Congenital Bleeding Disorder, Haemophilia A With Inhibitors, Haemophilia B With Inhibitors
Conditions
Brief summary
This trial is conducted globally. The purpose of this trial is to confirm the efficacy and safety of NNC 0078-0000-0007 in patients with congenital haemophilia and inhibitors.
Detailed description
Scheduled dose visit in a non-bleeding state. Single dose of NNC 0078-0000-0007 (vatreptocog alfa (activated)) every 3 months.
Interventions
1-3 doses per bleeding episode
DRUGeptacog alfa (activated)
1-3 doses per bleeding episode
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male patient with clinical diagnosis of congenital haemophilia A or B and inhibitors to coagulation factors VIII or IX * Minimum of five bleeds requiring haemostatic drug treatment within the previous 12 months at trial entry
Exclusion criteria
* Previous participation in this trial defined as withdrawal after administration of trial product * Patient has received an investigational medicinal product within 30 days prior to this trial * Congenital or acquired coagulation disorders other than haemophilia A or B * Any clinical signs or known history of arterial thrombotic events or of deep venous thrombosis or pulmonary embolism (as defined by available medical records) * Platelet count of less than 50,000 platelets/mcL (at the screening visit) * ALAT (alanine-transaminase) of more than 3 times the upper normal limit (according to laboratory reference ranges) * Factor VIII/IX Immune Tolerance Induction regimen planned to occur during the trial * Ongoing bleeding prophylaxis regimens or planned bleeding prophylaxis to occur during the trial * HIV (Human Immunodeficiency Virus) positive with current CD4+ count of less than 200/mcL (defined by medical records)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Effective Bleeding Control Defined as no Additional Haemostatic Medication (Other Than Trial Product) Given | Within 12 hours of first trial product administration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effective and Sustained Bleeding Control | Up to 48 hours after first trial product administration | — |
| Number of Doses of Trial Product Given for Each Acute Bleed | Up to 6 hours after first trial product administration | — |
| Number of Adverse Events | Adverse events were captured from the time of consent to 1 month (+14 days) after last administration of trial product. | Any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Immunogenicity (Inhibitor Development) | Adverse events were captured from the time of consent to the end of trial visit 1 month (+14 days) after last administration of trial product. | Immunogenicity was tested by formation of neutralising antibodies towards vatreptacog alfa and/or FVII. Radioimmunoassay using \[125I\]-labelled vatreptacog alfa or rFVIIa was used to screen plasma samples for development of anti-drug antibodies |
Countries
Austria, Brazil, Croatia, Greece, Hungary, Italy, Japan, Malaysia, Poland, Puerto Rico, Romania, Russia, Serbia, South Africa, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Patients treated with vatreptacog alfa were recruited from a total of 46 sites globally in 18 countries, including Austria, Brazil, Croatia, Greece, Hungary, Italy, Japan, Malaysia, Poland, Romania, Russia, Serbia, South Africa, Taiwan, Thailand, Turkey, United Kingdom and United States of America.
Participants by arm
| Arm | Count |
|---|---|
| Vatrepcacog Alfa and rFVIIa Subjects participating in the trial were randomised to receive vatreptacog alfa and rFVIIa in a cross-over manner. | 72 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Non-compliance | 2 |
| Overall Study | Unclassified | 1 |
| Overall Study | Withdrawal criteria | 3 |
Baseline characteristics
| Characteristic | Vatrepcacog Alfa and rFVIIa |
|---|---|
| Age, Continuous | 30.19 years STANDARD_DEVIATION 13.84 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 72 | 3 / 57 |
| serious Total, serious adverse events | 4 / 72 | 4 / 57 |
Outcome results
Primary
Effective Bleeding Control Defined as no Additional Haemostatic Medication (Other Than Trial Product) Given
Time frame: Within 12 hours of first trial product administration
Population: Patients with ≥1 efficacy data point. 567 bleeds in 69 patients were treated with vatreptacog/rFVIIa in random sequence. Bleeds excluded in case of identical consecutive treatments, use of both trial products, unknown dispensing unit number.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vatreptacog Alfa 80 µg/kg | Effective Bleeding Control Defined as no Additional Haemostatic Medication (Other Than Trial Product) Given | Additional haemostatic given | 22 bleeding episodes |
| Vatreptacog Alfa 80 µg/kg | Effective Bleeding Control Defined as no Additional Haemostatic Medication (Other Than Trial Product) Given | Additional haemostatic not given | 318 bleeding episodes |
| rFVIIa 90 µg/kg | Effective Bleeding Control Defined as no Additional Haemostatic Medication (Other Than Trial Product) Given | Additional haemostatic given | 16 bleeding episodes |
| rFVIIa 90 µg/kg | Effective Bleeding Control Defined as no Additional Haemostatic Medication (Other Than Trial Product) Given | Additional haemostatic not given | 211 bleeding episodes |
Secondary
Effective and Sustained Bleeding Control
Time frame: Up to 48 hours after first trial product administration
Population: Patients with ≥1 efficacy data point. 567 bleeds in 69 patients were treated with vatreptacog/rFVIIa in random sequence. Bleeds excluded in case of identical consecutive treatments, use of both trial products, unknown dispensing unit number.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vatreptacog Alfa 80 µg/kg | Effective and Sustained Bleeding Control | Additional haemostatic given | 53 bleeding episodes |
| Vatreptacog Alfa 80 µg/kg | Effective and Sustained Bleeding Control | Additional haemostatic not given | 268 bleeding episodes |
| rFVIIa 90 µg/kg | Effective and Sustained Bleeding Control | Additional haemostatic given | 51 bleeding episodes |
| rFVIIa 90 µg/kg | Effective and Sustained Bleeding Control | Additional haemostatic not given | 163 bleeding episodes |
Secondary
Immunogenicity (Inhibitor Development)
Immunogenicity was tested by formation of neutralising antibodies towards vatreptacog alfa and/or FVII. Radioimmunoassay using \[125I\]-labelled vatreptacog alfa or rFVIIa was used to screen plasma samples for development of anti-drug antibodies
Time frame: Adverse events were captured from the time of consent to the end of trial visit 1 month (+14 days) after last administration of trial product.
