Evaluate Safety and Efficacy of Fibrin Sealant Grifols in children
Research type
Research Study
Full title
A prospective, Randomised, Active-Controlled, Single-blind, Parallel Group Clinical Trial to Evaluate the Safety and Efficacy of Fibrin Sealant Grifols (FS Grifols) as an Adjunct to Haemostasis during Surgery in Paediatric Subjects.
IRAS ID
257130
Contact name
Khalid Sharif
Contact email
Sponsor organisation
Instituto Grifols, S.A
Eudract number
2016-004489-24
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 0 months, 0 days
Research summary
Research Summary
This study aims to see how good and safe a new body glue (fibrin sealant)
product called FS Grifols is in children undergoing surgery. We want to see
if it can reduce the time taken to stop bleeding when it is tested against a
commercially available body glue called EVICEL®.Summary of Results
WHY WAS THIS STUDY DONE?
What was the purpose of this study?
Hemostasis is your body’s natural reaction to an injury that stops bleeding and repairs the damage. This capability is usually for your benefit, conserving blood and preventing infections. In some cases, the process does not work as it should, and this can cause problems with too much or too little clotting.
This study examined the safety and efficacy of Fibrin Sealant Grifols (FS Grifols) in paediatric patients undergoing a scheduled surgery where bleeding was present on the cut parenchymous surface of a solid organ (i.e., liver) or soft tissue (i.e., fat, muscle, or connective tissue). The aim of this study was to demonstrate that FS Grifols application is as effective or at least not worse in providing benefit by stopping bleeding as compared to a commercially available fibrin sealant solution called EVICEL® (Omrix Biopharmaceuticals N.V., [Diegem, Belgium]), applied according to the instructions in the package insert and according to the surgeons’ usual clinical practice.
FS Grifols is made up of two solutions which are natural parts of the blood (thrombin and fibrinogen). Both parts of FS Grifols come from human blood (plasma). The two solutions are provided separately in two syringes ensembles in a device. An applicator is scrolled to the device so that both solutions are mixed together when they are put onto to a bleeding site. Using FS Grifols causes a clot to form over the cut surface to stop the bleeding. This is the final stage of the normal process of clotting. Similar products are commonly used during surgery to help blood to clot. There were two treatment medicinal products in this research study: FS Grifols (the product to be tested) and Evicel (the comparator). Both treatments are body glues that were used to shorten bleeding time during surgery.
The main goal of this study was to assess if FS Grifols is as effective or at least not worse than EVICEL in the paediatric patients in cessation of bleeding at the target bleeding site (TBS) by 4 minutes (T4) from the initial study medication application with no occurrence of rebleeding (to bleed again) until completion of surgical procedure. Additionally, the safety and tolerability of FS Grifols in paediatric patients undergoing surgery was evaluated.
This study was part of the Paediatric Study Plan of Fibrin Sealant Grifols, which was agreed both with European Medicines Agency (EMA) and US Food and Drug Administration (FDA). This means that this study was asked by EMA and FDA to be performed to demonstrate that the product is safe and effective to be used in children. FS Grifols is already approved to be used in adults.
Who was eligible to take part in the study?
The study included paediatric patients who:
• Were having a planned surgery where the bleeding would be mild or moderate;
• Might need a body glue during surgery;
• Were under the age of 18.
Patients could not be included in the study if:
• Had a known history of allergic reactions to blood products;
• Were pregnant, breastfeeding or adolescent unwilling to practice a highly effective method of contraception during the study;
• Were participating in a different study;
• Might have a kind of surgery where the bleeding would be severe.
These were just some of the main criteria patients needed to have/not to have to enter the study. There were other criteria to be or not to be in the study which are not listed here.
This was a Phase 3b clinical study: the study was conducted to test the FS Grifols in paediatric patients but FS Grifols had already been tested in adults over 18 years of age. FS Grifols was shown to be useful, safe, and well tolerated in surgery. FS Grifols has been approved to be used in adults over 18 years of age in US, EU countries, Australia, Canada, Taiwan, Singapore and United Kingdom. Neither similar products are licensed to be used in children nor alternative treatments.
WHAT HAPPENED DURING THE STUDY?
First, the children were checked by the study doctor to make sure they were a good fit for the study. This was called “screening”.
Each patient was assigned treatment by chance (randomly) and had 1 in 2 chance of receiving FS Grifols and a 1 in 2 chance of receiving EVICEL. A bleeding site was identified during the surgery and the assigned treatment (FS Grifols or EVICEL) was applied to the bleeding site.
