Severe Hemophilia A
Conditions
Keywords
Hemophilia A, Blood Coagulation Disorders, Inherited, Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic Diseases, Inborn, Factor VIII
Brief summary
This Phase 1/2 study will be a dose escalation study in adults in 5 cohorts (named cohorts 1, 2, 3, 5 and 6), with the main purpose to assess the safety of subcutaneous injection of OCTA101 (a human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer) in previously treated adult patients with severe hemophilia A. The study also aims to assess the pharmacokinetics (PK) characteristics, dose proportionality, and subcutaneous bioavailability of OCTA101 compared with intravenous administration of Nuwiq (Human-cl rh FVIII), in order to define the prophylactic treatment (dose and injection interval) that would result in protective trough levels of FVIII:C for future Phase 3 studies. Cohorts 1, 2, 3 and 5 will undergo a single injection of OCTA101, with cohorts 1, 2 and 3 proceeding to 3-month daily dosing prophylactic treatment for 3 months by Data Monitoring Committee recommendation. Cohorts 1 and 2 will undergo a further PK at the end of the daily injection period. A further cohort, cohort 6, will have an initial 4 to 6-week run-in treatment period with Nuwiq intravenous prophylaxis followed by 12.5 IU/kg OCTA101 subcutaneous daily prophylaxis for \>3 up to 6-7 months.
Interventions
DRUGOCTA101
OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).
Sponsors
Octapharma
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Severe hemophilia A (\<1% FVIII:C) as documented in medical records 2. Males ≥18 years of age 3. Subjects who have had ≥150 exposure days (EDs) with a FVIII product 4. Written informed consent for study participation obtained before undergoing any study specific procedures
Exclusion criteria
1. Previous participation in this trial 2. Use of an Investigational Medicinal Product within 30 days prior to the first OCTA101 injection 3. History of FVIII inhibitors titre ≥0.6 BU/mL defined by medical records 4. Inhibitors to FVIII (≥0.6 BU/mL) at screening measured by Nijmegen modified Bethesda method at central laboratory 5. Human immunodeficiency virus (HIV) positive subjects with a CD4+ count \<200/mL 6. Clinically significant anemia at screening (hemoglobin \<8 g/dL) 7. Presence of any significant comorbidity (at the discretion of the investigator) that might confound the interpretation of the study data and/or that might put the patient at undue risk by participating in the trial 8. Any coagulation disorder other than hemophilia A 9. AST or ALT levels \>3 times the upper limit of normal 10. Creatinine \>120 μmol/L 11. Platelet count \<100,000 μL 12. BMI ≥30 kg/m² 13. For Cohort 6, patients with a positive LumiTope test at screening will be excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patients Experiencing Adverse Events | Approximately 4 months; up to 11 months for cohort 6 | — |
| Participants Experiencing Dose-limiting Toxicities (DLTs) | Approximately 4 months; up to 11 months for cohort 6 | Pre-defined DLTs for this study are: 1. Severe allergic reactions at least possibly related to study drug. 2. Severe vital organ toxicity at least possibly related to study drug that does not resolve to at least mild severity within 48 to 72 hours. 3. Any treatment-emergent severe toxicity at least possibly related to study drug other than the toxicities referenced in 2) that does not decrease to mild or resolve within 7 days |
| Patients Experiencing Thromboembolic Events | Approximately 4 months; up to 11 months for cohort 6 | The definition of the cluster thromboembolic events was based on the standardised MedDRA query (SMQ) Embolic and thrombotic events: Definition: Thrombotic disorders are diseases characterized by formation of a thrombus that obstructs vascular blood flow locally or detaches and embolizes to occlude blood flow downstream. Embolism is the sudden blocking of a vessel by a clot or foreign material which has been brought to its site of lodgment by the blood current. (Thrombo-)phlebitis is an inflammation of a vein (phlebitis) associated with thrombus formation (thrombosis). This SMQ includes 3 sub-SMQ: * Embolic and thrombotic events, venous (SMQ) * Embolic and thrombotic events, arterial (SMQ) * Embolic and thrombotic events, vessel type unspecified and mixed arterial and venous (SMQ) |
| Patients Experiencing Local Injection Site Reactions of Any Grade | Approximately 4 months; up to 11 months for cohort 6. Local injection site reactions were captured throughout the period where OCTA-101 was injected subcutaneously (sc). | Investigator (and patient in case of home treatment) assessed local injection reactivity directly after injection and at 15 ± 5 min post-injection as per the ISO10999-10 standard: 0=no skin reactivity; 1. mild (subject is aware of the signs/symptoms, but finds it easily tolerated) 2. moderate (discomfort enough to cause interference with usual activities) 3. severe (subject is incapacitated and unable to work or participate in many or all usual activities). |
| Inhibitor Formation to FVIII | From first injection to 4 months after start of of daily injection (cohorts 1, 2 and 3), 4 weeks after last PK injection (cohort 5), monthly during the daily sc treatment period (cohort 6) | Development of an inhibitor was defined as a neutralizing antibody value of greater than or equal to (\>=) 0.6 Bethesda units per milliliter (BU/mL) identified and confirmed by a second test on an independent sample. In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample was to be performed, preferably within 15 days of becoming aware of the positive result. Both tests performed by the central laboratory using Nijmegen-modified Bethesda assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Mean Residence Time (MRT) of FVIII:C | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | The average time at which the number of absorbed FVIII molecules reside in the body, after PK injection of OCTA101 as measured by chromogenic assay. |
