A clinical trial looking at the effectiveness and safety of a human plasma-derived antithrombin called Atenativ, for patients who are resistant to heparin (a blood thinner) and are undergoing cardiac surgery with cardiopulmonary bypass
| ISRCTN | ISRCTN55521313 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN55521313 |
| EudraCT/CTIS number | 2023-507560-39 |
| IRAS number | 1009957 |
| ClinicalTrials.gov number | NCT06096116 |
| Secondary identifying numbers | ATN-108, IRAS 1009957 |
- Submission date
- 01/08/2024
- Registration date
- 24/10/2024
- Last edited
- 24/10/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Haematological Disorders
Plain English summary of protocol
Background and study aims
The study evaluates how well different doses of the drug, Atenativ work to restore and maintain participants’ responsiveness to another drug called heparin. Heparin is given during cardiac surgery to prevent blood from clotting whilst on a heart and lung machine.
Who can participate?
Male and female patients aged 18-85 years old who require cardiac surgery using a heart and lung machine and who are found to be ‘heparin resistant’.
What does the study involve?
Patients who consent to the study and are ‘heparin resistant’ will be randomised (allocated by chance) into one of three groups: 1) Atenativ at a dose of 15 International Units per kilogram body weight; 2) Atenativ at a dose of 30 International Units per kilogram body weight; 3) Placebo (a liquid that looks like the study drug but contains no medicine). Participants will be treated as per their allocated treatment group alongside the usual treatment required for cardiac surgery. During surgery, blood samples will be taken at predetermined time points to monitor levels of a compound known as ‘antithrombin’ and blood cell levels. In addition to the expected hospital visits for cardiac surgery patients, participants will receive a final phone call 28 days after their procedure when they will be asked about their health. The time from consenting to the study until the final phone call will be between 28-35 days.
What are the possible benefits and risks of participating?
Taking part in this study may not result in personal medical benefit however the knowledge gained may benefit future patients.
Some risks are associated with taking part, as sometimes, people receiving medications made from human blood plasma, such as Atenativ, have allergic/hypersensitivity reactions.
Risk from the study drug: Some people treated with medications made from human blood plasma, such as Atenativ, have allergic or hypersensitivity reactions. To minimise this risk the protocol excludes the inclusion of patients with known hypersensitivity/allergic reaction to antithrombin or any of Atenativ excipients and patients with a history of anaphylactic reaction(s) to blood or blood components.
Despite Atenativ undergoing stringent treatment to render it ‘safe’, the risk that it may transmit infections/viruses, cannot be removed entirely. Some viruses remain and these are dangerous to the foetus and people with immune system disorders or some types of anaemia. There may also be unknown risks to the embryo/foetus. The protocol therefore excludes pregnant females and requires that females use effective contraception throughout the study and report any pregnancy immediately.
Risks from a blood draw and the infusion. Both procedures may cause pain, bruising, light-headedness, fainting, scarring, infection and clotting. To minimise this risk these procedures will be performed only by appropriately qualified staff.
The study staff will closely monitor the participants for any signs of adverse reactions during surgery, when the study drug is administered and during the participant’s hospital stay; if the participants display any signs or symptoms they will be treated accordingly. Once discharged from the hospital there is a telephone call to monitor the participants' health approximately 28 days after surgery.
All the risks associated with the study are found in the Participant Information Sheet and the participants are informed to speak with their study doctor if they have any concerns.
Where is the study run from?
Octapharma AG
When is the study starting and how long is it expected to run for?
July 2024 to September 2026
Who is funding the study?
Octapharma AG
Who is the main contact?