Population: All patients exposed to at least one dose of trial product was included in the safety analysis set. Patients received scheduled doses with rFVIIa, and treatment (rVIIa and vatreptacog alfa) for each bleeding episode.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vatreptacog Alfa 80 µg/kg | Immunogenicity (Inhibitor Development) | Cross-reactive with rFVIIa | 4 Subjects |
| Vatreptacog Alfa 80 µg/kg | Immunogenicity (Inhibitor Development) | In vitro vatreptacog alfa-neutralising | 1 Subjects |
| Vatreptacog Alfa 80 µg/kg | Immunogenicity (Inhibitor Development) | Positive for anti-rFVIIa | 0 Subjects |
| Vatreptacog Alfa 80 µg/kg | Immunogenicity (Inhibitor Development) | In vitro FVII/rFVIIa-neutralising | 0 Subjects |
| Vatreptacog Alfa 80 µg/kg | Immunogenicity (Inhibitor Development) | Positive for anti-vatreptacog alfa | 8 Subjects |
| rFVIIa 90 µg/kg | Immunogenicity (Inhibitor Development) | In vitro FVII/rFVIIa-neutralising | 0 Subjects |
| rFVIIa 90 µg/kg | Immunogenicity (Inhibitor Development) | Positive for anti-vatreptacog alfa | 0 Subjects |
| rFVIIa 90 µg/kg | Immunogenicity (Inhibitor Development) | Cross-reactive with rFVIIa | 0 Subjects |
| rFVIIa 90 µg/kg | Immunogenicity (Inhibitor Development) | Positive for anti-rFVIIa | 1 Subjects |
| rFVIIa 90 µg/kg | Immunogenicity (Inhibitor Development) | In vitro vatreptacog alfa-neutralising | 0 Subjects |
Secondary
Number of Adverse Events
Any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Adverse events were captured from the time of consent to 1 month (+14 days) after last administration of trial product.
Population: All patients exposed to at least one dose of trial product was included in the safety analysis set. Patients received scheduled doses with rFVIIa, and treatment (rVIIa and vatreptacog alfa) for each bleeding episode.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vatreptacog Alfa 80 µg/kg | Number of Adverse Events | All adverse events | 55 events |
| Vatreptacog Alfa 80 µg/kg | Number of Adverse Events | Mild adverse events | 33 events |
| Vatreptacog Alfa 80 µg/kg | Number of Adverse Events | Moderate adverse events | 15 events |
| Vatreptacog Alfa 80 µg/kg | Number of Adverse Events | Severe adverse events | 7 events |
| rFVIIa 90 µg/kg | Number of Adverse Events | Severe adverse events | 4 events |
| rFVIIa 90 µg/kg | Number of Adverse Events | All adverse events | 11 events |
| rFVIIa 90 µg/kg | Number of Adverse Events | Moderate adverse events | 2 events |
| rFVIIa 90 µg/kg | Number of Adverse Events | Mild adverse events | 5 events |
Secondary
Number of Doses of Trial Product Given for Each Acute Bleed
Time frame: Up to 6 hours after first trial product administration
Population: Patients with ≥1 efficacy data point. 567 bleeds in 69 patients were treated with vatreptacog/rFVIIa in random sequence. Bleeds excluded in case of identical consecutive treatments, use of both trial products, unknown dispensing unit number.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vatreptacog Alfa 80 µg/kg | Number of Doses of Trial Product Given for Each Acute Bleed | 1 dose | 51 bleeding episodes |
| Vatreptacog Alfa 80 µg/kg | Number of Doses of Trial Product Given for Each Acute Bleed | 2 doses | 94 bleeding episodes |
| Vatreptacog Alfa 80 µg/kg | Number of Doses of Trial Product Given for Each Acute Bleed | 3 doses | 195 bleeding episodes |
| rFVIIa 90 µg/kg | Number of Doses of Trial Product Given for Each Acute Bleed | 1 dose | 23 bleeding episodes |
| rFVIIa 90 µg/kg | Number of Doses of Trial Product Given for Each Acute Bleed | 2 doses | 62 bleeding episodes |
| rFVIIa 90 µg/kg | Number of Doses of Trial Product Given for Each Acute Bleed | 3 doses | 142 bleeding episodes |