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Efficacy and Safety Study of Octafibrin for On-demand Treatment of Acute Bleeding and to Prevent Bleeding During and After Surgery

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ClinicalTrials.gov Identifier: NCT02267226
Recruitment Status : Completed
First Posted : October 17, 2014
Results First Posted : February 20, 2019
Last Update Posted : March 22, 2019
Sponsor:
Information provided by (Responsible Party):
Octapharma

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Congenital Fibrinogen Deficiency
Intervention Drug: Octafibrin
Enrollment 25
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Octafibrin
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Thirty-three patients were screened and 25 patients received at least one administration of Octafibrin for treatment of bleeding or as surgical prophylaxis. Eight patients received Octafibrin for both bleeding and a surgical procedure. One patient was treated for a surgical procedure only.

Octafibrin was individually dosed to achieve a recommended target plasma fibrinogen level of 100 mg/dL for minor bleeds/surgery or 150 mg/dL for major bleeds/surgery

Period Title: Overall Study
Started 25
SAFETY Population [1] 25
FAS-Bleeding Population [2] 24
Surgical Prophylaxis Population [3] 9
Completed 18
Not Completed 7
[1]
25 patients received at least one administration of Octafibrin.
[2]
Patients received Octafibrin for treatment of bleeding.
[3]
Patients received Octafibrin for surgical procedures.
Arm/Group Title SAFETY Population
Hide Arm/Group Description All patients who received at least one Octafibrin administration during the study.
Overall Number of Baseline Participants 25
Hide Baseline Analysis Population Description
All patients who received at least one Octafibrin administration during the study.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
<=18 years
6
  24.0%
Between 18 and 65 years
19
  76.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 25 participants
29.04  (12.95)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
Female
11
  44.0%
Male
14
  56.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
American Indian or Alaska Native
0
   0.0%
Asian
5
  20.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
19
  76.0%
More than one race
0
   0.0%
Unknown or Not Reported
1
   4.0%
1.Primary Outcome
Title Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient.
Time Frame 24 hours after last infusion for each bleeding episode
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[Not Specified]
Arm/Group Title Investigator Assessment IDMEAC Assessment
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Efficacy as assessed by the investigator
Efficacy as assessed by the IDMEAC
Overall Number of Participants Analyzed 24 24
Measure Type: Count of Participants
Unit of Measure: Participants
Excellent
19
  79.2%
23
  95.8%
Good
5
  20.8%
1
   4.2%
Moderate
0
   0.0%
0
   0.0%
None
0
   0.0%
0
   0.0%
Missing
0
   0.0%
0
   0.0%
Overall treatment success
24
 100.0%
24
 100.0%
2.Secondary Outcome
Title Maximum Clot Firmness (MCF) After Fibrinogen Infusion in Each Documented Bleeding Episode (BE), Measured in Frozen Plasma in a Central Laboratory.
Hide Description MCF (mm) was determined using ROTEM and was used as a surrogate marker for haemostatic efficacy. ROTEM is a method for the continuous measurement of clot formation and clot firmness. It utilises a mechanical detection system which is based on the ability of the blood or plasma clot to form a mechanical coupling over a distance of 1 mm.
Time Frame Before first infusion and 1 hour after end of first and last infusion of each documented bleeding episode
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[Not Specified]
Arm/Group Title FAS Bleeding
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FAS-Bleeding population (change from pre fibrinogen infusion)
Overall Number of Participants Analyzed 24
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes (BEs)
86
Mean (Standard Deviation)
Unit of Measure: mm
5.79  (2.53)
3.Secondary Outcome
Title Fibrinogen Plasma Level
Hide Description Fibrinogen plasma level was assessed using the Clauss fibrinogen assay
Time Frame Before (pre-infusion), 1 hour and 3 hours after the end of each subsequent infusion as well as at the time of the overall clinical assessment of haemostatic efficacy (i.e., 24 hours after the last infusion of each documented bleeding episode)
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Pre-infusion Day 1 Post-infusion 1 h Day 1 Post-infusion 3 h 1 Day After Last Infusion
Hide Arm/Group Description:
FAS-Bleeding population pre-infusion.
FAS-Bleeding population, day 1 post-infusion 1h
FAS-Bleeding population, day 1 post-infusion 3h
FAS-Bleeding population 1 day after last infusion
Overall Number of Participants Analyzed 24 24 24 24
Overall Number of Units Analyzed
Type of Units Analyzed: BEs
88 89 82 84
Mean (Standard Deviation)
Unit of Measure: mg/dL
0.13  (1.17) 109.01  (24.38) 104.46  (21.51) 70.77  (20.59)