Sigurd Knaub (Octapharma AG), sigurd.knaub@octapharma.com
Contact information
Scientific
Sigurd Knaub, Senior Vice President CR&D Haematology on behalf of the Sponsor Octapharma AG
Seidenstrasse 2
Lachen
8853
Switzerland
| Phone | +41 55 4512141 |
|---|---|
| sigurd.knaub@octapharma.com |
Principal Investigator
Royal Papworth Hospital
Cambridge Biomedical Campus
Cambridge
CB2 0AY
United Kingdom
| Phone | +44 7789865077 |
|---|---|
| F.Falter@nhs.net |
Study information
| Study design | Interventional double blind randomized parallel group placebo controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital, Telephone |
| Study type | Safety, Efficacy |
| Scientific title | Phase 3, double-blind, placebo-controlled, multicentre study on the efficacy and safety of human plasma derived antithrombin (Atenativ) in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass |
| Study acronym | ATN-108 |
| Study objectives | The primary objective of this study is to evaluate the efficacy of two different doses of Atenativ, versus placebo, in restoring and maintaining heparin responsiveness in adult patients undergoing cardiac surgery necessitating cardiopulmonary bypass (CPB) Secondary objectives: 1. Amounts of further therapy containing antithrombin required for restoring heparin responsiveness before CPB & maintaining it during CPB 2. Effect of Atenativ on the coagulation parameter used for evaluating heparin resistance, namely the activated clotting time (ACT) 3. Capacity of Atenativ to modify the antithrombin plasma concentration 4. The impact of Atenativ on the intraoperative use of heparin following the infusion of Atenativ or placebo 5. Any requirement for frozen plasma (FP) or antithrombin concentrates for reasons other than restoring or maintaining heparin responsiveness, both intraoperatively & postoperatively 6. Any intraoperative and postoperative use of other allogeneic blood products, coagulation factor concentrates & other haemostatic-relevant therapies 7. Volume of chest tube drainage & the need for reoperation due to bleeding 8. Safety of Atenativ 9. Any post-CPB requirement for additional therapy containing antithrombin to restore heparin responsiveness |
| Ethics approval(s) |
Approved 15/10/2024, Yorkshire & The Humber - Sheffield Research Ethics Committee (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, United Kingdom; +44 (0)2071048139, (0)2071048135, (0)207 104 8210; sheffield.rec@hra.nhs.uk), ref: 24/YH/0183 |
| Health condition(s) or problem(s) studied | Restoring and maintaining heparin responsiveness, acquired antithrombin deficiency (heparin resistance) in adult patients undergoing cardiac surgery necessitating cardiopulmonary bypass (CPB) |
| Intervention | The intervention is a one-time infusion of Atenativ (a solvent/detergent and heat-treated antithrombin concentrate derived from human plasma) at a dose of 15 International Units per kilogram body weight or 30 International Units per kilogram body weight or placebo (a liquid that looks like the study drug but contains no medicine) at a volume corresponding to either the low dose or high dose of Atenativ. Atenativ or placebo will be administered during cardiac surgery before going on cardiopulmonary bypass. Computer software and an online tool (IVRS system) will be used to randomly allocate the treatment groups in a 2:2:1:1 ratio. Neither the investigator nor the participant will know to which group they have been allocated. All participants will be followed up during their post-operative hospital stay and they will receive an additional telephone call approximately 28 days after their surgery. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Dose response, Therapy |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Antithrombin III |
| Primary outcome measure | The percentage of patients in each group in whom no further therapy containing antithrombin (i.e., frozen plasma (FP) or other antithrombin concentrates) is needed for restoring pre-CPB heparin responsiveness after administration of Atenativ or placebo, and for maintaining it until the completion of the cardiopulmonary bypass (CPB). The CPB period includes any additional CPB time if a return to CPB is needed before protamine administration but excludes any additional CPB time required after protamine administration. |
| Secondary outcome measures | The following secondary outcome measures are assessed at various intraoperative and postoperative timepoints between initial heparin administration and 28 days following IMP infusion: 1. The comparison between the amounts of further therapy containing antithrombin (i.e., FP or antithrombin concentrates) needed for restoring pre-CPB heparin responsiveness after administration of Atenativ or placebo, and for maintaining it during CPB 2. The comparison between the change in ACT values following infusion of each of the Atenativ doses and placebo 3. The comparison between the change in antithrombin plasma levels following infusion of each of the Atenativ doses and placebo 4. The comparison between heparin usage following the infusion of each of the Atenativ doses and placebo 5. The comparison between the number of units of FP transfused for reasons other than restoring or maintaining heparin responsiveness, both intraoperatively (from the start of Atenativ or placebo infusion until the start of CPB, during CPB, and from the end of CPB until the end of surgery) and postoperatively (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first), as well as cumulatively 6. The comparison between postoperative use of antithrombin concentrates for reasons other than restoring heparin responsiveness (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first) 7. The comparison between transfusion of other allogeneic blood products (e.g., red blood cells [RBCs], platelets, cryoprecipitate), both intraoperatively (from the start of Atenativ or placebo infusion until the start of CPB, during CPB, and from the end of CPB until the end of surgery) and postoperatively (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first), as well as cumulatively 8. The comparison between administration of coagulation factor concentrates such as fibrinogen concentrate, prothrombin complex concentrate (PCC), factor XIII concentrate and recombinant activated factor VII, both intraoperatively and postoperatively 9. The comparison between administration of other haemostatic-relevant therapies (e.g., tranexamic acid, protamine), both intraoperatively (from the start of Atenativ or placebo infusion until the start of CPB, during CPB, and from the end of CPB until the end of surgery) and postoperatively (from the end of surgery until 24 hours after the start of Atenativ or placebo infusion and until discharge or 7 days after surgery, whichever comes first), as well as cumulatively This document is an unpublished preview, not for official use 10. The comparison between postoperative chest tube drainage volume at 24 hours after the start of Atenativ or placebo infusion, and the comparison between total chest tube drainage volume until discharge or 7 days after surgery, whichever comes first 11. Comparison of the need for reoperation for bleeding, including description of the cause of bleeding (surgical vs. non-surgical) 12. The comparison between cell saver volume until the end of surgery 13. Incidence of AEs in the three study groups 14. Standard haematological parameters (i.e., RBC count, white blood cell count, haemoglobin levels, haematocrit, and platelet count) following Atenativ or placebo infusion, after the end of CPB, at the end of surgery, and at 24 hours after the start of Atenativ or placebo infusion 15. Survival status in the different treatment groups 16. The comparison between the amounts of further therapy containing antithrombin (i.e., FP or antithrombin concentrates) needed for restoring heparin responsiveness from the end of CPB until 24 hours after start of Atenativ or placebo infusion and from the end of CPB until discharge or 7 days postoperatively, whichever comes first 17. Comparison of the length of ICU stay between treatment groups |
| Overall study start date | 30/07/2024 |
| Completion date | 30/09/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Upper age limit | 85 Years |
| Sex | Both |
| Target number of participants | 120 |
| Key inclusion criteria | 1. Planned cardiac surgery with CPB 2. Heparin-resistant patients: pre-CPB Hemochron ACT less than 480 seconds in the measurement performed between 2 and 5 minutes following intravenous administration of 500 U/kg BW UFH 3. Patients ≥18 and ≤85 years of age 4. Freely given written or electronic informed consent 5. In female patients of childbearing potential (i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile), a pre-existing negative pregnancy test within 14 days before surgery |
| Key exclusion criteria | 1. Receiving or have received one or more of the following medications within the specified time frames before the start of the surgery: a) warfarin (within 3 days) b) direct oral anticoagulants (within 2 days) c) ticlopidine (within 14 days) d) prasugrel (within 7 days) e) clopidogrel (within 5 days) f) ticagrelor (within 5 days) g) glycoprotein IIb/IIIa antagonist (within 1 day) 2. Pre-existing coagulopathy, a history of bleeding problems or a laboratory-diagnosed bleeding disorder (e.g., von Willebrand disease, platelet disorder) 3. Renal insufficiency, defined as serum creatinine level >1.5 mg/dL 4. Known hypersensitivity or allergic reaction to antithrombin or any of the excipients in Atenativ, i.e., human albumin, sodium chloride, acetyl tryptophan and caprylic acid 5. History of anaphylactic reaction(s) to blood or blood components 6. Refusal to receive a transfusion of blood or blood-derived products 7. Current participation in another interventional clinical trial with an investigational medicinal product (IMP) or previous participation in the current trial 8. Treatment with any IMP within 30 days before the screening visit |
| Date of first enrolment | 21/08/2024 |
| Date of final enrolment | 31/08/2026 |
Locations
Countries of recruitment
- Austria
- England
- France
- Lithuania
- Romania
- Slovenia
- United Kingdom
Study participating centre
Cambridge Biomedical Campus
Cambridge
CB2 0AY
United Kingdom
Sponsor information
Industry
Sigurd Knaub, Senior Vice President CR&D Haematology on behalf of the Sponsor Octapharma AG
Seidenstrasse 2
Lachen
8853
Switzerland
| Phone | +41 55 4512141 |
|---|---|
| sigurd.knaub@octapharma.com | |
| Website | https://www.octapharma.com/ |
"ROR" |
https://ror.org/022k50n33 |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Octapharma AG
- Location
- Switzerland
Results and Publications
| Intention to publish date | 30/09/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Stored in non-publicly available repository, Published as a supplement to the results publication |
| Publication and dissemination plan | 1. Peer reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on website 5. Submission to regulatory authorities |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a non-publicly available repository (Medidata Rave: https://www.medidata.com/). A summary of the results will be shared in the clinical study report, at scientific conferences, and in public databases. There is a clause in the Informed Consent Form for participants to optionally consent to their data, saved from this study, to be used in future research. Additionally, data rendered anonymous from this study may be shared with other researchers. |
Editorial Notes
16/10/2024: ISRCTN received notification of combined HRA/MHRA approval for this trial on 16/10/2024
01/08/2024: Trial's existence confirmed by NHS HRA.