| Efficacy: Area Under the Concentration-time Curve (AUC(0-tz)) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment. |
| Efficacy: Maximum Plasma Concentration (Cmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment. |
| Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment. |
| Efficacy: In Vivo Recovery (IVR) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | In vivo recovery (IVR) = dose-normalised and body weight-normalised maximum gain in OCTA-12 (ug/dL per ug/kg). |
| Efficacy: Half Life (t1/2) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: t(1/2) could not be determined for OTCA12 as the OCTA12 concentrations had not yet declined during the observation time prior to prior to end of sampling period. |
| Efficacy: Mean Residence Time (MRT) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Note: MRT could not be determined for OCTA12 as the OCTA12 concentrations had not yet declined during the observation time prior to end of sampling period. |
| Efficacy: Total Annualized Bleeding Rate | The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93). | Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate for cohort 6. |
| Patients With Changes to Vital Signs | 5 days to approximately 11 months | Vitals signs changes from baseline, reported as AEs. Number of Participants with changes to vital signs that were considered as Adverse Events. |
| Efficacy: Spontaneous Annualized Bleeding Rate | The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93) | Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total spontaneous annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate |
| Efficacy: Total Annualized Treated Bleeding Rate | The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93) | Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total annualized treated bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate. |
| Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Mean AUC of FVIII after PK injection of OCTA101 as measured by chromogenic assay. |
| Efficacy: Spontaneous Annualized Treated Bleeding Rate | The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93) | Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3. An estimated total spontaneous annualized treated bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate. |
| Efficacy: Traumatic Annualized Bleeding Rate | The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93) | Traumatic annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total traumatic annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate. |
| Efficacy: Joint Annualized Bleeding Rate | The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93) | Joint annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3. An estimated total joint annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate. |
| Efficacy: FVIII:C Trough and Peak Plasma Levels | 3 months; maximally 6 months for cohort 6 | FVIII:C trough and peak plasma levels during daily dosing for cohorts 1, 2, 3 and 6 |
| Efficacy: Efficacy of Treatment of Bleeding Episodes Using Score (4-point). | 5 days to approximately 11 months | Score (4-point) to assess the efficacy of treatment of bleeding episodes with Human-cl rhFVIII. Treatment efficacy will be assessed using predefined criteria to score either 'Excellent', 'Good', 'Moderate' or 'None'. All efficacy ratings assessed as either 'excellent' or 'good' will be considered 'successfully treated'. |
| Safety: Antibody Formation to OCTA12 | From 0 hours (pre-dose) to 72 hours (cohorts 1,2,3,5) or 96 hours (cohort 2). | Samples were checked for the presence of antibodies to OCTA12 by using a validated ELISA in a central lab. |
| Safety: OCTA12 Plasma Levels | 3 months; maximally 6 months for cohort 6 | OCTA12 plasma levels during daily dosing (cohorts 1, 2, 3 and 6). |
| Safety: Change in Hemoglobin | 5 days to approximately 11 months. All routine lab parameters and vital signs were measured at various times, until end of PK and also monthly during daily prophylaxis.) | Number of Participants with changes in hemoglobin levels that were considered as Adverse Events. |
| Safety: Change in Alanine Aminotransferase (ALT) | 5 days to approximately 11 months. All routine lab parameters and vital signs were measured at various times, until end of PK and also monthly during daily prophylaxis.) | Alanine aminotransferase (ALT) compared to baseline, measured in U/L. Number of Participants with changes in ALT that were considered as Adverse Events. |
| Safety: Change in Aspartate Transaminase (AST) | 5 days to approximately 11 months | Aspartate transaminase (AST) compared to baseline, measured in U/l. Number of Participants with changes in AST that were considered as Adverse Events. |
| Patients With Changes in Physical Examination Results | 5 days to approximately 11 months | Number of Participants with changes to their physical examination results from baseline that were considered as Adverse Events |
| Efficacy: Maximum Plasma Concentration (Cmax) of FVIII:C | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Maximum observed concentration of FVIII:C after PK injection of OCTA101 as measured by chromogenic assay. |
| Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of FVIII:C | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Time of occurrence of Cmax after PK injection of OCTA101 as measured by chromogenic assay. |
| In Vivo Recovery (IVR) of FVIII:C | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | In vivo recovery (IVR) = dose-normalised and body weight-normalised maximum gain in FVIII:C (IU/dL per IU/kg) |
| Efficacy: Half-life (t1/2) of FVIII:C | From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2) | Apparent terminal log-linear half-life of FVIII:C after PK injection of OCTA101 as measured by chromogenic assay. |
Countries
Bulgaria
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 50 IU/kg (n=4): single-period investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 72 hours after dosing in adult male patients with severe hemophilia A.
Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 2, alongside daily prophylactic dosing (40-60 IU/kg) for 3 months.
OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer). | 4 |
| Cohort 2 100 IU/kg (n=4): single-period investigation with a single sc dose of 100 IU/kg OCTA101 profiled up to 96 hours after dosing in adult male patients with severe hemophilia A.
Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 3, alongside daily prophylactic dosing (40-60 IU/kg) for 3 months.
OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer). | 4 |
| Cohort 3 50 IU/kg (n=8): two-period investigation of a single iv dose of 50 IU/kg Human-cl rhFVIII (Nuwiq) profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg OCTA101 profiled up to 72 hours in adult male patients with severe hemophilia A.
Treatments will be administered in fixed sequence, with Human-cl rhFVIII first.
Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months.
OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer). | 8 |
| Cohort 5 (n=4): Three-period investigation of single sc doses of 20, 40, and 60 IU/kg OCTA101 profiled up to 72 hours after dosing. Treatments were to be administered in fixed dose-ascending sequence.
OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer). | 4 |
| Cohort 6 (n≥16): following an initial 4-6-week run-in period with Nuwiq iv prophylaxis, 6-month prophylactic treatment with 12.5 IU/kg OCTA101 sc daily was planned. Sixteen patients entered the Nuwiq iv run-in and 10 patients went on to receive OCTA101 12.5 IU/kg. The study was terminated before treatment could be completed.
OCTA101: OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer). | 16 |
| Total | 36 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 5 | Cohort 6 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 37.0 years STANDARD_DEVIATION 7.35 | 40.5 years STANDARD_DEVIATION 11.82 | 43.5 years STANDARD_DEVIATION 12.78 | 29.5 years STANDARD_DEVIATION 5.51 | 41.9 years STANDARD_DEVIATION 12.37 | 38.8 years STANDARD_DEVIATION 11.15 |
| BMI | 27.7 kg per m2 STANDARD_DEVIATION 2.79 | 27.1 kg per m2 STANDARD_DEVIATION 3.14 | 25.3 kg per m2 STANDARD_DEVIATION 3.89 | 27.8 kg per m2 STANDARD_DEVIATION 3.59 | 24.6 kg per m2 STANDARD_DEVIATION 5.03 | 26.6 kg per m2 STANDARD_DEVIATION 3.42 |
| Haemophilia joint health score | 24.3 units on a scale STANDARD_DEVIATION 19.65 | 27.8 units on a scale STANDARD_DEVIATION 26.11 | 23.3 units on a scale STANDARD_DEVIATION 12.61 | 16.3 units on a scale STANDARD_DEVIATION 8.14 | 21.25 units on a scale STANDARD_DEVIATION 11.38 | 23.0 units on a scale STANDARD_DEVIATION 15.89 |
| Race/Ethnicity, Customized White/Non-Hispanic or Latino | 4 Participants | 4 Participants | 8 Participants | 4 Participants | 16 Participants | 36 Participants |
| Region of Enrollment Bulgaria | 4 participants | 4 participants | 8 participants | 4 participants | 16 participants | 36 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants | 4 Participants | 16 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 1 / 4 | 0 / 8 | 0 / 4 | 0 / 16 |
| other Total, other adverse events | 0 / 4 | 2 / 4 | 0 / 8 | 0 / 4 | 2 / 16 |
| serious Total, serious adverse events | 0 / 4 | 2 / 4 | 1 / 8 | 0 / 4 | 2 / 16 |
Outcome results
Primary
Inhibitor Formation to FVIII
Development of an inhibitor was defined as a neutralizing antibody value of greater than or equal to (\>=) 0.6 Bethesda units per milliliter (BU/mL) identified and confirmed by a second test on an independent sample. In case of positive inhibitor results, inhibitor retesting using a second, separately drawn sample was to be performed, preferably within 15 days of becoming aware of the positive result. Both tests performed by the central laboratory using Nijmegen-modified Bethesda assay.
