LR769 in Congenital Hemophilia Patients With Inhibitors Undergoing Elective Surgery or Invasive Procedures (PerSept3)

• ClinicalTrials.gov Identifier: NCT02548143
• Recruitment Status: Completed
• First Posted: September 14, 2015
• Results First Posted: September 6, 2019
• Last Update Posted: February 25, 2022
• Sponsor: Laboratoire français de Fractionnement et de Biotechnologies
• Collaborator: LFB USA, Inc.
• Information provided by (Responsible Party): Laboratoire français de Fractionnement et de Biotechnologies

Tracking Information

• First Submitted Date: September 9, 2015
• First Posted Date: September 14, 2015
• Results First Submitted Date: August 13, 2019
• Results First Posted Date: September 6, 2019
• Last Update Posted Date: February 25, 2022
• Actual Study Start Date: August 25, 2016
• Actual Primary Completion Date: August 6, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 6, 2020)

Percentage of Surgical or Other Invasive Procedures Defined as "Good" or "Excellent" Response to LR769 Treatment as Assessed by the Investigator, Based on the Totality of the Assessments Performed on the Patient [ Time Frame: 48 (±4) hours after the last administration of LR769 ]

The final assessment was performed by the investigator at the study center 48 hours after the last dose of LR769 and was based upon the totality of the assessments performed on the patient at each time point. Excellent: postoperative blood loss similar to or less than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure; no blood component transfusion is required. Good: postoperative blood loss greater, but not substantially greater than expected, following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure, not explained by a surgical/medical issue other than hemophilia; no unexpected need for blood component transfusion.

Original Primary Outcome Measures (submitted: September 11, 2015)

Percentage of surgical or other invasive procedures with a "good" or "excellent" response to LR769 treatment [ Time Frame: 48 (±4) hours after the last administration of LR769 ]

Excellent: postoperative blood loss similar to or less than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure Good: postoperative blood loss greater, but not substantially greater than expected, following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure, not explained by a surgical/medical issue other than hemophilia; no unexpected need for blood component transfusion

Current Secondary Outcome Measures (submitted: August 13, 2019)

• Percentages of Success as Defined as the Combination of "Good" and "Excellent" Responses by the Investigator or Designee [ Time Frame: 24 hours after procedure completion ]
  Good: postoperative blood loss greater than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure, not explained by a surgical/medical issue other than hemophilia; no unexpected need for blood component transfusion Excellent: postoperative blood loss similar to or less than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure; no blood component transfusion is required
• Percentages of Success as Defined as the Combination of "Good" and "Excellent" Responses by the Investigator or Designee [ Time Frame: 72 hours after procedure completion ]
  Good: postoperative blood loss greater than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure, not explained by a surgical/medical issue other than hemophilia; no unexpected need for blood component transfusion Excellent: postoperative blood loss similar to or less than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure; no blood component transfusion is required

Original Secondary Outcome Measures (submitted: September 11, 2015)

• Percentages of success as defined as the combination of "good" and "excellent" responses by the investigator or designee [ Time Frame: Immediately post operative to 48(±4) after the last administration of LR769 average time 5 weeks ]
  Good: postoperative blood loss greater than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure, not explained by a surgical/medical issue other than hemophilia; no unexpected need for blood component transfusion Excellent: postoperative blood loss similar to or less than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure
• Percentages of "poor," "moderate," "good," and "excellent" response by the investigator or designee [ Time Frame: Immediately post operative to 48(±4) after the last administration of LR769 average time 5 weeks ]
  Poor: uncontrolled postoperative blood loss, not explained by a surgical/medical issue other than hemophilia that requires intervention (rescue therapy requirement (bypass agent or porcine FVIII), and/or increased blood component (>2 fold greater than expected) transfusion, and/or leads to hypotension or unexpected transfer to Intensive Care Unit Moderate: postoperative blood loss that is substantially greater than expected following this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure, not explained by a surgical/medical issue other than hemophilia; additional blood component [within 2 fold greater than expected] transfusion is necessary
• Percentages of success as defined as the combination of "good" and "excellent" responses by the surgeon /practitioner [ Time Frame: Intraoperative period ]
  Excellent: intraoperative blood loss similar to or less than expected for this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure Good: intraoperative blood loss that is greater than expected (but not more than 50% greater) for this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure; no unexpected increased blood component transfusion requirement
• Percentages of "poor," "moderate," "good," and "excellent" response by the surgeon/practitioner [ Time Frame: Intraoperative period ]
  Poor: uncontrolled intraoperative blood loss, not explained by a surgical/medical issue other than hemophilia, that requires intervention (rescue therapy requirement (bypass agent or porcine FVIII), and/or increased blood component (>2 fold greater than expected) transfusion, and/or leads to hypotension or unexpected transfer to Intensive Care Unit [ICU]) Moderate: intraoperative blood loss that is substantially greater than expected (more than 50% greater) for this type of procedure in a patient who does not have a bleeding disorder and who is undergoing the same surgical or other invasive procedure, not explained by a surgical/medical issue other than hemophilia; additional blood component (within 2 fold greater than expected) transfusion is necessary
• Intraoperative blood loss [ Time Frame: Intraoperative period ]
  The maximum expected volume of blood loss and the estimated volume of blood loss during the procedure will be recorded.
• Number of events requiring transfusion [ Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769 average time 5 weeks ]
• Changes in hemoglobin [ Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769 average time 5 weeks ]
• Amount of LR769 used [ Time Frame: Intraoperative period to last dose of LR769 average time 5 weeks ]
  Total, and separated by use in hospital, at home, or for specific reasons (eg, physical therapy, or other reasons like drain or suture removal)
• Number and type of bleeding episodes at the surgical site [ Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769 average time 5 weeks ]
• Number of surgical interventions/re-explorations for bleeding episodes [ Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769 average time 5 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: September 11, 2015)

