Pre-assignment details
The study consisted of a screening period up to 8 weeks.
Participants by arm
| Arm | Count |
|---|---|
| LNP023 200mg b.i.d. Iptacopan (LNP023) at a dose of 200 mg b.i.d. orally | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | LNP023 200mg b.i.d. |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants |
| Age, Continuous | 46.0 years STANDARD_DEVIATION 13.67 |
| Race/Ethnicity, Customized Asian | 4 Participants |
| Race/Ethnicity, Customized Not Reported | 9 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants |
| Race/Ethnicity, Customized White | 35 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 52 |
| other Total, other adverse events | 25 / 52 |
| serious Total, serious adverse events | 2 / 52 |
Outcome results
Primary
Change in Hb Levels as Mean of Visits Between Day 126 and Day 168 Compared to Baseline Tested for Non-inferiority
Change in hemoglobin (Hb) levels as mean of visits between Day 126 and Day 168 compared to baseline. Baseline is defined as as the mean of three Hb assessments conducted at the central laboratory: two during screening and the third on Day 1. The estimation of change from baseline in Hb levels was handled by the hypothetical strategy where participants were assumed as if they did not receive RBC transfusions while on treatment (RBC transfusions were expected to be rare). Assuming that participants had stable Hb levels at study entry, the mean change from baseline in Hb level between Day 126 and Day 168 was expected to be unchanged should participants have continued on anti-C5 treatment. Non-inferiority of iptacopan was therefore tested by the null hypothesis (H0) against the alternate hypothesis (H1) comparing the mean change from baseline in Hb level in iptacopan between Day 126 and Day 168 (μ) to -1 g/dL: H0: μ \<= -1, H1: μ \> -1.
Time frame: Baseline, Day 126 to Day 168
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned. The number of participants analyzed corresponds to the number of subjects who had values at baseline and Day 126 and Day 168.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LNP023 200mg b.i.d. | Change in Hb Levels as Mean of Visits Between Day 126 and Day 168 Compared to Baseline Tested for Non-inferiority | 2.01 g/dL |
p-value: <0.0001Mixed Models Analysis
Secondary
Change From Baseline in Absolute Reticulocytes Count (ARC) Levels
Change from baseline in ARC levels as mean of visits between Day 126 and Day 168
Time frame: Baseline, Day 126 to Day 168
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned. The number of participants analyzed corresponds to the number of subjects who had values at Day 126 and Day 168.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LNP023 200mg b.i.d. | Change From Baseline in Absolute Reticulocytes Count (ARC) Levels | -89.19 10^9 cells/L |
Secondary
Change From Baseline in Fatigue Score Using FACIT-F Questionnaire
Change from baseline in patient-reported scores for the functional assessment of chronic illness therapy - Fatigue (FACIT-F) collected at Day 84 and Day 168. The FACIT-F is a 13-item questionnaire that assesses self-reported fatigue and its impact upon 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.
Time frame: Baseline, Day 84 and Day 168
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned. The number of participants analyzed corresponds to the number of subjects who had values at Day 84 and Day 168.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| LNP023 200mg b.i.d. | Change From Baseline in Fatigue Score Using FACIT-F Questionnaire | Day 84 | 4.88 score on a scale |
| LNP023 200mg b.i.d. | Change From Baseline in Fatigue Score Using FACIT-F Questionnaire | Day 168 | 4.29 score on a scale |
Secondary
Change From Baseline in Treatment Satisfaction Score Using TSQM-9 Questionnaire
Difference in scores of the Treatment Satisfaction Questionnaire for Medication(TSQM-9) between baseline and Day 84 and Day 168 assessed after switching from SoC (anti-C5) to iptacopan. TSQM-9 is a patient reported outcomes measure that was designed to assess patients' satisfaction with medication across three domains of effectiveness, convenience and global satisfaction. The TSQM-9 contains 3 questions in each domain. Domain scores range from 0 - 100 with higher scores representing better outcomes for the domain.
