Paroxysmal Nocturnal Hemoglobinuria (PNH)
Conditions
Brief summary
The primary objective of the study is to demonstrate a reduction in intravascular hemolysis by REGN3918 over 26 weeks of treatment in patients with active PNH who are treatment-naive to complement inhibitor therapy or have not recently received complement inhibitor therapy. The secondary objectives of the study are: * To evaluate the safety and tolerability of REGN3918. * To evaluate the effect of REGN3918 on parameters of intravascular hemolysis * To assess the concentrations of total REGN3918 in serum. * To evaluate the incidence of treatment-emergent anti-drug antibodies to REGN3918 over time * To evaluate the effect of REGN3918 on patient-reported outcomes (PROs) measuring fatigue and health-related quality of life
Interventions
DRUGREGN3918
Single intravenous (IV) dose, then a subcutaneous (SC) dose once weekly (QW).
Sponsors
Regeneron Pharmaceuticals
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) confirmed by high-sensitivity flow cytometry * PNH granulocytes \> 10% at screening visit * Active disease, as defined by the presence of 1 or more PNH-related signs or symptoms (eg, fatigue, hemoglobinuria, abdominal pain, shortness of breath \[dyspnea\], anemia \[hemoglobin \<10 g/dL\], history of a MAVE \[including thrombosis\], dysphagia, or erectile dysfunction) or history of red blood cell (RBC) transfusion due to PNH within 3 months of screening. * Lactate dehydrogenase (LDH) level ≥ 2 × upper limit of normal (ULN) at screening visit. Key
Exclusion criteria
* Prior treatment with a complement inhibitor either within 6 months prior to screening visit or at any time where the patient was refractory to complement inhibitor therapy, in the opinion of the investigator (with the exception of eculizumab refractory patients due to the C5 variant R885H/C) * History of bone marrow transplantation * Body weight \< 40 kilograms at screening visit * Peripheral blood absolute neutrophil count (ANC) \<500/μL \[\<0.5 x 109/L\] or peripheral blood platelet count \<50,000/μL * Documented history of systemic fungal disease or unresolved tuberculosis, or evidence of active or latent tuberculosis infection (LTBI) during screening period * Any contraindication for receiving Neisseria meningitidis vaccination and antibiotic prophylaxis therapy as recommended in the study * Any active, ongoing infection within 2 weeks of screening or during the screening period * Any clinically significant abnormality identified at the time of screening that in the judgment of the Investigator or any sub-Investigator would preclude safe completion of the study or constrain endpoints assessment such as major systemic diseases, or patients with short life expectancy * Women who are pregnant, breastfeeding, or who have a positive pregnancy test at screening visit or day 1 NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Adequate Control of Intravascular Hemolysis | Week 4 through Week 26 | Participants were considered to have had adequate control of intravascular hemolysis if all of their lactose dehydrogenase (LDH) readings from Week 4 through Week 26 inclusive had values less than or equal to ≤ 1.5 × upper limit of normal (ULN). Participants must have greater than or equal to (≥) 50 percent (%) of scheduled LDH measures in those weeks, must not have had more than (\>) 2 consecutive visits without LDH measures, must not have experienced breakthrough hemolysis, and must not have discontinued study treatment early. Participants were considered not to have had adequate control of intravascular hemolysis if they failed any of these criteria. |
| Percentage of Participants Who Achieved Transfusion Avoidance | Up to 26 Weeks | Transfusion avoidance was defined as not having received red blood cell (RBC) transfusion during the first 26 weeks. A transfusion was counted only if it was per-protocol, that is, it followed the predefined transfusion algorithm: RBC transfusion due to a post-baseline hemoglobin level \< 9 grams per deciliter (g/dL) (with anemia symptoms) or a post-baseline hemoglobin level \< 7 g/dL (without anemia symptoms). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Lactate Dehydrogenase (LDH) ≤1.5 x ULN | Up to Week 26 | A time-to-first-event analysis was used to estimate the proportion of participants achieving transfusion avoidance at Week 26. |