• Analysis (including relationship to LR769, severity , and outcome) of adverse events (AE) and serious adverse events (SAE) [ Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769 average time 5 weeks ]
• Analysis of treatment-emergent thromboembolic events [ Time Frame: Post operative period to 28 (±3) hours after last administration of LR769 average time 9 weeks ]
• Analysis of allergic and anaphylactic reactions [ Time Frame: Intraoperative period to 48 (±4) hours after last administration of LR769 average time 5 weeks ]
• Analysis of treatment-emergent antibodies against LR769 or host-related impurities [ Time Frame: Intraoperative period to 28 (±3) hours after last administration of LR769 average time 9 weeks ]

Descriptive Information

• Brief Title: LR769 in Congenital Hemophilia Patients With Inhibitors Undergoing Elective Surgery or Invasive Procedures
• Official Title: Phase 3 Study of Safety and Efficacy of Coagulation Factor VIIa (Recombinant) for Prevention of Excessive Bleeding in Congenital Hemophilia A/B Patients With Inhibitors to Factor VIII/IX Undergoing Elective Surgery/Other Invasive Procedures
• Brief Summary: The purpose of this study, PerSept 3, is to evaluate LR769 for the prevention of excessive bleeding and achievement of hemostasis in congenital hemophilia A or B patients who have inhibitors to Factor VIII or Factor IX , are aged 6 months to 75 years, inclusive; and who are undergoing elective surgical or other invasive procedures. Administration of LR769 will be performed just prior to surgery/procedure and will be repeated during and after the surgery/procedure to achieve and maintain adequate hemostasis as determined by the investigator's judgment.

Detailed Description

This study is an international, multicenter, single-arm, Phase 3 study. Patients aged 6 months to 75 years, inclusive, who have congenital hemophilia A or B with inhibitors to Factor VIII or Factor IX and who are scheduled for an elective surgical or other invasive procedure will be enrolled. Both major and minor surgical or other invasive procedures are allowed in the study.

Initial Treatment: Regardless of procedure, patients who meet all eligibility criteria will receive an initial intravenous (IV) bolus dose of LR769 within ≤2 minutes before the surgical incision or start of the invasive procedure. For a minor elective surgery or other minor invasive procedure, a dose of 75 μg/kg will be used as the initial dose; for a major elective surgery or other major invasive procedure, a dose of 200 μg/kg of LR769 will be used as the initial dose. For both minor and major procedures, administration will be repeated no more frequently than every 2 hours (±5 minutes) at a dose of 75 μg/kg during and after surgery or invasive procedure.

Treatment for Major Surgical Procedures: The initial dose of LR769 will be followed by repeated administration of 75 µg/kg of LR769 every 2 hours (±5 minutes) for the first 48 hours after completion of the procedure. The minimum duration of LR769 treatment for major procedures will be 5 days and dosing frequency will be followed according to the guidelines specified in the protocol.