This study was single blinded, this means that the children and their parents/guardians did not know which medicine the children received during the study (FS Grifols or EVICEL) but the doctor did know. A total of 197 patients were screened and 186 patients were randomized (randomly assigned to FS Grifols or EVICEL), of that, 95 patients were randomized to FS Grifols group and 91 patients were randomized to EVICEL group. Children from the following age categories were included:
• Adolescents (12 to 17 years): 76 (40.9%)
• Children (2 to 11 years): 67 (36.0%)
• Infants and toddlers (28 days to 23 months): 37 (19.9%)
• Preterm (up to gestational age <37 weeks) and term newborn infants (0 to 27 days): 6 (3.2%)
The study required the children to come to a total of 5 visits at the study centre, each lasting up to 2 hours. One of these visits was the day of surgery. The length of this visit was dependent on how long child’s surgery took.
The study was divided into 4 parts:
• Screening Visit (within 21 days prior to surgical procedure): in this phase, suitability of patients was checked to participate in the study based on some parameters.
• Baseline Assessment Visit (within 24 hours prior to surgical procedure): patients were checked for any new events, changes in health, medical or surgical history, and medicine since screening visit.
• Surgical Procedure Day: the day when surgical procedure was performed.
• Postoperative Visits (Day 4 and Day 30): assessments and procedures to assess outcomes after surgery.
Children were in the study for up to 8 weeks.
The study was conducted in 10 countries (Hungary, Serbia, Bulgaria, Canada, Romania, United Kingdom, United States, Sweden, Germany, and France). It began 18 Jan 2019 and finished 20 May 2022. A total of 70 girls and 116 boys participated.
A total of 178 patients received at least 1 dose of the assigned medicine (either FS Grifols or EVICEL). A total of 171 (91.9%) children completed the study. Seven children (3.8%) did not finish the study due to lost to follow-up, death, or any ‘other’ unspecified reasons. For the children who did not complete the study after receiving medicine, 4 (4.2%) were in the FS Grifols group and 3 (3.3%) were in the EVICEL group.
When the study ended in May 2022, the Sponsor began reviewing the information collected. The Sponsor then created a report of the results. This is a summary of that report.
WHAT WERE THE RESULTS OF THE STUDY?
Was FS Grifols as effective and at least not worse than EVICEL?
To answer this question, the researchers compared the proportion of patients achieving hemostasis (cessation of bleeding) at the bleeding site by minute 4 from the start of initial study medicine application with no occurrence of rebleeding (to bleed again) until completion of surgical procedure.
Cessation of bleeding at minute 4 (T4) was reached in 88 out of 91 patients (96.7%) in FS Grifols treatment group and in 83 out of 87 patients (95.4%) in the EVICEL treatment group. The proportion of patients who stopped bleeding by minute 4 receiving FS Grifols relative to Evicel was 1.01 which demonstrated that FS Grifols was as effective (non-inferior) as Evicel.
The researchers also assessed the cumulative proportion of patients achieving hemostasis at the bleeding site by minute 7 and 10 minutes.
All patients (91 out of 91 in FS Grifols group and 87 out of 87 in Evicel group) achieved the cessation of bleeding at minute 7 (T7). The proportion of patients who stopped bleeding by minute 7 receiving FS Grifols relative to Evicel was 1.00 which demonstrated that FS Grifols was as effective (non-inferior) as Evicel.
Cessation of bleeding at minute 10 (T10) was reached in 90* out of 91 patients (98.9%) in FS Grifols treatment group and in all (87 out of 87) patients (95.4%) in the EVICEL treatment group. The proportion of patients who stopped bleeding by minute 10 receiving FS Grifols relative to Evicel was 0.99 which demonstrated that FS Grifols was as effective (non-inferior) as Evicel.
*The assessment of bleeding cessation was not done in one patient in FS Grifols group at minute 10 so that it was considered as non-achieved at this time point. Nevertheless, this patient had already stopped bleeding at minute 4 and minute 7.
Were there any patients who experienced treatment failure?
To answer this question, the researchers assessed occurrence of persistent bleeding, breakthrough bleeding, re-bleeding, use of additional/ alternative hemostatic treatment, or re-application of study medicine after 4 minutes and until completion of surgical procedure.
There were not any case of treatment failure, i.e., no patient experienced re-bleeding in the study.