| Percentage of Days With LDH ≤ 1.5 ULN From Week 4 Through Week 26 | Week 4 through Week 26 | Percentage of days was calculated as number of days with LDH ≤ 1.5 x ULN divided by the participant's total treatment duration (total number of days on treatment from Week 4 through Week 26). LDH ≤ 1.5 x ULN was used as an indicator of adequate control of intravascular hemolysis. |
| Change From Baseline in LDH Levels at Week 26 | Baseline, Week 26 | Change from baseline in LDH levels at Week 26 was reported. |
| Percent Change From Baseline in LDH Levels at Week 26 | Baseline, Week 26 | Percent change from baseline in LDH levels at Week 26 was reported. |
| Rate of Transfusion With Red Blood Cells (RBCs) | Baseline up to Week 26 | The rate of transfusion with RBCs for a participant was the total number of transfusions divided by total person-years of time on treatment. |
| Number of Units of Transfusion With RBCs | Baseline up to Week 26 | Transfusions with RBCs proceeded according to the following predefined criteria that triggered a transfusion; however, the actual number of units to be transfused is at the discretion of the investigator: • Transfuse with RBC(s) if the post-baseline hemoglobin level is \<9 g/dL with symptoms resulting from anemia or • Transfuse with RBC(s) if the post-baseline hemoglobin level is \<7 g/dL. |
| Change From Baseline in RBC Hemoglobin Levels at Week 26 | Baseline, Week 26 | Hemoglobin levels in participants with PNH was measured. Change from baseline in RBC hemoglobin at Week 26 was reported. |
| Change From Baseline in Free Hemoglobin Levels at Week 26 | Baseline, Week 26 | Change from baseline in free hemoglobin levels at Week 26 was assessed. |
| Change From Baseline in Total Complement Hemolytic Activity Assay (CH50) at Week 26 | Baseline, Week 26 | Change from baseline in total CH50 at Week 26 was reported. Here International units per milliliter was abbreviated as IU/mL. |
| Percent Change From Baseline in CH50 up to Week 26 | Baseline up to Week 26 | Percent change from baseline in CH50 up to Week 26 was reported. |
| Percentage of Participants Who Had Breakthrough Hemolysis (BTH) | Baseline up to 26 Weeks | Breakthrough hemolysis was defined as the measurement of LDH ≥ 2 ULN concomitant with associated signs or symptoms at any time subsequent to an initial achievement of disease control (i.e., LDH ≤ 1.5 ULN). |
| Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Baseline, Week 26 | The EORTC QLQ-C30 was a 30-item questionnaire used to assess symptoms and side effects of treatment and the impact on everyday life. It consists of 15 domains: 5 multi-item functioning scales (physical, role, social, emotional and cognitive), answered on a 4-point scale (1=Not at all,2=A Little,3=Quite a Bit,4=Very Much). Each score ranges from 0-100 with a higher score indicates higher level of functioning and a better QoL. A global health status/QoL scale that was answered on a 7-point scale (1=Very Poor to 7=Excellent). Each score ranges from 0-100 with a higher score indicates a better QoL. 9 symptom scales (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact), answered on a 4-point scale (1=Not at all, 2=A Little, 3=Quite a Bit, 4=Very Much). Each score ranges from 0 to 100 with a higher score indicates a higher level of symptoms, and a negative change from baseline indicates an improvement in symptoms. |
| Change From Baseline in European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Index Score | Baseline, Week 26 | EQ-5D-3L was a self-administered standardized instrument for use as measure of health outcome. It comprised 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension rated on 3 levels scale: 1 (no problems), 2 (some problems), 3 (extreme problems). The summed score ranges from 5-15 with 5 corresponding to no problems and 15 to severe problems in 5 dimensions. EQ-5D index calculated by applying preference-based weights (tariffs) to scores of five health state dimensions. Index values range from -1 to 1, with 0 representing a health state equivalent to death and 1 representing perfect health. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best). |