Time frame: From first injection to 4 months after start of of daily injection (cohorts 1, 2 and 3), 4 weeks after last PK injection (cohort 5), monthly during the daily sc treatment period (cohort 6)
Population: The population included all patients who received at least one dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Inhibitor Formation to FVIII | 0 Participants |
| Cohort 2 | Inhibitor Formation to FVIII | 2 Participants |
| Cohort 3 | Inhibitor Formation to FVIII | 1 Participants |
| Cohort 5 | Inhibitor Formation to FVIII | 0 Participants |
| Cohort 6 | Inhibitor Formation to FVIII | 2 Participants |
Primary
Participants Experiencing Dose-limiting Toxicities (DLTs)
Pre-defined DLTs for this study are: 1. Severe allergic reactions at least possibly related to study drug. 2. Severe vital organ toxicity at least possibly related to study drug that does not resolve to at least mild severity within 48 to 72 hours. 3. Any treatment-emergent severe toxicity at least possibly related to study drug other than the toxicities referenced in 2) that does not decrease to mild or resolve within 7 days
Time frame: Approximately 4 months; up to 11 months for cohort 6
Population: The population included all patients who received at least one dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Participants Experiencing Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort 2 | Participants Experiencing Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort 3 | Participants Experiencing Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort 5 | Participants Experiencing Dose-limiting Toxicities (DLTs) | 0 Participants |
| Cohort 6 | Participants Experiencing Dose-limiting Toxicities (DLTs) | 0 Participants |
Primary
Patients Experiencing Adverse Events
Time frame: Approximately 4 months; up to 11 months for cohort 6
Population: The population included all patients who received at least one dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Patients Experiencing Adverse Events | 0 Participants |
| Cohort 2 | Patients Experiencing Adverse Events | 2 Participants |
| Cohort 3 | Patients Experiencing Adverse Events | 1 Participants |
| Cohort 5 | Patients Experiencing Adverse Events | 0 Participants |
| Cohort 6 | Patients Experiencing Adverse Events | 3 Participants |
Primary
Patients Experiencing Local Injection Site Reactions of Any Grade
Investigator (and patient in case of home treatment) assessed local injection reactivity directly after injection and at 15 ± 5 min post-injection as per the ISO10999-10 standard: 0=no skin reactivity; 1. mild (subject is aware of the signs/symptoms, but finds it easily tolerated) 2. moderate (discomfort enough to cause interference with usual activities) 3. severe (subject is incapacitated and unable to work or participate in many or all usual activities).
Time frame: Approximately 4 months; up to 11 months for cohort 6. Local injection site reactions were captured throughout the period where OCTA-101 was injected subcutaneously (sc).
Population: The population included all patients who received at least one dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Patients Experiencing Local Injection Site Reactions of Any Grade | 0 Participants |
| Cohort 2 | Patients Experiencing Local Injection Site Reactions of Any Grade | 1 Participants |
| Cohort 3 | Patients Experiencing Local Injection Site Reactions of Any Grade | 0 Participants |
| Cohort 5 | Patients Experiencing Local Injection Site Reactions of Any Grade | 0 Participants |
| Cohort 6 | Patients Experiencing Local Injection Site Reactions of Any Grade | 0 Participants |
Primary
Patients Experiencing Thromboembolic Events
The definition of the cluster thromboembolic events was based on the standardised MedDRA query (SMQ) Embolic and thrombotic events: Definition: Thrombotic disorders are diseases characterized by formation of a thrombus that obstructs vascular blood flow locally or detaches and embolizes to occlude blood flow downstream. Embolism is the sudden blocking of a vessel by a clot or foreign material which has been brought to its site of lodgment by the blood current. (Thrombo-)phlebitis is an inflammation of a vein (phlebitis) associated with thrombus formation (thrombosis). This SMQ includes 3 sub-SMQ: * Embolic and thrombotic events, venous (SMQ) * Embolic and thrombotic events, arterial (SMQ) * Embolic and thrombotic events, vessel type unspecified and mixed arterial and venous (SMQ)
Time frame: Approximately 4 months; up to 11 months for cohort 6
Population: The population included all patients who received at least one dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Patients Experiencing Thromboembolic Events | 0 Participants |
| Cohort 2 | Patients Experiencing Thromboembolic Events | 0 Participants |
| Cohort 3 | Patients Experiencing Thromboembolic Events | 0 Participants |
| Cohort 5 | Patients Experiencing Thromboembolic Events | 0 Participants |
| Cohort 6 | Patients Experiencing Thromboembolic Events | 0 Participants |
Secondary
Efficacy: Area Under the Concentration-time Curve (AUC(0-tz)) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Efficacy: Area Under the Concentration-time Curve (AUC(0-tz)) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 3083.3 ng*h/mL | Standard Deviation 701.3 |
| Cohort 2 | Efficacy: Area Under the Concentration-time Curve (AUC(0-tz)) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 7061.5 ng*h/mL | Standard Deviation 3436.5 |
| Cohort 3 | Efficacy: Area Under the Concentration-time Curve (AUC(0-tz)) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 2897.9 ng*h/mL | Standard Deviation 1049.2 |
| Cohort 5 | Efficacy: Area Under the Concentration-time Curve (AUC(0-tz)) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 1762.9 ng*h/mL | Standard Deviation 589.9 |
Secondary
Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C
Mean AUC of FVIII after PK injection of OCTA101 as measured by chromogenic assay.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: Cohort 5 data is given for 40 IU/kg dose. No PK data for cohort 6. For 1 patient in cohort 2, the measurable the levels of FVIII:C were very low and not evaluable by conventional non-compartmental PK
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C | 0.06265 IU*h/mL per IU/kg dosed | Standard Deviation 0.02606 |
| Cohort 2 | Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C | 0.05453 IU*h/mL per IU/kg dosed | Standard Deviation 0.01934 |
| Cohort 3 | Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C | 0.06558 IU*h/mL per IU/kg dosed | Standard Deviation 0.04452 |
| Cohort 5 | Efficacy: Area Under the Concentration-time Curve (AUC) of FVIII:C | 0.0695 IU*h/mL per IU/kg dosed | Standard Deviation 0.0274 |
Secondary
Efficacy: Efficacy of Treatment of Bleeding Episodes Using Score (4-point).