Treatment for Minor Surgical or Other Invasive Procedures: The initial dose of LR769 will be followed by repeated administration of 75 µg/kg of LR769 every 2 hours (±5 minutes) for the first 48 hours. The minimum duration of LR769 infusion for minor procedures will be 2 days, except for certain procedures that may not require this duration of treatment to achieve hemostasis as noted in the protocol. Dosing frequency will be according to the guidelines specified in protocol for minor surgical or other invasive procedures.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemophilia

Intervention

Biological: Coagulation Factor VIIa (Recombinant)

LR769

Study Arms

Experimental: Coagulation Factor VIIa (Recombinant)

A dose of 75 μg/kg (minor surgery or invasive procedure) or 200 μg/kg (major surgery or major invasive procedure) of LR769 will be administered as an initial intravenous (IV) bolus dose of LR769 within ≤2 minutes before the surgical incision or start of the invasive procedure. For both minor and major procedures, the initial dose will be followed by repeated administration of 75 µg/kg of LR769 every 2 hours (±5 minutes) for the first 48 hours after completion of the procedure and then as per the dosing schedules in the protocol for major or minor surgeries or invasive procedures. The minimum duration of LR769 treatment for major procedures will be 5 days, and for minor procedures 2 days except for certain procedures that may not require this duration of treatment.

Intervention: Biological: Coagulation Factor VIIa (Recombinant)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 11, 2015): 12
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 31, 2017
• Actual Primary Completion Date: August 6, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in this study:

1. be male with a diagnosis of congenital hemophilia A or B of any severity

2. have one of the following:

   1. a positive inhibitor test Bethesda Unit (BU) ≥5 (as confirmed at screening by the institutional lab), OR
   2. a BU <5 but expected to have a high anamnestic response to FVIII or FIX, as demonstrated from the patient's medical history, precluding the use of FVIII or FIX products to treat or prevent bleeding, OR
   3. a BU <5 but expected to be refractory to increased dosing of FVIII or FIX, as demonstrated from the patient's medical history, precluding the use of FVIII or FIX products to treat or prevent bleeding episodes
3. be ≥6 months to ≤75 years of age; different age restrictions may apply per local regulation and ethical considerations (enrollment of children <12 years of age will not begin until after review of data from the PERSEPT 2 study by the DMC)
4. be scheduled for an elective surgical or other invasive procedure
5. be capable of understanding and willing to comply with the conditions of the protocol OR in the case of a patient <18 years of age, parent(s)/legal guardian(s) must be capable of understanding and willing to comply with the conditions of the protocol
6. have read, understood, and provided written Informed Consent (patient and/or parent(s)/legal guardian(s) if the patient is <18 years of age) or Assent, if applicable

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study:

1. have any coagulation disorder other than hemophilia A or B
2. be immunosuppressed (ie, the patient should not be receiving systemic immunosuppressive medication; cluster of differentiation 4 (CD4) counts at screening should be >200/µL)
3. known intolerance to LR769 or any of its excipients
4. currently receiving immune tolerance induction (ITI) therapy
5. have a known allergy or hypersensitivity to rabbits
6. have a platelet count<100,000/µL
7. have received an investigational drug within 30 days of the planned first LR769 administration , or is expected to receive such drug during participation in this study (with the exception of patients who are or were participating in another LR769 study, eg, a study assessing the treatment of bleeding episodes with LR769)
8. have a clinically relevant hepatic (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN)) and/or renal impairment (creatinine >2 times the ULN)
9. have a history of arterial and/or venous thromboembolic events (such as myocardial infarction, ischemic strokes, transient ischemic attacks, deep venous thrombosis (DVT) or pulmonary embolism (PE)) within 2 years prior to the planned first dose of LR769, uncontrolled arrhythmia, or current New York Heart Association (NYHA) functional classification score of stages II - IV
10. have an active malignancy (those with non-melanoma skin cancer are allowed)
11. have any life-threatening disease or other disease or condition which, according to the investigator's judgment, could imply a potential hazard to the patient, or interfere with the trial participation or trial outcome (eg, a history of non-responsiveness to bypassing products)
12. be using aspirin, NSAIDS, herbs, natural medications, or other drugs with platelet inhibitory properties within one week prior to surgery and for the duration of treatment with LR769
13. have active gastric or duodenal ulcer disease

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 6 Months to 75 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Mexico, Russian Federation, South Africa, Spain, Ukraine, United States

Administrative Information

• NCT Number: NCT02548143
• Other Study ID Numbers: LFB-FVIIa-008-14
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Laboratoire français de Fractionnement et de Biotechnologies
• Original Responsible Party: rEVO Biologics
• Current Study Sponsor: Laboratoire français de Fractionnement et de Biotechnologies
• Original Study Sponsor: rEVO Biologics
• Collaborators: LFB USA, Inc.

Investigators

• Principal Investigator: Miguel Escobar, MD; Memorial Hermann Texas Medical Center

• PRS Account: Laboratoire français de Fractionnement et de Biotechnologies
• Verification Date: February 2022