| Change From Baseline in EQ-5D-3L Visual Analogue Scale (VAS) at Week 26 | Baseline, Week 26 | The EQ-5D-3L was a standardized instrument for use as a measure of health outcome and was administered to all participants to assess the effect of the treatment on the participants' quality of life. The EQ-5D-3L includes a visual analog scale (VAS) which is a vertical scale with numbers ranging from 0 to 100. Participants were asked to draw a line to the place on the scale that best represented how good or bad his health was on that day. The worst state a participant can imagine was marked zero, and the best state the participant can imagine was marked 100. Mean change in VAS score from baseline was reported. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Baseline up to Week 26 | An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs was defined as AEs that developed or worsened during the on-treatment period. SAE was defined as any untoward medical occurrence that resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. TEAEs included both Serious TEAEs and non-serious TEAEs. |
| Number of Participants With TEAEs Based on Severity | Baseline up to Week 26 | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Severity of AEs was graded according to the following scale, Mild: event that does not generally interfere with usual activities of daily living; Moderate: event that interferes with usual activities of daily living, causing discomfort, permanent risk of harm; Severe: AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention. |
| Number of Participants With Clinically Meaningful Changes in Clinical Laboratory Parameters | Baseline up to Week 26 | Clinical laboratory parameters included biochemistry, hematology and urinalysis. Number of participants with potential clinically significant changes in laboratory parameters which were deemed clinically meaningful by the investigator were reported. |
| Number of Participants With Clinically Meaningful Changes in Vital Signs | Baseline up to Week 26 | Vital sign assessments included pulse rate, blood pressure (systolic and diastolic blood pressure) and body temperature. Number of participants with potential clinically meaningful changes in vital signs which were deemed clinically significant by the investigator were reported. |
| Number of Participants With Clinically Meaningful Changes in 12-lead Electrocardiograms (ECGs) | Baseline up to Week 26 | 12-lead ECGs were evaluated. Any change in ECG assessments which are deemed clinically meaningful by the investigator were reported. |
| Serum Concentrations of Total REGN3918 | Pre-dose (Day 0), End of infusion at Days 0, 2, 7, 28, 56, 84, 112, 140, and 182 | Serum Concentrations of total REGN3918 was reported. |
| Number of Participants With Treatment-emergent Anti-Drug Antibodies (ADA) Response to REGN3918 | Baseline up to Week 26 | Number of Participants with treatment-emergent ADA response to REGN3918 was reported. |
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 26 | Baseline, Week 26 | The FACIT-F was a 13-item, self-reported PRO measure assessing an individual's level of fatigue during their usual daily activities over the past week. This questionnaire was part of the FACIT measurement system, a compilation of questions measuring health-related QoL in participants with cancer and other chronic illnesses. The FACIT-fatigue assessed the level of fatigue using a 4-point Likert scale ranging from 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit), 4 (very much) The sum of all responses resulted in the FACIT-F score for a total possible score of 0 to 52, with higher scores indicated greater fatigue. |
| Percentage of Participants Who Achieved Normalization of Intravascular Hemolysis | Week 4 through Week 26 | A participant was considered to have achieved normalization of intravascular hemolysis if their LDH readings between Week 4 through Week 26 inclusive had values ≤ 1.0 ULN. A participant must have ≥ 50% of scheduled LDH measures in those weeks, must not have had \> 2 consecutive visits without LDH measures, must not have experienced breakthrough hemolysis, and must not have discontinued study treatment early. A participant was considered not to have achieved normalization of intravascular hemolysis if they failed any of these criteria. |
Countries
Hong Kong, Hungary, Malaysia, South Korea, United Kingdom
Participant flow
Pre-assignment details
During the study, the sponsor made an administrative decision to stop enrollment in order to pursue a combination program of REGN3918 & cemdisiran for treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). Study was not stopped for any safety concerns or lack of efficacy. 28 participants were screened: 4 were screen failures (1-Lost to follow-up, 1-did not meet criteria, 1-other) & 24 were enrolled & treated. Enrollment was closed at 24 participants instead of 30-42 as planned in the protocol.