4.Secondary Outcome
Title Response as Indicated by Incremental in Vivo Recovery (IVR)
Hide Description Incremental IVR (response): calculated as the maximum increase in plasma fibrinogen (i.e., Clauss data) between pre-infusion and 1 and 3 hours post-infusion, divided by the exact dose of Octafibrin.
Time Frame Pre-infusion and 1 and 3 hours post-infusion
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title FAS-Bleeding
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FAS-Bleeding population
Overall Number of Participants Analyzed 24
Overall Number of Units Analyzed
Type of Units Analyzed: BEs
88
Mean (Standard Deviation)
Unit of Measure: mg/dL/(mg/kg)
1.82  (0.42)
5.Secondary Outcome
Title Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study
Hide Description The investigator's overall clinical assessment of haemostatic efficacy for bleeding will be based on a 4-point haemostatic efficacy scale. The final efficacy assessment of each patient will be adjudicated by the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC)
Time Frame 24 hours after last infusion for each bleeding episode
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Investigator IDMEAC
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FAS-Bleeding population (all bleeding episodes) as assessed by the investigator
FAS-Bleeding population (all bleeding episodes) as assessed by the IDMEAC
Overall Number of Participants Analyzed 24 24
Overall Number of Units Analyzed
Type of Units Analyzed: BEs
89 89
Count of Units
Unit of Measure: BEs
Excellent
70
  78.7%
81
  91.0%
Good
16
  18.0%
7
   7.9%
Moderate
1
   1.1%
1
   1.1%
None
0
   0.0%
0
   0.0%
Missing
2
   2.2%
0
   0.0%
Overall treatment success
86
  96.6%
88
  98.9%
6.Secondary Outcome
Title Efficacy of Octafibrin in Preventing Bleeding During and After Surgery
Hide Description The efficacy of Octafibrin will be assessed at the end of surgery by the surgeon and post-operatively by the haematologist using two 4-point haemostatic efficacy scales. An overall efficacy assessment taking both the intra- and post-operative assessment into account will be adjudicated by the IDMEAC
Time Frame First dose of Octafibrin administered prior to elective surgery to at least 3 post-operative days for minor and 7 post-operative days for major surgeries or last post-operative infusion, whichever comes last
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Surgeon (Intra-op) IDMEAC (Intra-op) Haematologist (Post-op) IDMEAC (Post-op)
Hide Arm/Group Description:
Octafibrin efficacy assessed by the surgeon during the operation.
Octafibrin efficacy assessed by IDMEAC during the operation.
Octafibrin efficacy assessed by the Haematologist after the operation.
Octafibrin efficacy assessed by IDMEAC after the operation.
Overall Number of Participants Analyzed 9 9 9 9
Overall Number of Units Analyzed
Type of Units Analyzed: Surgeries
12 12 12 12
Count of Units
Unit of Measure: Surgeries
Excellent
11
  91.7%
11
  91.7%
12
 100.0%
11
  91.7%
Good
1
   8.3%
1
   8.3%
0
   0.0%
1
   8.3%
Moderate
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
None
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Missing
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Overall treatment success
12
 100.0%
12
 100.0%
12
 100.0%
12
 100.0%
7.Other Pre-specified Outcome
Title Analysis of Safety: Immunogenicity Testing for Anti-fibrinogen Antibodies
Hide Description Immunogenicity testing for the presence of anti-fibrinogen antibodies at Day 14 and Day 30 after the administration of Octafibrin for bleeding. An experimental non-standard ELISA was developed for this study for evaluating anti-fibrinogen antibodies. No specific test was performed to discern for neutralizing antibodies. The clinical implications of the assay results are not known.
Time Frame Up to 30 days (start of the first Octafibrin infusion until the end of each 30-day observation and follow-up period for on-demand treatment or until the Last Post-Operative Day in surgeries)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Pre-infusion Observational Period
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FAS-Bleeding population, immunogenicity testing prior to infusion.
FAS-Bleeding population, immunogenicity testing during the observational period.*
Overall Number of Participants Analyzed 24 24
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with Anti-fibrinogen Antibodies
4
  16.7%
6
  25.0%
Participants without Anti-fibrinogen Antibodies
20
  83.3%
18
  75.0%
Time Frame Up to 30 days (start of the first Octafibrin infusion until the end of each 30-day observation and follow-up period for on-demand treatment or until the Last Post-Operative Day in surgeries).
Adverse Event Reporting Description AEs occurring between the start of the first Octafibrin infusion and the end of each 30-day observation and follow-up period and during the surgical follow-up were recorded as treatment-emergent adverse events (TEAEs). Non-TEAEs were all AEs not falling into the follow-up periods
 
