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Study to Evaluate the Efficacy and Safety of REGN3918 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

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ClinicalTrials.gov Identifier: NCT03946748
Recruitment Status : Recruiting
First Posted : May 13, 2019
Last Update Posted : June 13, 2019
Sponsor:
Information provided by (Responsible Party):
Regeneron Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE May 8, 2019
First Posted Date  ICMJE May 13, 2019
Last Update Posted Date June 13, 2019
Actual Study Start Date  ICMJE May 16, 2019
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
  • Proportion of patients achieving adequate control of their intravascular hemolysis [ Time Frame: Week 4 through week 26 ]
    Defined as lactate dehydrogenase (LDH) ≤ 1.5 x upper limit of normal (ULN)
  • Proportion of patients achieving transfusion avoidance [ Time Frame: Up to 26 weeks ]
    Defined as no post baseline transfusion of red blood cells (RBCs)
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03946748 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2019)
  • Rate of breakthrough hemolysis [ Time Frame: Up to 26 Weeks ]
    Defined as the measurement of LDH) ≥ 2 x ULN concomitant with associated signs or symptoms at any time subsequent to an initial achievement of disease control.
  • Proportion of patients achieving normalization of their intravascular hemolysis [ Time Frame: Week 4 through week 26 ]
    Defined as LDH ≤ 1.0 x ULN
  • Time to first LDH ≤ 1.5 x ULN [ Time Frame: Up to week 26 ]
  • Percentage of days with LDH ≤ 1.5 x ULN [ Time Frame: Week 4 through week 26 ]
  • Change in LDH levels [ Time Frame: Baseline to week 26 ]
  • Percent change in LDH levels [ Time Frame: Baseline to week 26 ]
  • Rate of transfusion with RBCs [ Time Frame: Up to 26 weeks ]
  • Number of units of transfusion with RBCs [ Time Frame: Up to 26 weeks ]
  • Change in RBC hemoglobin levels [ Time Frame: Baseline to week 26 ]
  • Change in free hemoglobin levels [ Time Frame: Baseline to week 26 ]
  • Change in total complement hemolytic activity assay (CH50) [ Time Frame: Baseline to week 26 ]
  • Percent change in CH50 [ Time Frame: Baseline to week 26 ]
  • Changes in scores of patient-reported outcomes as measured by FACIT-Fatigue [ Time Frame: Baseline to week 26 ]
    The FACIT-F is 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 is part of the FACIT measurement system, a compilation of questions measuring health-related QoL in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a 4-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue.
  • Changes in scores of patient-reported outcomes as measured by European Cooperative Oncology Group [EORTC]- Quality of life questionnaire-core 30 (QLQ-30) [ Time Frame: Baseline to week 26 ]
    EORTC QLQ-C30 is a self-reported, 30-item generic questionnaire developed to assess 15 domains: global health status scale, five functional scales (physical, role, emotional, cognitive, and social functioning) and nine symptom scales (fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All the scales range from 0 to 100. A high score on the functional scales represents a high level of functioning, and a high score on the symptom scales represents a high level of symptomatology. A high score on the global QOL represents a high general quality of life.
  • Changes in scores of patient-reported outcomes as measured by EQ-5D-3L [ Time Frame: Baseline to week 26 ]
    The EQ-5D-3L is a self-administered standardized instrument for use as a measure of health outcome. It is a health questionnaire that consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems.
  • Incidence and severity of treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 26 weeks ]
  • Safety measured by number of patients who experience abnormal laboratory values [ Time Frame: Up to 26 weeks ]
  • Safety measured by number of patients who experience abnormal vital signs [ Time Frame: Up to 26 weeks ]
  • Concentrations of total REGN3918 in serum [ Time Frame: Up to week 26 ]
  • Incidence of treatment-emergent anti-drug antibodies to REGN3918 [ Time Frame: Up to week 26 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
  • Rate of breakthrough hemolysis [ Time Frame: Up to 26 Weeks ]
    Defined as the measurement of LDH) ≥ 2 x ULN concomitant with associated signs or symptoms at any time subsequent to an initial achievement of disease control.
  • Proportion of patients achieving normalization of their intravascular hemolysis [ Time Frame: Week 4 through week 26 ]
    Defined as LDH ≤ 1.0 x ULN
  • Time to first LDH ≤ 1.5 x ULN [ Time Frame: Up to week 26 ]
  • Percentage of days with LDH ≤ 1.5 x ULN [ Time Frame: Week 4 through week 26 ]
  • Change in LDH levels [ Time Frame: Baseline to week 26 ]
  • Percent change in LDH levels [ Time Frame: Baseline to week 26 ]
  • Rate of transfusion with RBCs [ Time Frame: Up to 26 weeks ]
  • Number of units of transfusion with RBCs [ Time Frame: Up to 26 weeks ]
  • Change in RBC hemoglobin levels [ Time Frame: Baseline to week 26 ]
  • Change in free hemoglobin levels [ Time Frame: Baseline to week 26 ]
  • Change in total complement hemolytic activity assay (CH50) [ Time Frame: Baseline to week 26 ]
  • Percent change in CH50 [ Time Frame: Baseline to week 26 ]
  • Changes in scores of patient-reported outcomes as measured by FACIT-Fatigue [ Time Frame: Baseline to week 26 ]
    The FACIT-F is 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 is part of the FACIT measurement system, a compilation of questions measuring health-related QoL in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a 4-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue.
  • Changes in scores of patient-reported outcomes as measured by European Cooperative Oncology Group [EORTC]-QLQ-30 [ Time Frame: Baseline to week 26 ]
    EORTC QLQ-C30 is a self-reported, 30-item generic questionnaire developed to assess 15 domains: global health status scale, five functional scales (physical, role, emotional, cognitive, and social functioning) and nine symptom scales (fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties).
  • Changes in scores of patient-reported outcomes as measured by EQ-5D-3L [ Time Frame: Baseline to week 26 ]
    The EQ-5D-3L is a self-administered standardized instrument for use as a measure of health outcome. It is a health questionnaire that consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems.
  • Incidence and severity of treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 26 weeks ]
  • Safety measured by number of patients who experience abnormal laboratory values [ Time Frame: Up to 26 weeks ]
  • Safety measured by number of patients who experience abnormal vital signs [ Time Frame: Up to 26 weeks ]
  • Concentrations of total REGN3918 in serum [ Time Frame: Up to week 26 ]
  • Incidence of treatment-emergent anti-drug antibodies to REGN3918 [ Time Frame: Up to week 26 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate the Efficacy and Safety of REGN3918 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Official Title  ICMJE 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
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.
  • To evaluate the effect of REGN3918 on patient-reported outcomes (PROs) measuring fatigue and health-related quality of life
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Paroxysmal Nocturnal Hemoglobinuria (PNH)
Intervention  ICMJE Drug: REGN3918
Single intravenous (IV) dose, then a subcutaneous (SC) dose once weekly (QW).
Study Arms  ICMJE Experimental: REGN3918