Score (4-point) to assess the efficacy of treatment of bleeding episodes with Human-cl rhFVIII. Treatment efficacy will be assessed using predefined criteria to score either 'Excellent', 'Good', 'Moderate' or 'None'. All efficacy ratings assessed as either 'excellent' or 'good' will be considered 'successfully treated'.
Time frame: 5 days to approximately 11 months
Secondary
Efficacy: FVIII:C Trough and Peak Plasma Levels
FVIII:C trough and peak plasma levels during daily dosing for cohorts 1, 2, 3 and 6
Time frame: 3 months; maximally 6 months for cohort 6
Population: Not all patients in cohort 2 and 3 were analyzed at month 2 and 3 due to study termination. Only 3 patients were analyzed in cohort 6 at month 3 due to study termination. No PK analysis were performed for cohort 6.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.1885 IU/mL |
| Cohort 1 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0035 IU/mL |
| Cohort 1 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.1125 IU/mL |
| Cohort 1 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 2 | 0.1510 IU/mL |
| Cohort 1 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 3 | 0.1645 IU/mL |
| Cohort 2 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 2 | 0.1920 IU/mL |
| Cohort 2 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.1395 IU/mL |
| Cohort 2 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0210 IU/mL |
| Cohort 2 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.1995 IU/mL |
| Cohort 2 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 3 | 0.1995 IU/mL |
| Cohort 3 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 3 | 0.2250 IU/mL |
| Cohort 3 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.1580 IU/mL |
| Cohort 3 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0375 IU/mL |
| Cohort 3 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.2175 IU/mL |
| Cohort 3 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 2 | 0.2155 IU/mL |
| Cohort 5 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 3 | 0.0655 IU/mL |
| Cohort 5 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.0465 IU/mL |
| Cohort 5 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 2 | 0.0120 IU/mL |
| Cohort 5 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0058 IU/mL |
| Cohort 5 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.0620 IU/mL |
| Cohort 6 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.0515 IU/mL |
| Cohort 6 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.1015 IU/mL |
| Cohort 6 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 3 | 0.0698 IU/mL |
| Cohort 6 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 2 | 0.0110 IU/mL |
| Cohort 6 | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0160 IU/mL |
| Cohort 2 - 6 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.0615 IU/mL |
| Cohort 2 - 6 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.1270 IU/mL |
| Cohort 2 - 6 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 2 | 0.0100 IU/mL |
| Cohort 2 - 6 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 3 | 0.0775 IU/mL |
| Cohort 2 - 6 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0245 IU/mL |
| Cohort 3 Predose | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.1025 IU/mL |
| Cohort 3 Predose | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.1080 IU/mL |
| Cohort 3 Predose | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0090 IU/mL |
| Cohort 3 - 3 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.1120 IU/mL |
| Cohort 3 - 3 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0405 IU/mL |
| Cohort 3 - 3 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.1250 IU/mL |
| Cohort 3 - 6 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.1610 IU/mL |
| Cohort 3 - 6 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0645 IU/mL |
| Cohort 3 - 6 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.1440 IU/mL |
| Cohort 6 Predose | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 2 | 0.0190 IU/mL |
| Cohort 6 Predose | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0035 IU/mL |
| Cohort 6 Predose | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 3 | 0.0120 IU/mL |
| Cohort 6 Predose | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.0150 IU/mL |
| Cohort 6 Predose | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.0185 IU/mL |
| Cohort 6 - 8 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Start of daily treatment | 0.0170 IU/mL |
| Cohort 6 - 8 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 0.5 | 0.0250 IU/mL |
| Cohort 6 - 8 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 1 | 0.0280 IU/mL |
| Cohort 6 - 8 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 2 | 0.0325 IU/mL |
| Cohort 6 - 8 Hours | Efficacy: FVIII:C Trough and Peak Plasma Levels | Month 3 | 0.0230 IU/mL |
Secondary
Efficacy: Half-life (t1/2) of FVIII:C