Participants by arm
| Arm | Count |
|---|---|
| REGN3918 Participants received a single loading dose of REGN3918 30 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Day 1, followed by a maintenance regimen of 800 milligrams (mg) subcutaneous (SC) injection on Day 8 once weekly (QW) up to 26 weeks of treatment period. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | REGN3918 |
|---|---|
| Age, Continuous | 45.4 Years STANDARD_DEVIATION 17.28 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 24 |
| other Total, other adverse events | 13 / 24 |
| serious Total, serious adverse events | 0 / 24 |
Outcome results
Primary
Percentage of Participants Who Achieved Adequate Control of Intravascular Hemolysis
Participants were considered to have had adequate control of intravascular hemolysis if all of their lactose dehydrogenase (LDH) readings from Week 4 through Week 26 inclusive had values less than or equal to ≤ 1.5 × upper limit of normal (ULN). Participants must have greater than or equal to (≥) 50 percent (%) of scheduled LDH measures in those weeks, must not have had more than (\>) 2 consecutive visits without LDH measures, must not have experienced breakthrough hemolysis, and must not have discontinued study treatment early. Participants were considered not to have had adequate control of intravascular hemolysis if they failed any of these criteria.
Time frame: Week 4 through Week 26
Population: The full analysis set (FAS) included all enrolled participants who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN3918 | Percentage of Participants Who Achieved Adequate Control of Intravascular Hemolysis | 75.0 Percentage of Participants |
Primary
Percentage of Participants Who Achieved Transfusion Avoidance
Transfusion avoidance was defined as not having received red blood cell (RBC) transfusion during the first 26 weeks. A transfusion was counted only if it was per-protocol, that is, it followed the predefined transfusion algorithm: RBC transfusion due to a post-baseline hemoglobin level \< 9 grams per deciliter (g/dL) (with anemia symptoms) or a post-baseline hemoglobin level \< 7 g/dL (without anemia symptoms).
Time frame: Up to 26 Weeks
Population: The FAS included all enrolled participants who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN3918 | Percentage of Participants Who Achieved Transfusion Avoidance | 87.5 Percentage of Participants |
Secondary
Change From Baseline in EQ-5D-3L Visual Analogue Scale (VAS) at Week 26
The EQ-5D-3L was a standardized instrument for use as a measure of health outcome and was administered to all participants to assess the effect of the treatment on the participants' quality of life. The EQ-5D-3L includes a visual analog scale (VAS) which is a vertical scale with numbers ranging from 0 to 100. Participants were asked to draw a line to the place on the scale that best represented how good or bad his health was on that day. The worst state a participant can imagine was marked zero, and the best state the participant can imagine was marked 100. Mean change in VAS score from baseline was reported.
Time frame: Baseline, Week 26
Population: The FAS included all enrolled participants who received any study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Change From Baseline in EQ-5D-3L Visual Analogue Scale (VAS) at Week 26 | 8.4 Score on a Scale | Standard Error 2.18 |
Secondary
Change From Baseline in European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Index Score
EQ-5D-3L was a self-administered standardized instrument for use as measure of health outcome. It comprised 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension rated on 3 levels scale: 1 (no problems), 2 (some problems), 3 (extreme problems). The summed score ranges from 5-15 with 5 corresponding to no problems and 15 to severe problems in 5 dimensions. EQ-5D index calculated by applying preference-based weights (tariffs) to scores of five health state dimensions. Index values range from -1 to 1, with 0 representing a health state equivalent to death and 1 representing perfect health. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best).
Time frame: Baseline, Week 26
Population: The FAS included all enrolled participants who received any study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Change From Baseline in European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Index Score | 0.136 Score on a Scale | Standard Error 0.0238 |
Secondary
Change From Baseline in Free Hemoglobin Levels at Week 26
Change from baseline in free hemoglobin levels at Week 26 was assessed.
Time frame: Baseline, Week 26
Population: The SAF included all enrolled participants who received any study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Change From Baseline in Free Hemoglobin Levels at Week 26 | -9.19 milligrams per deciliter (mg/dL) | Standard Deviation 16.264 |
Secondary
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 26
The FACIT-F was a 13-item, self-reported PRO measure assessing an individual's level of fatigue during their usual daily activities over the past week. This questionnaire was part of the FACIT measurement system, a compilation of questions measuring health-related QoL in participants with cancer and other chronic illnesses. The FACIT-fatigue assessed the level of fatigue using a 4-point Likert scale ranging from 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit), 4 (very much) The sum of all responses resulted in the FACIT-F score for a total possible score of 0 to 52, with higher scores indicated greater fatigue.
