Clinical Trial Results:
An Open Label, Single Arm Study to Evaluate the Efficacy and Safety of REGN3918 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Are Complement Inhibitor Naive or Have Not Recently Received Complement Inhibitor Therapy
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Summary
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EudraCT number |
2018-002734-20 |
Trial protocol |
CZ GB HU NL IT |
Global end of trial date |
10 Jun 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Jun 2022
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First version publication date |
24 Jun 2022
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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 |
R3918-PNH-1852
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03946748 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Regeneron Pharmaceuticals, Inc.
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Sponsor organisation address |
777 Old Saw Mill River Rd., Tarrytown, United States, 10591
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Public contact |
Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.com
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Scientific contact |
Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.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 |
10 Jun 2021
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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 |
10 Jun 2021
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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 of the study was to demonstrate a reduction in intravascular hemolysis by REGN3918 over 26 weeks of treatment in subjects with active PNH who are treatment naive to complement inhibitor therapy or have not recently received complement inhibitor therapy.
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Protection of trial subjects |
It was the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
16 May 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
United Kingdom: 2
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Country: Number of subjects enrolled |
Hungary: 1
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Country: Number of subjects enrolled |
Hong Kong: 1
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Country: Number of subjects enrolled |
Korea, Republic of: 12
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Country: Number of subjects enrolled |
Malaysia: 4
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Country: Number of subjects enrolled |
Taiwan: 4
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Worldwide total number of subjects |
24
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EEA total number of subjects |
1
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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) |
20
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||
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Pre-assignment
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Screening details |
Sponsor made administrative decision to stop enrollment to pursue combination program of REGN3918 & cemdisiran for treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). Study not stopped due to safety concerns or lack of efficacy. 28 screened, 24 were enrolled & treated: 4 screen failures (1-Lost to follow-up, 1-did not meet criteria, 1-other). | ||||||
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Period 1
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Period 1 title |
Overall study (overall 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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REGN3918 | ||||||
Arm description |
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. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Pozelimab
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Investigational medicinal product code |
REGN3918
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
Participants received REGN3918 30 mg/kg IV infusion, followed by a maintenance regimen of 800 mg SC injection up to 26 weeks of treatment period.
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Baseline characteristics reporting groups
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Reporting group title |
Overall study
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Reporting group description |
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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
REGN3918
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Reporting group description |
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. | ||
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End point title |
Percentage of Participants Who Achieved Adequate Control of Intravascular Hemolysis [1] | ||||||||
End point description |
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 more than 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. Full analysis set (FAS) included all enrolled participants who received any study drug.
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End point type |
Primary
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End point timeframe |
Week 4 through Week 26
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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: Results were descriptively summarized. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Achieved Transfusion Avoidance [2] | ||||||||
End point description |
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 is per-protocol, that is, it follows 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). The FAS included all enrolled participants who received any study drug.
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End point type |
Primary
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End point timeframe |
Up to 26 Weeks
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| Notes [2] - 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: Results were descriptively summarized. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Had Breakthrough Hemolysis (BTH) | ||||||||
End point description |
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). The FAS included all enrolled subjects who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to 26 Weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Achieved Normalization of Intravascular Hemolysis | ||||||||
End point description |
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. The FAS included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Week 4 through Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to First Lactate Dehydrogenase (LDH) ≤ 1.5 x ULN | ||||||||
End point description |
A time-to-first-event analysis was used to estimate the proportion of participants achieving transfusion avoidance at week 26 and a 95% confidence interval. 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. Hence, this endpoint was not analyzed.