Arm/Group Title Safety Population
Hide Arm/Group Description All patients who received at least one administration of Octafibrin during the study
All-Cause Mortality
Safety Population
Affected / at Risk (%)
Total   0/25 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Safety Population
Affected / at Risk (%) # Events
Total   5/25 (20.00%)    
Blood and lymphatic system disorders   
Iron deficiency anaemia  1  1/25 (4.00%)  2
Gastrointestinal disorders   
Upper gastrointestinal haemorrhage  1  1/25 (4.00%)  1
Infections and infestations   
Dengue fever  1  1/25 (4.00%)  1
Hepatitis C  1  1/25 (4.00%)  1
Injury, poisoning and procedural complications   
Ligament rupture  1  1/25 (4.00%)  1
Ligament sprain  1  1/25 (4.00%)  1
Patella fracture  1  1/25 (4.00%)  1
Transfusion reaction  1  1/25 (4.00%)  1
Metabolism and nutrition disorders   
Hypocalcaemia  1  1/25 (4.00%)  1
Nervous system disorders   
Haemorrhage intracranial  1  1/25 (4.00%)  1
Pregnancy, puerperium and perinatal conditions   
Abortion spontaneous  1  1/25 (4.00%)  1
Vascular disorders   
Accelerated hypertension  1  1/25 (4.00%)  1
Thrombosis  1  1/25 (4.00%)  1
Peripheral ischaemia  1  1/25 (4.00%)  1
1
Term from vocabulary, MedDRA V18.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Safety Population
Affected / at Risk (%) # Events
Total   19/25 (76.00%)    
Blood and lymphatic system disorders   
Reactive thrombocytosis  1 [1]  1/25 (4.00%)  1
Gastrointestinal disorders   
Gingival bleeding  1  2/25 (8.00%)  8
Vomiting  1 [2]  2/25 (8.00%)  4
Abdominal pain upper  1 [1]  1/25 (4.00%)  1
Constipation  1 [1]  1/25 (4.00%)  1
Gastritis  1  1/25 (4.00%)  1
Lip haemorrhage  1  1/25 (4.00%)  1
Rectal haemorrhage  1 [1]  1/25 (4.00%)  1
Toothache  1  1/25 (4.00%)  1
General disorders   
Asthenia  1 [1]  1/25 (4.00%)  1
Pain  1 [1]  1/25 (4.00%)  1
Infections and infestations   
Brucellosis  1  1/25 (4.00%)  1
Pharyngitis  1 [1]  1/25 (4.00%)  1
Purulent discharge  1 [1]  1/25 (4.00%)  1
Rash pustular  1  1/25 (4.00%)  1
Rhinitis  1  1/25 (4.00%)  1
Tonsillitis  1 [1]  1/25 (4.00%)  1
Injury, poisoning and procedural complications   
Limb injury  1 [1]  3/25 (12.00%)  3
Procedural pain  1 [1]  1/25 (4.00%)  2
Arthropod sting  1 [1]  1/25 (4.00%)  1
Contusion  1 [1]  1/25 (4.00%)  1
Epicondylitis  1 [1]  1/25 (4.00%)  1
Incision site pain  1 [1]  1/25 (4.00%)  1
Skin wound  1 [1]  1/25 (4.00%)  1
Traumatic haemorrhage  1 [1]  1/25 (4.00%)  1
Investigations   
Transaminases increased  1 [1]  1/25 (4.00%)  1
Musculoskeletal and connective tissue disorders   
Pain in extremity  1  3/25 (12.00%)  4
Arthralgia  1 [3]  2/25 (8.00%)  2
Groin pain  1  1/25 (4.00%)  1
Muscle haemorrhage  1 [1]  1/25 (4.00%)  1
Nervous system disorders   
Headache  1  1/25 (4.00%)  1
Hypoaesthesia  1  1/25 (4.00%)  1
Psychiatric disorders   
Depression  1 [1]  1/25 (4.00%)  1
Renal and urinary disorders   
Dysuria  1 [1]  1/25 (4.00%)  1
Reproductive system and breast disorders   
Genital lesion  1  1/25 (4.00%)  1
Menorrhagia  1  1/25 (4.00%)  1
Pelvic congestion  1  1/25 (4.00%)  1
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1 [1]  1/25 (4.00%)  1
Epistaxis  1  1/25 (4.00%)  1
Upper respiratory tract infection  1 [1]  1/25 (4.00%)  1
Skin and subcutaneous tissue disorders   
Ecchymosis  1  2/25 (8.00%)  4
Drug eruption  1 [1]  1/25 (4.00%)  1
Skin fissures  1 [1]  1/25 (4.00%)  1
Skin haemorrhage  1  1/25 (4.00%)  1
Skin lesion  1  1/25 (4.00%)  1
Vascular disorders   
Haemorrhage  1 [3]  1/25 (4.00%)  7
Hypertension  1 [3]  2/25 (8.00%)  2
Haematoma  1 [1]  1/25 (4.00%)  1
Phlebitis  1 [1]  1/25 (4.00%)  1
1
Term from vocabulary, MedDRA V18.1
Indicates events were collected by systematic assessment
[1]
This/these were deemed to be a TEAE.
[2]
Of these, 3 AEs in 2 patients were deemed to be TEAEs.
[3]
Of these, 1 AE was deemed to be a TEAE.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Director of Clinical Operations
Organization: Octapharma USA
Phone: 201 604-1149
Responsible Party: Octapharma
ClinicalTrials.gov Identifier: NCT02267226     History of Changes
Other Study ID Numbers: FORMA-02
First Submitted: August 7, 2014
First Posted: October 17, 2014
Results First Submitted: December 21, 2018
Results First Posted: February 20, 2019
Last Update Posted: March 22, 2019