Time frame: Baseline, Week 26
Population: The FAS included all enrolled participants who received any study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 26 | 9.9 Score on a Scale | Standard Error 1.52 |
Secondary
Change From Baseline in LDH Levels at Week 26
Change from baseline in LDH levels at Week 26 was reported.
Time frame: Baseline, Week 26
Population: The FAS included all enrolled participants who received any study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Change From Baseline in LDH Levels at Week 26 | -5.070 Units per liter (U/L) | Standard Error 0.1467 |
Secondary
Change From Baseline in RBC Hemoglobin Levels at Week 26
Hemoglobin levels in participants with PNH was measured. Change from baseline in RBC hemoglobin at Week 26 was reported.
Time frame: Baseline, Week 26
Population: The FAS included all enrolled participants who received any study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Change From Baseline in RBC Hemoglobin Levels at Week 26 | 15.0 grams per liter (g/L) | Standard Error 3.24 |
Secondary
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26
The EORTC QLQ-C30 was a 30-item questionnaire used to assess symptoms and side effects of treatment and the impact on everyday life. It consists of 15 domains: 5 multi-item functioning scales (physical, role, social, emotional and cognitive), answered on a 4-point scale (1=Not at all,2=A Little,3=Quite a Bit,4=Very Much). Each score ranges from 0-100 with a higher score indicates higher level of functioning and a better QoL. A global health status/QoL scale that was answered on a 7-point scale (1=Very Poor to 7=Excellent). Each score ranges from 0-100 with a higher score indicates a better QoL. 9 symptom scales (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact), answered on a 4-point scale (1=Not at all, 2=A Little, 3=Quite a Bit, 4=Very Much). Each score ranges from 0 to 100 with a higher score indicates a higher level of symptoms, and a negative change from baseline indicates an improvement in symptoms.
Time frame: Baseline, Week 26
Population: The FAS included all enrolled participants who received any study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| REGN3918 | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Global Health status/quality: Change at Week 26 | 12.509 Score on a Scale | Standard Error 3.2286 |
| REGN3918 | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Physical Functioning: Change at Week 26 | 17.511 Score on a Scale | Standard Error 2.6767 |
| REGN3918 | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Emotional Functioning: Change at Week 26 | 14.457 Score on a Scale | Standard Error 3.8645 |
| REGN3918 | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Social Functioning: Change at Week 26 | 15.846 Score on a Scale | Standard Error 3.8036 |
| REGN3918 | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Fatigue: Change at Week 26 | -18.904 Score on a Scale | Standard Error 2.9899 |
| REGN3918 | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Pain: Change at Week 26 | -13.537 Score on a Scale | Standard Error 3.0315 |
| REGN3918 | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Dyspnea: Change at Week 26 | -15.874 Score on a Scale | Standard Error 4.7953 |
| REGN3918 | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | Cognitive Functioning: Change at Week 26 | 9.840 Score on a Scale | Standard Error 2.971 |
Secondary
Change From Baseline in Total Complement Hemolytic Activity Assay (CH50) at Week 26
Change from baseline in total CH50 at Week 26 was reported. Here International units per milliliter was abbreviated as IU/mL.
Time frame: Baseline, Week 26
Population: The FAS included all enrolled participants who received any study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Change From Baseline in Total Complement Hemolytic Activity Assay (CH50) at Week 26 | -236.6 IU/mL | Standard Error 0.65 |
Secondary
Number of Participants With Clinically Meaningful Changes in 12-lead Electrocardiograms (ECGs)
12-lead ECGs were evaluated. Any change in ECG assessments which are deemed clinically meaningful by the investigator were reported.
Time frame: Baseline up to Week 26
Population: The SAF included all enrolled participants who received any study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| REGN3918 | Number of Participants With Clinically Meaningful Changes in 12-lead Electrocardiograms (ECGs) | 0 Participants |
Secondary
Number of Participants With Clinically Meaningful Changes in Clinical Laboratory Parameters
Clinical laboratory parameters included biochemistry, hematology and urinalysis. Number of participants with potential clinically significant changes in laboratory parameters which were deemed clinically meaningful by the investigator were reported.