Apparent terminal log-linear half-life of FVIII:C after PK injection of OCTA101 as measured by chromogenic assay.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: For 1 patient in cohort 2, the measurable the levels of FVIII:C were very low and not evaluable by conventional non-compartmental PK). Cohort 5 data is given for 40 IU/kg dose. No PK data for cohort 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Efficacy: Half-life (t1/2) of FVIII:C | 22.74 hours | Standard Deviation 12.4 |
| Cohort 2 | Efficacy: Half-life (t1/2) of FVIII:C | 24.45 hours | Standard Deviation 6.92 |
| Cohort 3 | Efficacy: Half-life (t1/2) of FVIII:C | 26.59 hours | Standard Deviation 10.19 |
| Cohort 5 | Efficacy: Half-life (t1/2) of FVIII:C | 22.77 hours | Standard Deviation 4.88 |
Secondary
Efficacy: Half Life (t1/2) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: t(1/2) could not be determined for OTCA12 as the OCTA12 concentrations had not yet declined during the observation time prior to prior to end of sampling period.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: The total of 20 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: Half Life (t1/2) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 1 | NA hours |
| Cohort 1 | Efficacy: Half Life (t1/2) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 2 | NA hours |
| Cohort 1 | Efficacy: Half Life (t1/2) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 3 | NA hours |
| Cohort 1 | Efficacy: Half Life (t1/2) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 5 | NA hours |
Secondary
Efficacy: In Vivo Recovery (IVR) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
In vivo recovery (IVR) = dose-normalised and body weight-normalised maximum gain in OCTA-12 (ug/dL per ug/kg).
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: The total of 20 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: In Vivo Recovery (IVR) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 5 | NA ug/dL per ug/kg |
| Cohort 1 | Efficacy: In Vivo Recovery (IVR) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 3 | NA ug/dL per ug/kg |
| Cohort 1 | Efficacy: In Vivo Recovery (IVR) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 1 | NA ug/dL per ug/kg |
| Cohort 1 | Efficacy: In Vivo Recovery (IVR) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 2 | NA ug/dL per ug/kg |
Secondary
Efficacy: Joint Annualized Bleeding Rate
Joint annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3. An estimated total joint annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate.
Time frame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
Population: The total of 26 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: Joint Annualized Bleeding Rate | Cohort 1 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Joint Annualized Bleeding Rate | Cohort 2 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Joint Annualized Bleeding Rate | Cohort 3 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Joint Annualized Bleeding Rate | Cohort 6 | NA Total bleeding events per year |
Secondary
Efficacy: Maximum Plasma Concentration (Cmax) of FVIII:C
Maximum observed concentration of FVIII:C after PK injection of OCTA101 as measured by chromogenic assay.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: For 1 patient in cohort 2, the measurable the levels of FVIII:C were very low and not evaluable by conventional non-compartmental PK). Cohort 5 data is given for 40 IU/kg dose. No PK data for cohort 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Efficacy: Maximum Plasma Concentration (Cmax) of FVIII:C | 0.082 IU/mL | Standard Deviation 0.012 |
| Cohort 2 | Efficacy: Maximum Plasma Concentration (Cmax) of FVIII:C | 0.143 IU/mL | Standard Deviation 0.065 |
| Cohort 3 | Efficacy: Maximum Plasma Concentration (Cmax) of FVIII:C | 0.074 IU/mL | Standard Deviation 0.034 |
| Cohort 5 | Efficacy: Maximum Plasma Concentration (Cmax) of FVIII:C | 0.107 IU/mL | Standard Deviation 0.014 |
Secondary
Efficacy: Maximum Plasma Concentration (Cmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Efficacy: Maximum Plasma Concentration (Cmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 59.6 ng/ml | Standard Deviation 11.69 |
| Cohort 2 | Efficacy: Maximum Plasma Concentration (Cmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 95.8 ng/ml | Standard Deviation 38.8 |
| Cohort 3 | Efficacy: Maximum Plasma Concentration (Cmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 54.31 ng/ml | Standard Deviation 19.25 |
| Cohort 5 | Efficacy: Maximum Plasma Concentration (Cmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 32.95 ng/ml | Standard Deviation 11.5 |
Secondary
Efficacy: Mean Residence Time (MRT) of FVIII:C
The average time at which the number of absorbed FVIII molecules reside in the body, after PK injection of OCTA101 as measured by chromogenic assay.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: For 1 patient in cohort 2, the measurable the levels of FVIII:C were very low and not evaluable by conventional non-compartmental PK). Cohort 5 data is given for 40 IU/kg dose. No PK data for cohort 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Efficacy: Mean Residence Time (MRT) of FVIII:C | 37.91 hours | Standard Deviation 18.9 |