Researchers concluded that based on these results FS Grifols was demonstrated to be as effective and at least not worse than Evicel so FS Grifols might be used as a hemostatic agent in paediatric patients. This does not mean that everyone in this study had these results. Other studies may produce different results, as well. These are just some of the main findings of the study, and more information may be available at the websites listed at the end of this summary.
WHAT MEDICAL PROBLEMS DID CHILDREN HAVE DURING THE STUDY?
The researchers recorded any medical problems the participants had during the study. Participants could have had medical problems for reasons not related to the study (for example, caused by an underlying disease or by chance). Or, medical problems could also have been caused by a study treatment, or by another medicine the participant was taking. Sometimes the cause of a medical problem is unknown. By comparing medical problems across many treatment groups in many studies, doctors try to understand what the side effects of an experimental drug might be.
If any new medical problems arose during the study, these were reported by the study doctors. In addition, if a preexisting medical problem worsened, these would also be reported.
Out of 178 children in this study, 40 children (22.5%) had at least 1 medical problem. The most common medical problems are listed below. No patient left the study because of any medical problems reported during the study.
Most Common Medical Problems (Reported by 2 or More Children in any Treatment Group):FS Grifols (91 Children Treated):
Medical problem:
Children with any medical problem - 24 (26.4%) Anaemia (insufficiency of red blood cells) - 2 (2.2%) Abdominal distension (abnormally swollen outward) - 2 (2.2%) Nausea - 1 (1.1%) Vomiting - 6 (6.6%) Pyrexia (high body temperature) - 1 (1.1%) Anaphylactic shock* (a serious, potentially life threatening allergic reaction) - 2 (2.2%) Wound infection - 2 (2.2%) Wound dehiscence (wound breakdown due to incomplete healing) - 2 (2.2%) Hypertension (high blood pressure) - 2 (2.2%) *One child experienced a serious medical problem due to Echinococcus granulosus cyst spillage (Echinococcus is a parasite that leads to cyst formation and spread of infection in human body) on Day 1. Because the starting time of the event was not documented in the clinical database, this event was considered as serious medical problem occurred due to study medicine. However, source data in the safety database indicate that the problem had started prior to study medicine administration, hence this serious medical problem is not considered related to study medicine.EVICEL (87 Children Treated):
Medical problem:
Children with any medical problem - 16 (18.4%) Anaemia (insufficiency of red blood cells) - 3 (3.4%) Abdominal distension (abnormally swollen outward) - 0 (0.0%) Nausea - 2 (2.3%) Vomiting - 3 (3.4%) Pyrexia (high body temperature) - 5 (5.7%) Anaphylactic shock* (a serious, potentially life threatening allergic reaction) - 0 (0.0%) Wound infection - 0 (0.0%) Wound dehiscence (wound breakdown due to incomplete healing) - 0 (0.0%) Hypertension (high blood pressure) - 0 (0.0%)
WERE THERE ANY SERIOUS MEDICAL PROBLEMS?
A medical problem is considered “serious” when it is life-threatening, needs hospital care, or causes long lasting problems.
Out of 178 children in this study, 17 children (9.6%) had serious medical problems, of that, 8 (8.8%) children were in the FS Grifols group and 9 (10.3%) children were in the EVICEL group. Three children passed away during the study, 1 in the FS Grifols group and 2 in the EVICEL group. The study doctor considered the that the serious medical problems that led to death were not related to study medicine.
WHERE CAN I LEARN MORE ABOUT THIS STUDY?
If you have questions about the results of your study, please speak with the doctor or staff at your child’s study site.
For more details on this study, please visit:
https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7Ca1c3b1462f3b4bdf60af08db57d0915c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638200325522747612%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=EPdYDgXjePjJcFx3I4EWQ0I33sgxpaq9a0FypCxyvyg%3D&reserved=0 Use the study identifier NCT03461406
https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7Ca1c3b1462f3b4bdf60af08db57d0915c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638200325522747612%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=AsasfPK5X63jVULBTEdywEJ5Qs2C%2F5KsHB6G2KFfN9M%3D&reserved=0 Use the study identifier 2016-004489-24
Please remember that researchers look at the results of many studies to find out which medicines can work and are safe for patients. Findings from this trial can be used in other studies to learn whether paediatric patients are helped by FS Grifols.REC name
South Central - Hampshire A Research Ethics Committee
REC reference
19/SC/0044
Date of REC Opinion
27 Mar 2019
REC opinion
Favourable Opinion