NCT03361137

Study of Emicizumab Prophylaxis in Participants With Hemophilia A With or Without Inhibitors Undergoing Minor Surgical Procedures

Terminated Phase 4 Results posted Last updated 1 March 2021

What this trial tests

Phase 4 trial testing Emicizumab in Hemophilia A in 14 participants. Terminated before completion.

Timeline

28 June 2018

Primary endpoint
13 March 2020

13 March 2020

Quick facts

Lead sponsor	Genentech, Inc.
Phase	Phase 4
Status	Terminated
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	14
Start date	28 June 2018
Primary completion	13 March 2020
Estimated completion	13 March 2020
Sites	8 locations across United States

Drugs / interventions tested

• Emicizumab (EMICIZUMAB) — full drug profile →

Conditions studied

• Hemophilia A — all drugs for Hemophilia A →

Sponsor

Genentech, Inc. — full company profile →

Who can join

Eligibility, any sex, with Hemophilia A. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants Without Excessive Bleeding at Surgical Sites and Did Not Require BPA/FVIII Use for Bleeding Related to the Surgery, From the Start of Surgery Until Discharge, as Measured by the ISTH Hemostatic Efficacy Scale Primary · Determined at the time of discharge (within approximately 48 hours after surgery)

The International Society on Thrombosis and Haemostasis (ISTH) Assessment of Hemostatic Response for Surgical Procedures scale (see reference PubMed ID:25059285) has four categories, listed here in order of best to worst response: Excellent, Good, Fair, and Poor. The participant's bleeding related to surgery was evaluated by the healthcare professional who performed the procedure using the hemostatic efficacy scale, with an absence of excessive bleeding at the surgical site indicated by a good to excellent rating. The endpoint was met when the response to "Intraoperative and/or postoperative b

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	66.7
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	100.0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	100.0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	100.0

Percentage of Participants With Excessive Bleeding at Surgical Sites and Required BPA/FVIII Use for Treating Bleeding Related to the Surgery, From the Start of Surgery Until Discharge, as Measured by the ISTH Hemostatic Efficacy Scale Primary · Determined at the time of discharge (within approximately 48 hours after surgery)

The ISTH Assessment of Hemostatic Response for Surgical Procedures scale (see reference PubMed ID:25059285) has four categories, listed here in order of best to worst response: Excellent, Good, Fair, and Poor. The participant's bleeding related to surgery was evaluated by the healthcare professional who performed the procedure using the hemostatic efficacy scale, with excessive bleeding at the surgical site indicated by a fair to poor rating. The endpoint was met when the response to "Intraoperative and/or postoperative blood loss increased over expectation for the non-hemophilic patient deter

Total with Excessive Bleeding and Received BPA/FVIII

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	11.1
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0

Treated with 2 mg rFVIIa

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	11.1
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0

Percentage of Participants Who, After Being Discharged From Surgery, Experienced Bleeds That Were Either Related or Unrelated to Surgery and Also Required BPA/FVIII Use Primary · Within 48 hours (if discharged home), and 8 and 28 days after surgery

Post-surgical bleeding information was self-reported by participants (or the participant's legally authorized representative) on the "Bleed and Medication Diary". Bypassing agents (BPAs)/factor VIII (FVIII) used to treat excessive bleeding were also self-reported by participants if it was self-administered. BPAs/FVIII administered by the investigators to treat the bleeding were reported on the "Concomitant Medications" case report form page. The percentage of participants by type and dose of BPA/FVIII used to treat the bleeding is also reported. rFVIIa = recombinant activated human factor VII

Total with Post-surgical Bleeding and Received BPA/FVIII

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	22.2
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	100.0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0

Treated with 2 mg rFVIIa

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	11.1
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	100.0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0

Treated with 5 mg rFVIIa

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	11.1
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0

Emicizumab Plasma Concentration on the Day of Surgery Primary · Approximately 24 hours prior to surgery

Enrolled participants received a minimum of four loading doses of emicizumab prior to their surgical procedure. Pharmacokinetic blood samples were obtained at study sites 24 hours before the procedures in order to describe emicizumab plasma concentration on the day of surgery for each of the inhibitor and non-inhibitor cohorts.