Time frame: Baseline up to Week 26
Population: The SAF included all enrolled participants who received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| REGN3918 | Number of Participants With Clinically Meaningful Changes in Clinical Laboratory Parameters | Hematology | 13 Participants |
| REGN3918 | Number of Participants With Clinically Meaningful Changes in Clinical Laboratory Parameters | Chemistry | 17 Participants |
| REGN3918 | Number of Participants With Clinically Meaningful Changes in Clinical Laboratory Parameters | Urinalysis | 0 Participants |
Secondary
Number of Participants With Clinically Meaningful Changes in Vital Signs
Vital sign assessments included pulse rate, blood pressure (systolic and diastolic blood pressure) and body temperature. Number of participants with potential clinically meaningful changes in vital signs which were deemed clinically significant by the investigator were reported.
Time frame: Baseline up to Week 26
Population: The SAF included all enrolled participants who received any study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| REGN3918 | Number of Participants With Clinically Meaningful Changes in Vital Signs | 12 Participants |
Secondary
Number of Participants With TEAEs Based on Severity
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Severity of AEs was graded according to the following scale, Mild: event that does not generally interfere with usual activities of daily living; Moderate: event that interferes with usual activities of daily living, causing discomfort, permanent risk of harm; Severe: AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention.
Time frame: Baseline up to Week 26
Population: The SAF included all enrolled participants who received any study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| REGN3918 | Number of Participants With TEAEs Based on Severity | Participants with Mild TEAEs | 13 Participants |
| REGN3918 | Number of Participants With TEAEs Based on Severity | Participants with Moderate TEAEs | 6 Participants |
| REGN3918 | Number of Participants With TEAEs Based on Severity | Participants with Severe TEAEs | 2 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs was defined as AEs that developed or worsened during the on-treatment period. SAE was defined as any untoward medical occurrence that resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time frame: Baseline up to Week 26
Population: The SAF included all enrolled participants who received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| REGN3918 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 21 Participants |
| REGN3918 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Anti-Drug Antibodies (ADA) Response to REGN3918
Number of Participants with treatment-emergent ADA response to REGN3918 was reported.
Time frame: Baseline up to Week 26
Population: The ADA analysis set (AAS) included all participants who received any study drug and who had at least 1 non-missing ADA result from the REGN3918 ADA assay after the first dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| REGN3918 | Number of Participants With Treatment-emergent Anti-Drug Antibodies (ADA) Response to REGN3918 | 0 Participants |
Secondary
Number of Units of Transfusion With RBCs
Transfusions with RBCs proceeded according to the following predefined criteria that triggered a transfusion; however, the actual number of units to be transfused is at the discretion of the investigator: • Transfuse with RBC(s) if the post-baseline hemoglobin level is \<9 g/dL with symptoms resulting from anemia or • Transfuse with RBC(s) if the post-baseline hemoglobin level is \<7 g/dL.
Time frame: Baseline up to Week 26
Population: As per changes in planned analysis, the sponsor made an administrative decision to close enrollment for this study due to a change in the clinical development program. The sample size was determined to be too small and the decision was made to not analyze the outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Number of Units of Transfusion With RBCs | 3.625 Number of units of transfusions of RBC | Standard Deviation 4.274 |
Secondary
Percentage of Days With LDH ≤ 1.5 ULN From Week 4 Through Week 26
Percentage of days was calculated as number of days with LDH ≤ 1.5 x ULN divided by the participant's total treatment duration (total number of days on treatment from Week 4 through Week 26). LDH ≤ 1.5 x ULN was used as an indicator of adequate control of intravascular hemolysis.
Time frame: Week 4 through Week 26
Population: The FAS included all enrolled participants who received any study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Percentage of Days With LDH ≤ 1.5 ULN From Week 4 Through Week 26 | 93.4 Percentage of Days | Standard Deviation 18.76 |
Secondary
Percentage of Participants Who Achieved Normalization of Intravascular Hemolysis
A participant was considered to have achieved normalization of intravascular hemolysis if their LDH readings between Week 4 through Week 26 inclusive had values ≤ 1.0 ULN. A participant must have ≥ 50% of scheduled LDH measures in those weeks, must not have had \> 2 consecutive visits without LDH measures, must not have experienced breakthrough hemolysis, and must not have discontinued study treatment early. A participant was considered not to have achieved normalization of intravascular hemolysis if they failed any of these criteria.