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End point type |
Secondary
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End point timeframe |
Up to Week 26
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| Notes [3] - Sponsor made administrative decision to close enrollment. Hence, this endpoint was not analyzed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Days With LDH ≤ 1.5 ULN From Week 4 Through Week 26 | ||||||||
End point description |
Percentage of days was calculated as number of days with LDH ≤ 1.5 x ULN divided by the participants' 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. The FAS included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Week 4 through Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in LDH Levels at Week 26 | ||||||||
End point description |
Change from baseline in LDH levels at Week 26 was reported. The FAS included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Percent Change From Baseline in LDH Levels at Week 26 | ||||||||
End point description |
Percent change from baseline in LDH levels at Week 26 was reported. The FAS included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Rate of Transfusion With Red Blood Cells (RBCs) | ||||||||
End point description |
The rate of transfusion with RBCs for a participant was the total number of transfusions divided by total person-years of time on treatment. The FAS included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Units of Transfusion With RBCs | ||||||||
End point description |
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. 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. Hence, this endpoint was not analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 26
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| Notes [4] - Sponsor made administrative decision to close enrollment. Hence, this endpoint was not analyzed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Free Hemoglobin Levels at Week 26 | ||||||||
End point description |
Change from baseline in free hemoglobin levels at Week 26 was assessed. The safety analysis set (SAF) included all enrolled participants who received any study drug. Here, “number of subjects analysed” signifies those participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in RBC Hemoglobin Levels at Week 26 | ||||||||
End point description |
Hemoglobin levels in participants with PNH was measured. Change from baseline in RBC hemoglobin at Week 26 was reported. The FAS included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Total Complement Hemolytic Activity Assay (CH50) at Week 26 | ||||||||
End point description |
Change from baseline in total CH50 at Week 26 was reported. Here “International units per milliliter” was abbreviated as “IU/mL”. The FAS included all enrolled participants who received any study drug. Here, “number of subjects analysed” signifies those participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Percent Change From Baseline in CH50 up to Week 26 | ||||||||||
End point description |
Percent change from baseline in CH50 up to Week 26 was reported. The FAS included all enrolled participants who received any study drug. Here, “number of subjects analysed” signifies those participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 26
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| No statistical analyses for this end point | |||||||||||
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End point title |
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 26 | ||||||||
End point description |
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. FAS population. Here, “number of subjects analyzed” signifies those participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
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 | ||||||||||||||||||||||||
End point description |
EORTC QLQ-C30 was a 30-item questionnaire used to assess symptoms & side effects of treatment. It consists of 15 domains: 5 multi-item functioning scales (physical, role, social, emotional & cognitive), answered on 4-point scale (1=Not at all,2=A Little,3=Quite a Bit,4=Very Much). Each score ranges: 0-100; higher score indicates higher level of functioning & better QoL. A global health status/QoL scale answered on 7-point scale (1=Very Poor to 7=Excellent). Each score ranges: 0-100; higher score indicates better QoL. 9 symptom scales (Fatigue, Nausea/Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact), answered on 4-point scale (1=Not at all, 2=A Little, 3=Quite a Bit, 4=Very Much). Each score ranges:0-100; higher score indicates higher level of symptoms, & negative change from baseline indicates an improvement in symptoms. FAS population. Here, “number of subjects analysed” signifies those participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline in European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Index Score at Week 26 | ||||||||
End point description |
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). FAS included all enrolled participants who received any study drug. Here, “number of subjects analysed” signifies those participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in EQ-5D-3L Visual Analogue Scale (VAS) at Week 26 | ||||||||
End point description |
The EQ-5D-3L was a standardized instrument for use as a measure of health outcome and was administered to all subjects 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. The FAS included all enrolled participants who received any study drug. Here, “number of subjects analysed” signifies those participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 26
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | ||||||||||
End point description |
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. The SAF included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 26
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Participants With TEAEs Based on Severity | ||||||||||||
End point description |
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. The SAF included all enrolled participants who received any study drug. Here, “number of subjects analysed” signifies those participants who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With Clinically Meaningful Changes in Clinical Laboratory Parameters | ||||||||||||
End point description |
Clinical laboratory parameters included biochemistry, hematology and urinalysis. Number of participants with potential clinically significant changes in laboratory parameters which were deemed clinically significant by the investigator were reported. The SAF included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 26
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With Clinically Meaningful Changes in Vital Signs | ||||||
End point description |
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. The SAF included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline Up to Week 26
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants With Clinically Meaningful Changes in 12-lead Electrocardiograms (ECGs) | ||||||
End point description |
12-lead ECGs were evaluated. Any change in ECG assessments which are deemed clinically significant by the investigator were reported. The FAS included all enrolled participants who received any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 26
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| No statistical analyses for this end point | |||||||
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End point title |
Serum Concentrations of Total REGN3918 | ||||||||||||||||||||||||||||
End point description |
Serum Concentrations of total REGN3918 was reported. 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, “n= number analysed” signifies those participants who were evaluable at the specified categories.
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End point type |
Secondary
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End point timeframe |
Pre-dose (Day 0), End of infusion at Days 0, 2, 7, 28, 56, 84, 112, 140, and 182
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Number of Participants With Treatment-emergent Anti-Drug Antibodies (ADA) Response to REGN3918 | ||||||
End point description |
Number of participants with treatment-emergent ADA response to REGN3918 was reported. 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.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 26
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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 |
From first dose to Week 26
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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 |
24.0
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Reporting groups
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Reporting group title |
REGN3918
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Reporting group description |
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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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21 Jun 2019 |
Protocol Amendment 2: Removed Sponsor as a responsible party in the confirmation of a breakthrough hemolysis event. Added language to clarify that blood collection should occur if a breakthrough hemolysis event is suspected. Updated the duration of the open-label extension study. Removed irrelevant information related to blinding for the interim analysis. This is an open-label study. Revised exclusion requirement for peripheral blood absolute neutrophil count to <500/μL. Revised description of PNH erythrocytes and granulocytes to reflect typical laboratory output for these analytes. Updated inclusion criterion #3 to specify PNH granulocytes that are denoted as polymorphonuclear (PMN). |
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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 | |||