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: All Surgery Cohorts	53.74	± 28.67
PwHA Without Inhibitors, Emicizumab: All Surgery Cohorts	38.40	± 8.95

Safety Summary of the Number of Participants With at Least One Adverse Event Primary · From Baseline up to 30 days after surgery

All adverse events (AEs) that occurred after informed consent was obtained were coded using the Medical Dictionary for Regulatory Activities (MedDRA) v23.0, summarized by severity according to the World Health Organization (WHO) toxicity grading scale (Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death related to AE), and tabulated by body system and preferred term (PT) for individual events within each system organ class (SOC). For each AE, the investigator independently assessed its severity and seriousness, and whether it was considere

Any Adverse Event (AE)

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort	1
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	4
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0

AE with Fatal Outcome

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort	0
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0

Serious Adverse Event (SAE)

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort	0
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0

SAE Leading to Withdrawal from Treatment

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort	0
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0

SAE Leading to Dose Modification/Interruption

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort	0
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0

Related SAE

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort	0
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0

AE Leading to Withdrawal from Treatment

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort	0
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0

AE Leading to Dose Modification/Interruption

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort	0
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0

Percentage of Participants With Surgical Complications Requiring Hospitalization or Return to Surgery Primary · Within 48 hours after surgery, and 8 and 28 days after initial surgery

This safety endpoint was a composite endpoint. Surgical complications were entered as adverse events on the case report form page with "Other suspected causes" marked as "Study Surgery or Procedure". This endpoint was met when response to "It required or prolonged inpatient hospitalization" was checked OR response to "Was procedure/surgery performed?" was "Yes".

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0

Percentage of Participants Who Needed Blood/Blood Product Transfusions During Surgery Primary · Within 48 hours after surgery, and 8 and 28 days after initial surgery

The percentage of participants who needed blood or blood product transfusions (e.g., platelets, plasma, etc.) during surgery was evaluated.

Group	Value	95% CI
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort	0.0
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort	0.0

Adverse events — posted to ClinicalTrials.gov

Time frame: From Baseline up to 30 days after surgery. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort

Serious: 0/1 (0%)

Deaths: 0/1

PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort

Serious: 0/9 (0%)

Deaths: 0/9

PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort

Serious: 0/1 (0%)

Deaths: 0/1

PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort

Serious: 0/2 (0%)

Deaths: 0/2

PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort

Serious: 0/1 (0%)

Deaths: 0/1

Other adverse events (8 terms — click to expand)

Reaction	System	PwHA With Inhibitors, Emic…	PwHA With Inhibitors, Emic…	PwHA With Inhibitors, Emic…	PwHA Without Inhibitors, E…	PwHA Without Inhibitors, E…
Headache	Nervous system disorders	—	—	—	—	—
Limb injury	Injury, poisoning and procedural complications	—	—	—	—	—
Procedural pain	Injury, poisoning and procedural complications	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Device occlusion	Product Issues	—	—	—	—	—
Adhesiolysis	Surgical and medical procedures	—	—	—	—	—
Haematoma	Vascular disorders	—	—	—	—	—

Data from ClinicalTrials.gov NCT03361137 adverse events section.

Sponsor's own description

This Phase IV, multicenter study will evaluate whether participants with Hemophilia A (PwHA) with or without inhibitors receiving emicizumab prophylaxis can safely undergo minor surgical procedures without additional prophylactic bypassing agents (BPA; for participants with inhibitors) or factor VIII (FVIII; for participants without inhibitors).

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

1. The role of emicizumab, a bispecific factor IXa- and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A.
   Knight T, Callaghan MU. · · 2018 · cited 31× · PMID 30344994 · DOI 10.1177/2040620718799997
2. A phase IV, multicentre, open-label study of emicizumab prophylaxis in people with haemophilia A with or without FVIII inhibitors undergoing minor surgical procedures.
   Escobar M, Dunn A, Quon D, Trzaskoma B, et al · · 2022 · cited 7× · PMID 35510949 · DOI 10.1111/hae.14574
3. Navigating Speed Bumps on the Innovation Highway in Hemophilia Therapeutics.
   DiMichele DM. · · 2018 · cited 6× · PMID 30887008 · DOI 10.1097/hs9.0000000000000144