A study in healthy volunteers to assess how safe and effective the test medicine is at reversing anticoagulant medicines

ISRCTN	ISRCTN28849775
DOI	https://doi.org/10.1186/ISRCTN28849775
Clinical Trials Information System (CTIS)	2022-002756-39
Integrated Research Application System (IRAS)	1006328
Protocol serial number	Quotient Code: QSC300320
Sponsor	Norgine (United Kingdom)
Funder	Norgine

Submission date: 23/09/2022
Registration date: 05/10/2022
Last edited: 08/07/2026

Recruitment status: Stopped
Overall study status: Stopped
Condition category: Other

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
The Sponsor is developing the test medicine, ciraparantag, for situations when the effects of a commonly prescribed type of oral anticoagulant drug (blood thinner) needs to be reversed quickly.

This healthy volunteer study will evaluate the efficacy and safety of a single intravenous (IV, administered via injection into a vein) dose of the test medicine for reversal of anticoagulation (blood thinning) that has been caused by three different oral anticoagulant drugs.

Who can participate?
Healthy male and non-pregnant, non-lactating female volunteers aged between 18 and 55 years.

What does the study involve?
Three separate groups of volunteers will receive one of the three different oral anticoagulant drugs from Day 1 to Day 4 of the study. The test medicine or placebo (dummy drug) will be given on Day 4 to test whether it reverses the anticoagulant effect. Volunteers will have a 2:1 chance of getting the test medicine versus the placebo. The study is blinded, which means the volunteers and study team will not know which volunteers have received the test medicine and which volunteers have received the placebo. A further 3 groups of volunteers may be given a different dose of the test medicine, depending on the effect seen in the first three groups.
Volunteers will be discharged on Day 6 at the earliest, or when the discharge criteria are met, and return for a follow-up visit 3 to 5 days later.

What are the possible benefits and risks of participating?
Healthy volunteers will get no medical benefit from the test medicine; however, the aims of the study can be most efficiently met in volunteers with no concurrent medical conditions and who do not need to take concomitant medication that might interfere with the study objectives or increase the risk of the study. The risk/benefit evaluation in this study supports the use of healthy volunteers.

Where is the study run from?
Quotient Sciences Limited (United Kingdom)

When is the study starting and how long is it expected to run for?
November 2022 to April 2024

Who is funding the study?
Norgine, Ltd (UK)

Who is the main contact?
recruitment@weneedyou.co.uk

Contact information

Dr Litza McKenzie
Principal investigator

Quotient Sciences Limited
Mere Way
Ruddington Fields
Nottingham
NG11 6JS
United Kingdom

Phone	+44 (0)330 303 1000
Email	recruitment@weneedyou.co.uk

Mr Richard Ng
Scientific

Norgine House
Widewater Place
Moorhall Road
Uxbridge
UB9 6NS
United Kingdom

Phone	+44(0)1895453584
Email	rng@norgine.com

Mr Jeff Pilot
Public

Norgine House
Widewater Place
Moorhall Road
Uxbridge
UB9 6NS
United Kingdom

Phone	+44(0)1895453736
Email	jpilot@norgine.com

Study information

Primary study design	Interventional
Allocation	Randomized controlled trial
Masking	Blinded (masking used)
Control	Placebo
Assignment	Parallel
Purpose	Efficacy and safety trial in healthy volunteers
Scientific title	A phase I randomized, double-blind, placebo-controlled study to assess the efficacy and safety of ciraparantag for reversal of supratherapeutic doses of anticoagulants in healthy adults
Study objectives	The trial will meet the following primary and secondary objectives: Primary objectives - To demonstrate that a single IV administration of ciraparantag is superior to placebo in the reversal of anticoagulation induced by each of the evaluated anticoagulant drugs (edoxaban, apixaban, or rivaroxaban) in healthy adults, as assessed by whole blood clotting time (WBCT) measured at a predefined time point with Perosphere Technologies’ Point-of-Care (PoC) Coagulometer. Secondary objectives - To further evaluate the efficacy of a single IV administration of ciraparantag compared to placebo in the reversal of anticoagulation induced by each of the evaluated anticoagulant drugs (edoxaban, apixaban, or rivaroxaban) in healthy adults, as assessed by WBCT measured at multiple time points with Perosphere Technologies’ PoC Coagulometer. - To provide additional safety and tolerability information for ciraparantag. - To evaluate the PK of ciraparantag in healthy adults. - To evaluate the PK of the evaluated anticoagulant drugs (edoxaban, apixaban, and rivaroxaban) in healthy adults.
Ethics approval(s)	1. Approved 25/10/2022, South Central - Oxford A REC (Ground Floor, Temple Quay House, 2 The Square, Bristol, BS1 6PN, UK; +44 (0)207 104 8290, (0)207 104 8206, (0)207 104 8061; oxforda.rec@hra.nhs.uk); Ref - 22/SC/0294 2. Approved 25/10/2022, MHRA (10 South Colonnade, Canary Wharf, London, E14 4PU, UK; +44 (0)20 3080 6000; info@mhra.gov.uk), ref: CTA 00322/0315/001-0001
Health condition(s) or problem(s) studied	Anticoagulant reversal therapy
Intervention	This healthy volunteer study will evaluate the efficacy and safety of a single intravenous (IV, administered via injection into a vein) dose of the test medicine for reversal of anticoagulation (blood thinning) that has been caused by three different oral anticoagulant drugs. This study will take place at 1 non-NHS site, enrolling up to 126 healthy male and non-pregnant, non-lactating female volunteers aged between 18 and 55 years. Three separate groups of volunteers will receive one of the three different oral anticoagulant drugs from Day 1 to Day 4 of the study. The test medicine or placebo will be given on Day 4 to test whether it reverses the anticoagulant effect. Volunteers will have a 2:1 chance of getting the test medicine versus the placebo. The study is blinded, which means the volunteers and study team will not know which volunteers have received the test medicine and which volunteers have received the placebo. A further 3 groups of volunteers may be given a different dose of the test medicine, depending on the effect seen in the first three groups. Volunteers will be discharged on Day 6 at the earliest, or when the discharge criteria are met, and return for a follow-up visit 3 to 5 days later.
Intervention type	Drug
Phase	Phase I
Drug / device / biological / vaccine name(s)	Ciraparantag Solution for Injection, Placebo Solution for Injection (Sodium Chloride Injection), Edoxaban tablets, Apixaban tablets, Rivaroxaban tablets
Primary outcome measure(s)	Results of the formal statistical analysis of the proportion of subjects who achieve a WBCT ≤ the upper limit of normal (295 secs) within 1 h after administration of ciraparantag/placebo, which is subsequently sustained after 1 h through to at least 6 h after ciraparantag/placebo dosing measured using Perosphere Technologies’ Point-of-Care (PoC) Coagulometer at Screening until the follow-up visit (up to 6 days post-discharge)
Key secondary outcome measure(s)	Statistical analysis of the proportion of subjects who achieve WBCT ≤ the upper limit of normal (295 secs) within 30 min after administration of ciraparantag/placebo, which is subsequently sustained after 30 min through to at least 6 h after ciraparantag/placebo dosing measured using PoC Coagulometer at Screening until the follow-up visit (up to 6 days post-discharge) Statistical analysis of the proportion of subjects who achieve a WBCT ≤ the upper limit of normal (295 secs) within 15 min after administration of ciraparantag/placebo, which is subsequently sustained after 15 min through to at least 6 h after ciraparantag/placebo dosing, measured using PoC Coagulometer at Screening until the follow-up visit (up to 6 days post-discharge) Statistical analysis of the proportion of subjects who achieve a WBCT ≤ the upper limit of normal (295 secs) at each of the planned WBCT assessment time points: 15 min, 30 min, 1 h, 3 h, 6 h and 24 h after administration of ciraparantag/placebo (relative to the end of infusion) measured using PoC Coagulometer at Screening until the follow-up visit (up to 6 days post-discharge) To provide additional safety and tolerability information for ciraparantag, measured using the incidence of AEs, treatment-emergent AEs and SAEs, changes from baseline in vital signs, electrocardiograms (ECGs), physical examinations and changes from baseline in laboratory safety tests at Day -1 until the follow-up visit (up to 6 days post-discharge) PK parameters for ciraparantag and metabolite (1,4-bis (3- aminopropyl) piperazine [BAP]), including the following: tmax, Cmax, AUC(0-last), AUC(0-inf), λz, t1/2, CL and Vz measured using Serum concentration data at Day 4 until discharge PK parameters for edoxaban, apixaban, and rivaroxaban, including the following: tmax, Cmax, and CL/F measured using Plasma concentration-time data at Day 4 until discharge
Completion date	12/04/2024
Reason abandoned (if study stopped)	Other reason not related to safety

Eligibility

Participant type(s)	Healthy volunteer
Age group	Adult
Lower age limit	18 Years
Upper age limit	55 Years
Sex	All
Target sample size at registration	126
Total final enrolment	48
Key inclusion criteria	1. Must provide written informed consent 2. Must be willing and able to communicate and participate in the whole study 3. 18 to 55 years inclusive at the time of signing informed consent 4. Must agree to adhere to the contraception requirements defined in the clinical protocol 5. Healthy males or non-pregnant, non-lactating healthy females of non-childbearing potential (WONCBP) or non-pregnant, non-lactating healthy females on low-user-dependency progesterone-only contraception (e.g., injected, subdermal, intrauterine) who will not be menstruating at the time of study treatment. A woman is considered to be of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) or is postmenopausal (has had no menses for 12 months without an alternative medical cause and a serum follicle-stimulating hormone [FSH] concentration ≥40 IU/L. 6. Have suitable veins for multiple venepunctures/cannulation and IV infusions as assessed by the investigator or delegate at screening 7. Body mass index (BMI) of 18.0 to 32.0 kg/m2 as measured at screening 8. Weight >60 kg at screening 9. WBCT ≤ the upper limit of normal (295 secs) at screening and admission prior to the first NIMP dose
Key exclusion criteria	1. Serious adverse reaction or serious hypersensitivity to any drug or formulation excipients 2. Known allergy to edoxaban, apixaban, rivaroxaban or ciraparantag 3. Any contraindication to the use of the anticoagulant drugs (edoxaban, apixaban, or rivaroxaban) as per the Summary of Product Characteristics for each product 4. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator; hay fever is allowed unless it is active 5. History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or GI disease, neurological or psychiatric disorder, as judged by the investigator 6. Subjects with a personal or family history of clotting disorder or haematologic abnormality, such as excessive bleeding, joint haematoma, thrombovascular disease, thrombocytopenia, or any chronic condition requiring treatment with transfusions 7. Subjects with a history of a significant head injury in the last 2 years 8. Subjects with a history of venous thromboembolic episodes (including deep vein thrombosis and pulmonary embolism) 9. Subjects with a history of unexplained syncope within 6 months prior to screening 10. Subjects with a history of major bleeding, trauma, surgical procedure of any type, or vaginal delivery within 6 months prior to screening 11. Presence or history of peptic ulcer or GI bleeding (including hematemesis, melena, or rectal bleeding) within 6 months prior to screening. 12. Presence or history of minor bleeding episodes (e.g., epistaxis, unexplained bruising or gingival bleeding) within 6 months prior to screening, or a long-standing history of such bleeding. 13. Dental extraction or surgery in the 4 weeks prior to admission or planned during the study until after the follow-up visit. 14. Female subjects only: history of excessive or dysfunctional uterine bleeding (unless the subject had a subsequent hysterectomy).
Date of first enrolment	16/11/2022
Date of final enrolment	12/04/2024

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

Quotient Sciences Limited

Mere Way
Ruddington Fields
Ruddington
Nottingham
NG11 6JS
England

Results and Publications

Individual participant data (IPD) Intention to share	No

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No

Editorial Notes

08/07/2026: The following changes were made:
1. The public and scientific titles were changed from "Phase I Trial, Quotient Code: QSC300320".
2. Study objectives, interventions, drug names, primary outcome and key secondary outcomes, key inclusion and exclusion criteria, final enrolment number, health condition(s) or problem(s) studied, and plain English summary of protocol were added.
3. The study design, allocation, masking, control and assignment were added.
4. Date of first enrolment was changed from 20/10/2022 to 16/11/2022.
5. Date of final enrolment was changed from 26/05/2023 to 12/04/2024.
6. Completion date was changed from 10/01/2024 to 12/04/2024.
14/02/2024: The following changes have been made:
1. The overall study end date was changed from 26/05/2023 to 10/01/2024.
2. The study was terminated due to another reason not related to safety.
3. A 30-month extension of the deferral from the overall study end date has been granted.
4. The intention to publish date was changed from 26/11/2025 to 10/07/2026.
17/11/2022: Ethics approval added.
16/11/2022: Deferral confirmed by the Health Research Authority.
05/10/2022: Trial's existence confirmed by the Medical & Healthcare products Regulatory Agency (MHRA).