Time frame: Week 4 through Week 26
Population: The FAS included all enrolled participants who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN3918 | Percentage of Participants Who Achieved Normalization of Intravascular Hemolysis | 16.7 Percentage of Participants |
Secondary
Percentage of Participants Who Had Breakthrough Hemolysis (BTH)
Breakthrough hemolysis was defined as the measurement of LDH ≥ 2 ULN concomitant with associated signs or symptoms at any time subsequent to an initial achievement of disease control (i.e., LDH ≤ 1.5 ULN).
Time frame: Baseline up to 26 Weeks
Population: The FAS included all enrolled participants who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN3918 | Percentage of Participants Who Had Breakthrough Hemolysis (BTH) | 0 Percentage of Participants |
Secondary
Percent Change From Baseline in CH50 up to Week 26
Percent change from baseline in CH50 up to Week 26 was reported.
Time frame: Baseline up to Week 26
Population: The FAS included all enrolled participants who received any study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Percent Change From Baseline in CH50 up to Week 26 | -99.99 Percent Change | Standard Error 0.243 |
Secondary
Percent Change From Baseline in LDH Levels at Week 26
Percent change from baseline in LDH levels at Week 26 was reported.
Time frame: Baseline, Week 26
Population: The FAS included all enrolled participants who received any study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Percent Change From Baseline in LDH Levels at Week 26 | -81.72 Percent Change | Standard Error 1.847 |
Secondary
Rate of Transfusion With Red Blood Cells (RBCs)
The rate of transfusion with RBCs for a participant was the total number of transfusions divided by total person-years of time on treatment.
Time frame: Baseline up to Week 26
Population: The FAS included all enrolled participants who received any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| REGN3918 | Rate of Transfusion With Red Blood Cells (RBCs) | 1.039 Infusions Per Participant Year |
Secondary
Serum Concentrations of Total REGN3918
Serum Concentrations of total REGN3918 was reported.
Time frame: Pre-dose (Day 0), End of infusion at Days 0, 2, 7, 28, 56, 84, 112, 140, and 182
Population: The pharmacokinetic (PK) analysis set includes all participants who received any study drug and who had at least 1 non-missing result for concentration of REGN3918 following the first dose of study drug. Participants will be analyzed according to the treatment actually received. Here, Number analyzed signifies those participants who were evaluable at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 140 (End of Infusion) | 430 Milligram/liter (mg/L) | Standard Deviation 225 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 0 (Pre-dose) | 0 Milligram/liter (mg/L) | Standard Deviation 0 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 0 (End of Infusion) | 605 Milligram/liter (mg/L) | Standard Deviation 214 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 2 (End of Infusion) | 429 Milligram/liter (mg/L) | Standard Deviation 159 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 7 (End of Infusion) | 292 Milligram/liter (mg/L) | Standard Deviation 80.5 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 28 (End of Infusion) | 324 Milligram/liter (mg/L) | Standard Deviation 97.5 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 56 (End of Infusion) | 368 Milligram/liter (mg/L) | Standard Deviation 148 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 84 (End of Infusion) | 363 Milligram/liter (mg/L) | Standard Deviation 152 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 112 (End of Infusion) | 379 Milligram/liter (mg/L) | Standard Deviation 186 |
| REGN3918 | Serum Concentrations of Total REGN3918 | At Day 182 (End of Infusion) | 435 Milligram/liter (mg/L) | Standard Deviation 221 |
Secondary
Time to First Lactate Dehydrogenase (LDH) ≤1.5 x ULN
A time-to-first-event analysis was used to estimate the proportion of participants achieving transfusion avoidance at Week 26.
Time frame: Up to Week 26
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| REGN3918 | Time to First Lactate Dehydrogenase (LDH) ≤1.5 x ULN | 13.625 Days | Standard Deviation 3.6927 |