Time frame: Baseline, Day 84 and Day 168
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned. The number of participants analyzed corresponds to the number of subjects who had values at baseline, Day 84 and Day 168.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| LNP023 200mg b.i.d. | Change From Baseline in Treatment Satisfaction Score Using TSQM-9 Questionnaire | TSQMS1-Effectiveness Day 84 | 15.08 score on a scale |
| LNP023 200mg b.i.d. | Change From Baseline in Treatment Satisfaction Score Using TSQM-9 Questionnaire | TSQMS1-Effectiveness Day 168 | 12.54 score on a scale |
| LNP023 200mg b.i.d. | Change From Baseline in Treatment Satisfaction Score Using TSQM-9 Questionnaire | TSQMS1-Convenience Day 84 | 20.34 score on a scale |
| LNP023 200mg b.i.d. | Change From Baseline in Treatment Satisfaction Score Using TSQM-9 Questionnaire | TSQMS1-Convenience 168 | 23.86 score on a scale |
| LNP023 200mg b.i.d. | Change From Baseline in Treatment Satisfaction Score Using TSQM-9 Questionnaire | TSQMS1-Global Satisfaction Day 84 | 14.26 score on a scale |
| LNP023 200mg b.i.d. | Change From Baseline in Treatment Satisfaction Score Using TSQM-9 Questionnaire | TSQMS1-Global Satisfaction Day 168 | 18.53 score on a scale |
Secondary
Change in Hb Levels as Mean of Visits Between Day 126 and Day 168 Compared to Baseline Tested for Superiority
Change in hemoglobin (Hb) levels as mean of visits between Day 126 and Day 168 compared to baseline. Baseline is defined as as the mean of three Hb assessments conducted at the central laboratory: two during screening and the third on Day 1.
Time frame: Baseline, Day 126 to Day 168
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned. The number of participants analyzed corresponds to the number of subjects who had values at baseline and Day 126 and Day 168.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LNP023 200mg b.i.d. | Change in Hb Levels as Mean of Visits Between Day 126 and Day 168 Compared to Baseline Tested for Superiority | 2.01 g/dL |
p-value: <0.0001Mixed Models Analysis
Secondary
Percentage Change From Baseline in Lactate Dehydrogenase (LDH) Levels
Percentage change from baseline in LDH levels as mean of visits between Day 126 and Day 168
Time frame: Baseline, Day 126 to Day 168
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned. The number of participants analyzed corresponds to the number of subjects who had values at Day 126 and Day 168.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LNP023 200mg b.i.d. | Percentage Change From Baseline in Lactate Dehydrogenase (LDH) Levels | -1.30 Percent change from baseline in LDH |
Secondary
Percentage of Patients Who Had Breakthrough Hemolysis (BTH) Event
Wilson method is used to calculate the confidence interval for the proportion of patients who had events. 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 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.
Time frame: Up to 168 Days
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LNP023 200mg b.i.d. | Percentage of Patients Who Had Breakthrough Hemolysis (BTH) Event | 0.00 Percentage of patients with BTH events |
Secondary
Percentage of Patients Who Had Major Adverse Vascular Events (MAVEs)
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.
Time frame: Up to 168 Days
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LNP023 200mg b.i.d. | Percentage of Patients Who Had Major Adverse Vascular Events (MAVEs) | 0.00 Percentage of patients with MAVEs |
Secondary
Proportion of Hematological Responders to Iptacopan Treatment
Response defined as Hb ≥12 g/dL assessed between visits Day 126 and Day 168 in the absence of RBC transfusions, on three out of four measurements taken at the visits occurring in last six weeks
Time frame: Day 126 to Day 168
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned. The number of participants analyzed corresponds to the number of subjects who had values at Day 126 and Day 168.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LNP023 200mg b.i.d. | Proportion of Hematological Responders to Iptacopan Treatment | 92.7 Proportion of participants |
Secondary
Proportion of Participants Who Remain Free From Transfusions
Number of participants with absence of administration of packed RBC transfusions between Day 1 and Day 168
Time frame: Day 1 to Day 168
Population: Full Analysis Set (FAS) comprised all participants with confirmed eligibility to whom study treatment was assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LNP023 200mg b.i.d. | Proportion of Participants Who Remain Free From Transfusions | 100.0 Proportion of participants |