| Cohort 2 | Efficacy: Mean Residence Time (MRT) of FVIII:C | 40.50 hours | Standard Deviation 3.86 |
| Cohort 3 | Efficacy: Mean Residence Time (MRT) of FVIII:C | 43.08 hours | Standard Deviation 15.7 |
| Cohort 5 | Efficacy: Mean Residence Time (MRT) of FVIII:C | 37.97 hours | Standard Deviation 7.99 |
Secondary
Efficacy: Mean Residence Time (MRT) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
Note: MRT could not be determined for OCTA12 as the OCTA12 concentrations had not yet declined during the observation time prior to end of sampling period.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: The total of 20 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: Mean Residence Time (MRT) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 1 | NA hours |
| Cohort 1 | Efficacy: Mean Residence Time (MRT) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 2 | NA hours |
| Cohort 1 | Efficacy: Mean Residence Time (MRT) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 3 | NA hours |
| Cohort 1 | Efficacy: Mean Residence Time (MRT) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | Cohort 5 | NA hours |
Secondary
Efficacy: Spontaneous Annualized Bleeding Rate
Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total spontaneous annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate
Time frame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
Population: The total of 26 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: Spontaneous Annualized Bleeding Rate | Cohort 1 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Spontaneous Annualized Bleeding Rate | Cohort 2 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Spontaneous Annualized Bleeding Rate | Cohort 3 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Spontaneous Annualized Bleeding Rate | Cohort 6 | NA Total bleeding events per year |
Secondary
Efficacy: Spontaneous Annualized Treated Bleeding Rate
Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3. An estimated total spontaneous annualized treated bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate.
Time frame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
Population: The total of 26 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: Spontaneous Annualized Treated Bleeding Rate | Cohort 1 | 0 bleeding events per year |
| Cohort 1 | Efficacy: Spontaneous Annualized Treated Bleeding Rate | Cohort 2 | 0 bleeding events per year |
| Cohort 1 | Efficacy: Spontaneous Annualized Treated Bleeding Rate | Cohort 3 | 0 bleeding events per year |
| Cohort 1 | Efficacy: Spontaneous Annualized Treated Bleeding Rate | Cohort 6 | NA bleeding events per year |
Secondary
Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of FVIII:C
Time of occurrence of Cmax after PK injection of OCTA101 as measured by chromogenic assay.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: For 1 patient in cohort 2, the measurable the levels of FVIII:C were very low and not evaluable by conventional non-compartmental PK). Cohort 5 data is given for 40 IU/kg dose. No PK data for cohort 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of FVIII:C | 8.04 hours | Standard Deviation 0.06 |
| Cohort 2 | Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of FVIII:C | 18.92 hours | Standard Deviation 10.23 |
| Cohort 3 | Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of FVIII:C | 13.56 hours | Standard Deviation 6.49 |
| Cohort 5 | Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of FVIII:C | 11.11 hours | Standard Deviation 0.02 |
Secondary
Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer)
Measurement of OCTA12 plasma concentrations using a validated ELISA in a central lab. Note: OCTA12 was not determined for cohort 6 regarding PK assessment.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 71.46 hours | Standard Deviation 1.01 |
| Cohort 2 | Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 71.39 hours | Standard Deviation 19.22 |
| Cohort 3 | Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 68.15 hours | Standard Deviation 8.41 |
| Cohort 5 | Efficacy: Time for Reaching Maximum Plasma Concentration (Tmax) of OCTA12 (a Recombinant Von Willebrand Factor Fragment Dimer) | 59.26 hours | Standard Deviation 13.71 |
Secondary
Efficacy: Total Annualized Bleeding Rate
Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate for cohort 6.
Time frame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93).
Population: The total of 26 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: Total Annualized Bleeding Rate | Cohort 1 | 0 Annualized number of bleedings |
| Cohort 1 | Efficacy: Total Annualized Bleeding Rate | Cohort 2 | 0 Annualized number of bleedings |
| Cohort 1 | Efficacy: Total Annualized Bleeding Rate | Cohort 3 | 0 Annualized number of bleedings |
| Cohort 1 | Efficacy: Total Annualized Bleeding Rate | Cohort 6 | NA Annualized number of bleedings |
Secondary
Efficacy: Total Annualized Treated Bleeding Rate
Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total annualized treated bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate.