Cohort A (Dose Confirmation) If a decision is made to expand Cohort A, patients will be assigned to Cohort A.

Cohort B (Dose Expansion) If a decision is made to progress to Cohort B, patients will be assigned to Cohort B.

Intervention: Drug: REGN3918
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 8, 2019)
42
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 21, 2021
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) confirmed by high-sensitivity flow cytometry
  • Type III 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) <1,000/μL [<1.0 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/Exclusion criteria apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Clinical Trials Administrator 844-734-6643 clinicaltrials@regeneron.com
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03946748
Other Study ID Numbers  ICMJE R3918-PNH-1852
2018-002734-20 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Individual anonymized participant data will be considered for sharing once the indication has been approved by a regulatory body, if there is legal authority to share the data and there is not a reasonable likelihood of participant re-identification.
Access Criteria: Qualified researchers may request access to anonymized patient level data or aggregate study data when Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency [EMA], Pharmaceuticals and Medical Devices Agency [PMDA], etc) for the product and indication, has the legal authority to share the data, and has made the study results publicly available (eg, scientific publication, scientific conference, clinical trial registry).
URL: https://errs.regeneron.com/external
Responsible Party Regeneron Pharmaceuticals
Study Sponsor  ICMJE Regeneron Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trial Management Regeneron Pharmaceuticals
PRS Account Regeneron Pharmaceuticals
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP