Congenital AfibrinogenemiaPhase 1/2IG0902NCT02281500
Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Participants With Congenital Afibrinogenemia
A Phase 1/2 study testing Human Plasma-Derived Fibrinogen Concentrate in people with Congenital Afibrinogenemia, run by Grifols Therapeutics LLC at 6 sites in 4 countries.
Trial summary
The main objective of this study was to evaluate the pharmacokinetics (PK), efficacy, and safety of human plasma-derived fibrinogen concentrate FIB Grifols after a single-dose 70 milligrams/kilogram (mg/kg) body weight administration. Read more about this study
- Who is it for?
- Ages Up to 70 years
- Conditions the study is for
- Congenital Afibrinogenemia
- What is being tested?
- Human Plasma-Derived Fibrinogen Concentrate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 6 sitesin 4 countries
- Study dates
- 22 Jul 2016to 11 Nov 2019
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 70 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Male or female participants less than 70 years old.
- Sign the written Informed Consent Form (ICF), or the subjects parent or legal guardian signs the ICF where applicable, and the subjects. Authorization Form where applicable. Pediatric subjects, as defined by local regulations, will be asked to sign an age appropriate assent form.
- Subjects diagnosed with congenital fibrinogen deficiency manifested as afibrinogenemia.
- Subjects with a fibrinogen level undetectable or equal or less than 30 mg/dL determined by both Clauss and antigen methods at baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit) or at Screening Visit (sample drawn at least 14 days prior to infusion on Day 0 Visit).
- Female subjects of child-bearing potential must have a negative test for pregnancy blood or urine human chorionic gonadotropin (HCG-based assay) at baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit).
- Female subjects of child-bearing potential and their partners have agreed to practice contraception using a method of proven reliability (i.e., hormonal methods; barrier methods; intrauterine devices methods) to prevent a pregnancy during the course of the clinical trial.
- Subjects ants must be willing to comply with all aspects of the clinical trial protocol, including blood sampling, for the whole duration of the study.
Who cannot join
- Subjects who received any fibrinogen-containing product within 21 days prior to Day 0 Visit - infusion day.
- Subjects who present with active bleeding within 10 days prior to infusion on Day 0 Visit.
- Subjects with acquired (secondary) fibrinogen deficiency.
- Subjects diagnosed with dysfibrinogenemia.
- Subjects with documented history of deep vein thrombosis, pulmonary embolism, or arterial thrombosis within 1 year prior to enrollment in this clinical trial.
- Subjects with known antibodies against fibrinogen.
Show all 18Show fewer
- Subjects with a history of anaphylactic reactions or severe reactions to any blood-derived product.
- Subjects with a history of intolerance to any component of the investigational products.
- Subjects with a documented history of Immunoglobulin A (IgA) deficiency and antibodies against IgA.
- Females who are pregnant or are breastfeeding.
- Subjects with renal impairment (i.e., serum creatinine exceeds more than 2.0 times the upper limit of normal [ULN] at baseline [sample drawn within 24 hours prior to infusion on Day 0 Visit]).
- Subjects with aspartate aminotransferase or alanine aminotransferase levels exceeding more than 2.5 times the ULN at baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit).
- Subjects with a history of chronic alcoholism or illicit drug addiction in the preceding 12 months prior to enrollment in this clinical trial.
- Subjects with any medical condition which is likely to interfere with the evaluation of the study drugs and/or the satisfactory conduct of the clinical trial according to the investigator's judgment (e.g., congenital or acquired bleeding disorders other than congenital fibrinogen deficiency, planned surgery needing blood transfusion).
- Subjects received aspirin-containing products and nonsteroidal anti-inflammatory drugs within 7 days prior to Day 0 Visit.
- Subjects currently receiving, or having received within 3 months prior to enrollment into this clinical trial, any investigational drug or device.
- Subjects who were previously administered the investigational product FIB Grifols during this clinical trial (i.e., every subject can only participate in the study once).
- Subjects who are unlikely to adhere the protocol requirements, or are likely to be uncooperative, or unable to provide a storage serum sample prior to investigational drug infusion.
Trial locations and contacts
6 sites in 4 countries.
6 sites in 4 countries
India3 sites
St. Johns Medical College and Hospital
Bangalore
S.S. Institute of Medical Sciences and Research Centre
Davangere, Karnataka
Sahyadri Specialty Hospital
Pune
United States1 site
Northshore Long Island Jewish Medical Center
New Hyde Park, New York, 11040
Italy1 site
Agenzia per l'Emofilia Centro di Riferimento Regionale per le Coaugulopatie Congenite A.O. di Carreggi
Florence, 50134
About this study
Official title: Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Patients With Congenital Afibrinogenemia
The main objective of this study was to evaluate the pharmacokinetics (PK), efficacy, and safety of human plasma-derived fibrinogen concentrate FIB Grifols after a single-dose 70 milligrams/kilogram (mg/kg) body weight administration.
Read the detailed description
This study is a phase I-II, multi-center, prospective, open-label, single-arm, clinical trial to evaluate Pharmacokinetic (PK), efficacy, and safety of human plasma-derived fibrinogen concentrate (FIB Grifols) in adult and pediatric participants with congenital afibrinogenemia.
Approximately 10 adult participants (≥18 years) with congenital afibrinogenemia will be administered a single dose of FIB Grifols at 70 mg/kg body weight and will be followed for PK, efficacy, and safety assessments.
After the safety of fibrinogen concentrate FIB Grifols is assessed in at least 10 adult participants and no safety issues are raised by the sponsor, the study will start to enroll approximately 10 pediatric subjects (<18 years) who will be dosed with study drug and followed for PK, efficacy, and safety assessments.
All enrolled participants (both adult and pediatric) will have documented congenital fibrinogen deficiency manifested as afibrinogenemia but will not have received any fibrinogen-containing product therapy within the preceding 21 days before the infusion of study drug.
All participants (both adult and pediatrics) will be infused with the investigational product at 70 mg/kg body weight. PK parameters that will be calculated from plasma fibrinogen levels measured at different time points include: incremental in vivo recovery [IVR], area under the curve (AUC) calculated as AUC from zero to 14 days (AUC^0-14days) and AUC from zero to infinity (AUC^0-∞), maximum plasma concentration (C^max), time to the observed maximum plasma concentration (t^max), half-life (t^1/2), mean residence time (MRT), volume of distribution (Vd), and clearance (Cl).
Hemostatic efficacy of the investigational product will be assessed by means of rotational thromboelastometry (ROTEM) measure of maximum clot firmness (MCF) at baseline and 1 hour post-infusion. Other thromboelastographic measures as well as standard coagulation tests will be also determined pre- and post-infusion.
Clinical safety, viral safety, and immunogenicity will be assessed in this clinical trial. Safety variables include adverse events (AEs), vital signs, physical assessments, laboratory tests, viral markers, and antibodies against human fibrinogen.
A monitoring plan will be implemented by the sponsor to carefully monitor and evaluate allergic/hypersensitivity reactions and thrombotic events during the study.
Stopping criteria have been established for immunogenic and thrombogenic events. If a single case of any these events is reported after a participants has been dosed with study drug, any further enrollment and dosing of participants in the study will be suspended until the event can be adequately assessed by the sponsor. The enrollment and dosing will only resume if the sponsor deems it is safe to do so.
- Conditions
- Congenital Afibrinogenemia
- Being tested
- Human Plasma-Derived Fibrinogen Concentrate
- Medical subject headings
- Afibrinogenemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Human Plasma-Derived Fibrinogen ConcentrateBiological
Also called FIB Grifols
A sterile freeze-dried fibrinogen concentrate filled in vials containing 1 g of FIB Grifols. FIB Grifols contains 20 mg/ml of active substance fibrinogen when reconstituted.
| Study group | Role | What they receive |
|---|---|---|
| Single | Experimental | Human Plasma-Derived Fibrinogen Concentrate Grifols (FIB Grifols) Receives: Biological: Human Plasma-Derived Fibrinogen Concentrate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method used for those arising from decreasing concentrations. Plasma fibrinogen activity determined by the Clauss method in the central laboratory of the study. Pharmacokinetic (PK) parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Enzyme-Linked Immunosorbent Assay (ELISA) Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
AUC From Time Zero to Infinite Time (AUC0-infinity) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration versus (vs) time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time^-1 units (1/h). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
AUC From Time Zero to Infinite Time (AUC0-infinity) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration vs. time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time^-1 units (1/h). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Cmax was obtained directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Cmax was obtained directly from directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by ELISA Method
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Mean Residence Time (MRT) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
MRT was calculated by AUC0-inf/AUC0-inf - (T1/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half-life of infusion. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Mean Residence Time (MRT) of FIB Grifols Assessed Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
MRT was calculated by AUC0-inf/AUC0-inf - (T1/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half life of infusion.PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Volume of Distribution (Vd) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Volume of Distribution (Vd) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Clearance (Cl) of FIB Grifols Determined By Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Clearance (Cl) of FIB Grifols Determined By ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
In Vivo Recovery (IVR) of FIB Grifols Determined by Clauss Method
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram [mg/dL]/[mg/kg]. IVR was determined for every participants using the following formula: ([FIB max (mg/dL)] - [FIB pre-infusion (mg/dL)])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the participant. FIB administered was the actual administered dose calculated using the actual volume administered to the participant, the declared potency, and the true concentration of FIB in the batch used.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
In Vivo Recovery (IVR) of FIB Grifols Determined by ELISA Method
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram [mg/dL]/[mg/kg]. IVR was determined for every participants using the following formula: ([FIB max (mg/dL)] - [FIB pre-infusion (mg/dL)])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the participants. FIB administered was the actual administered dose calculated using the actual volume administered to the participants, the declared potency, and the true concentration of FIB in the batch used.
Measured: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Mean Change on Maximum Clot Firmness (MCF) From Baseline to 1-hour Post-infusion
MCF was as a functional parameter of blood's ability to coagulate, provides an indirect measure of hemostatic efficacy of replacement treatment with fibrinogen concentrates in participants with fibrinogen deficiency. Rotational thromboelastography (ROTEM) was performed on frozen plasma samples by the central laboratory to measure MCF. Undetectable MCF values were set to 0.
Measured: Baseline to 1-hour post-infusion
Secondary outcomes (7)
Mean Change in Clotting Time (CT) From Baseline to 1-hour Post-infusion
Difference in adult participants plasma samples in CT from baseline to 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Measured: Baseline to 1-hour post-infusion
Clot Formation Time (CFT) at 1-hour Post-infusion
CFT value in participants plasma samples in CFT at 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Measured: 1-hour post-infusion
Mean Change in Alpha Angle (α) From Baseline to 1-hour Post-infusion
Difference in participants plasma samples in alpha angle from baseline to 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Measured: Baseline to 1-hour post-infusion
Mean Change in Prothrombin Time (PT) From Baseline to 1-hour Post-infusion
Difference in the participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Measured: Baseline to 1-hour post-infusion
Mean Change in Thrombin Time (TT) From Baseline to 1-hour Post-infusion
Difference in the participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with fibrinogen concentrate in participants with fibrinogen deficiency.
Measured: Baseline to 1-hour post-infusion
Mean Change in Activated Partial Thromboplastin Time (aPTT) From Baseline to 1-hour Post-infusion
Difference in participants plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with a fibrinogen concentrate in participants with fibrinogen deficiency.
Measured: Baseline to 1-hour post-infusion
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
An AE was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. SAE was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-participants hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Treatment-emergent defined as adverse events/serious adverse events that started or worsened on or after the start of the investigational product infusion.
Measured: From the start of the investigation product infusion up to Week 4
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Nov 2014 (estimated)
- Study start22 Jul 2016
- Primary completion11 Nov 2019
- Study completion11 Nov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Congenital AfibrinogenemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Grifols Therapeutics LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Instituto Grifols, S.A.
- Responsible party
- Sponsor
- Investigators
- Flora Peyvandi, MD, Study chair, Centro Emofilia & Trombosi Angelo Bianchi Bonomi
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02281500
- Sponsor's protocol ID
- IG0902
- Acronym
- IG0902
- Status last verified
- Mar 2022
- First submitted
- 24 Oct 2014
- Last updated
- 31 Mar 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 31 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Patients With Congenital Afibrinogenemia
- ClinicalTrials.gov ID
- NCT02281500
- Acronym / sponsor ID
- IG0902 / IG0902
- Conditions
- Congenital Afibrinogenemia
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Grifols Therapeutics LLCIndustry (pharma, biotech, devices)
- Collaborators
- Instituto Grifols, S.A.
- Study start
- 22 Jul 2016 (actual)
- Primary completion
- 11 Nov 2019 (actual)
- Study completion
- 11 Nov 2019 (actual)
- First posted
- 3 Nov 2014 (estimated)
- Results
- Posted 29 Oct 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The main objective of this study was to evaluate the pharmacokinetics (PK), efficacy, and safety of human plasma-derived fibrinogen concentrate FIB Grifols after a single-dose 70 milligrams/kilogram (mg/kg) body weight administration.
Detailed description
This study is a phase I-II, multi-center, prospective, open-label, single-arm, clinical trial to evaluate Pharmacokinetic (PK), efficacy, and safety of human plasma-derived fibrinogen concentrate (FIB Grifols) in adult and pediatric participants with congenital afibrinogenemia.
Approximately 10 adult participants (≥18 years) with congenital afibrinogenemia will be administered a single dose of FIB Grifols at 70 mg/kg body weight and will be followed for PK, efficacy, and safety assessments.
After the safety of fibrinogen concentrate FIB Grifols is assessed in at least 10 adult participants and no safety issues are raised by the sponsor, the study will start to enroll approximately 10 pediatric subjects (<18 years) who will be dosed with study drug and followed for PK, efficacy, and safety assessments.
All enrolled participants (both adult and pediatric) will have documented congenital fibrinogen deficiency manifested as afibrinogenemia but will not have received any fibrinogen-containing product therapy within the preceding 21 days before the infusion of study drug.
All participants (both adult and pediatrics) will be infused with the investigational product at 70 mg/kg body weight. PK parameters that will be calculated from plasma fibrinogen levels measured at different time points include: incremental in vivo recovery [IVR], area under the curve (AUC) calculated as AUC from zero to 14 days (AUC^0-14days) and AUC from zero to infinity (AUC^0-∞), maximum plasma concentration (C^max), time to the observed maximum plasma concentration (t^max), half-life (t^1/2), mean residence time (MRT), volume of distribution (Vd), and clearance (Cl).
Hemostatic efficacy of the investigational product will be assessed by means of rotational thromboelastometry (ROTEM) measure of maximum clot firmness (MCF) at baseline and 1 hour post-infusion. Other thromboelastographic measures as well as standard coagulation tests will be also determined pre- and post-infusion.
Clinical safety, viral safety, and immunogenicity will be assessed in this clinical trial. Safety variables include adverse events (AEs), vital signs, physical assessments, laboratory tests, viral markers, and antibodies against human fibrinogen.
A monitoring plan will be implemented by the sponsor to carefully monitor and evaluate allergic/hypersensitivity reactions and thrombotic events during the study.
Stopping criteria have been established for immunogenic and thrombogenic events. If a single case of any these events is reported after a participants has been dosed with study drug, any further enrollment and dosing of participants in the study will be suspended until the event can be adequately assessed by the sponsor. The enrollment and dosing will only resume if the sponsor deems it is safe to do so.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single | Experimental | Biological: Human Plasma-Derived Fibrinogen ConcentrateHuman Plasma-Derived Fibrinogen Concentrate Grifols (FIB Grifols) |
Who may qualify
- Ages
- Up to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (7 listed)
- Male or female participants less than 70 years old.
- Sign the written Informed Consent Form (ICF), or the subjects parent or legal guardian signs the ICF where applicable, and the subjects. Authorization Form where applicable. Pediatric subjects, as defined by local regulations, will be asked to sign an age appropriate assent form.
- Subjects diagnosed with congenital fibrinogen deficiency manifested as afibrinogenemia.
- Subjects with a fibrinogen level undetectable or equal or less than 30 mg/dL determined by both Clauss and antigen methods at baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit) or at Screening Visit (sample drawn at least 14 days prior to infusion on Day 0 Visit).
- Female subjects of child-bearing potential must have a negative test for pregnancy blood or urine human chorionic gonadotropin (HCG-based assay) at baseline (sample drawn within 24 hours prior to infusion on Day 0 Visit).
Key exclusion criteria (18 listed)
- Subjects who received any fibrinogen-containing product within 21 days prior to Day 0 Visit - infusion day.
- Subjects who present with active bleeding within 10 days prior to infusion on Day 0 Visit.
- Subjects with acquired (secondary) fibrinogen deficiency.
- Subjects diagnosed with dysfibrinogenemia.
- Subjects with documented history of deep vein thrombosis, pulmonary embolism, or arterial thrombosis within 1 year prior to enrollment in this clinical trial.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Human Plasma-Derived Fibrinogen ConcentrateAlso: FIB GrifolsA sterile freeze-dried fibrinogen concentrate filled in vials containing 1 g of FIB Grifols. FIB Grifols contains 20 mg/ml of active substance fibrinogen when reconstituted. | Biological | Single |
Primary outcome
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method used for those arising from decreasing concentrations. Plasma fibrinogen activity determined by the Clauss method in the central laboratory of the study. Pharmacokinetic (PK) parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Enzyme-Linked Immunosorbent Assay (ELISA) Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
AUC From Time Zero to Infinite Time (AUC0-infinity) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration versus (vs) time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time^-1 units (1/h). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
AUC From Time Zero to Infinite Time (AUC0-infinity) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration vs. time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time^-1 units (1/h). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Cmax was obtained directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Cmax was obtained directly from directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study.
Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by ELISA Method
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study.
Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Mean Residence Time (MRT) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
MRT was calculated by AUC0-inf/AUC0-inf - (T1/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half-life of infusion. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Mean Residence Time (MRT) of FIB Grifols Assessed Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
MRT was calculated by AUC0-inf/AUC0-inf - (T1/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half life of infusion.PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Volume of Distribution (Vd) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Volume of Distribution (Vd) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Clearance (Cl) of FIB Grifols Determined By Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
Clearance (Cl) of FIB Grifols Determined By ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation.
In Vivo Recovery (IVR) of FIB Grifols Determined by Clauss Method
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram [mg/dL]/[mg/kg]. IVR was determined for every participants using the following formula: ([FIB max (mg/dL)] - [FIB pre-infusion (mg/dL)])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the participant. FIB administered was the actual administered dose calculated using the actual volume administered to the participant, the declared potency, and the true concentration of FIB in the batch used.
In Vivo Recovery (IVR) of FIB Grifols Determined by ELISA Method
Time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram [mg/dL]/[mg/kg]. IVR was determined for every participants using the following formula: ([FIB max (mg/dL)] - [FIB pre-infusion (mg/dL)])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the participants. FIB administered was the actual administered dose calculated using the actual volume administered to the participants, the declared potency, and the true concentration of FIB in the batch used.
Mean Change on Maximum Clot Firmness (MCF) From Baseline to 1-hour Post-infusion
Time frame: Baseline to 1-hour post-infusion
MCF was as a functional parameter of blood's ability to coagulate, provides an indirect measure of hemostatic efficacy of replacement treatment with fibrinogen concentrates in participants with fibrinogen deficiency. Rotational thromboelastography (ROTEM) was performed on frozen plasma samples by the central laboratory to measure MCF. Undetectable MCF values were set to 0.
7 secondary outcomes
Mean Change in Clotting Time (CT) From Baseline to 1-hour Post-infusion
Time frame: Baseline to 1-hour post-infusion
Clot Formation Time (CFT) at 1-hour Post-infusion
Time frame: 1-hour post-infusion
Mean Change in Alpha Angle (α) From Baseline to 1-hour Post-infusion
Time frame: Baseline to 1-hour post-infusion
Mean Change in Prothrombin Time (PT) From Baseline to 1-hour Post-infusion
Time frame: Baseline to 1-hour post-infusion
Mean Change in Thrombin Time (TT) From Baseline to 1-hour Post-infusion
Time frame: Baseline to 1-hour post-infusion
Mean Change in Activated Partial Thromboplastin Time (aPTT) From Baseline to 1-hour Post-infusion
Time frame: Baseline to 1-hour post-infusion
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Time frame: From the start of the investigation product infusion up to Week 4
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Mar 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Flora Peyvandi, MD study chair
Centro Emofilia & Trombosi Angelo Bianchi Bonomi
6 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Human Plasma-Derived Fibrinogen Concentrate in people with Congenital Afibrinogenemia, run by Grifols Therapeutics LLC at 6 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in India, United States, Italy, Lebanon. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) From Time Zero to 14 Days (AUC0-14days) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration (time frame: Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion). The study lists 19 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Mar 2022.