Time frame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
Population: The total of 26 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: Total Annualized Treated Bleeding Rate | Cohort 1 | 0 bleeding events per year |
| Cohort 1 | Efficacy: Total Annualized Treated Bleeding Rate | Cohort 2 | 0 bleeding events per year |
| Cohort 1 | Efficacy: Total Annualized Treated Bleeding Rate | Cohort 3 | 0 bleeding events per year |
| Cohort 1 | Efficacy: Total Annualized Treated Bleeding Rate | Cohort 6 | NA bleeding events per year |
Secondary
Efficacy: Traumatic Annualized Bleeding Rate
Traumatic annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2 and 3 An estimated total traumatic annualized bleeding rate was calculated for cohorts 1,2 and 3. As these were estimated rates, there is only one value for each cohort with no measure of spread. As the study was terminated so soon, it was not considered accurate to extrapolate results to one year for annualized bleeding rate.
Time frame: The median (min, max) duration of daily sc treatment with OCTA101 in the 16 patients of cohort 1, 2 and 3 was 42 days (22, 93)
Population: The total of 26 participants were divided between their assigned cohorts.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Efficacy: Traumatic Annualized Bleeding Rate | Cohort 1 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Traumatic Annualized Bleeding Rate | Cohort 2 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Traumatic Annualized Bleeding Rate | Cohort 3 | 0 Total bleeding events per year |
| Cohort 1 | Efficacy: Traumatic Annualized Bleeding Rate | Cohort 6 | NA Total bleeding events per year |
Secondary
In Vivo Recovery (IVR) of FVIII:C
In vivo recovery (IVR) = dose-normalised and body weight-normalised maximum gain in FVIII:C (IU/dL per IU/kg)
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,3,5) or 96 hours (cohort 2)
Population: For 1 patient in cohort 2, the measurable the levels of FVIII:C were very low and not evaluable by conventional non-compartmental PK). Cohort 5 data is given for 40 IU/kg dose. No PK data for cohort 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | In Vivo Recovery (IVR) of FVIII:C | 0.146 IU/dL per IU/kg | Standard Deviation 0.021 |
| Cohort 2 | In Vivo Recovery (IVR) of FVIII:C | 0.132 IU/dL per IU/kg | Standard Deviation 0.056 |
| Cohort 3 | In Vivo Recovery (IVR) of FVIII:C | 0.135 IU/dL per IU/kg | Standard Deviation 0.058 |
| Cohort 5 | In Vivo Recovery (IVR) of FVIII:C | 0.233 IU/dL per IU/kg | Standard Deviation 0.033 |
Secondary
Patients With Changes in Physical Examination Results
Number of Participants with changes to their physical examination results from baseline that were considered as Adverse Events
Time frame: 5 days to approximately 11 months
Population: The population included all patients who received at least one dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Patients With Changes in Physical Examination Results | 0 Participants |
| Cohort 2 | Patients With Changes in Physical Examination Results | 2 Participants |
| Cohort 3 | Patients With Changes in Physical Examination Results | 1 Participants |
| Cohort 5 | Patients With Changes in Physical Examination Results | 0 Participants |
| Cohort 6 | Patients With Changes in Physical Examination Results | 3 Participants |
Secondary
Patients With Changes to Vital Signs
Vitals signs changes from baseline, reported as AEs. Number of Participants with changes to vital signs that were considered as Adverse Events.
Time frame: 5 days to approximately 11 months
Population: The population included all patients who received at least one dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Patients With Changes to Vital Signs | 0 Participants |
| Cohort 2 | Patients With Changes to Vital Signs | 0 Participants |
| Cohort 3 | Patients With Changes to Vital Signs | 0 Participants |
| Cohort 5 | Patients With Changes to Vital Signs | 0 Participants |
| Cohort 6 | Patients With Changes to Vital Signs | 0 Participants |
Secondary
Safety: Antibody Formation to OCTA12
Samples were checked for the presence of antibodies to OCTA12 by using a validated ELISA in a central lab.
Time frame: From 0 hours (pre-dose) to 72 hours (cohorts 1,2,3,5) or 96 hours (cohort 2).
Population: The population included all patients who received at least one dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Safety: Antibody Formation to OCTA12 | 0 Participants |
| Cohort 2 | Safety: Antibody Formation to OCTA12 | 0 Participants |
| Cohort 3 | Safety: Antibody Formation to OCTA12 | 0 Participants |
| Cohort 5 | Safety: Antibody Formation to OCTA12 | 0 Participants |
| Cohort 6 | Safety: Antibody Formation to OCTA12 | 0 Participants |
Secondary
Safety: Change in Alanine Aminotransferase (ALT)
Alanine aminotransferase (ALT) compared to baseline, measured in U/L. Number of Participants with changes in ALT that were considered as Adverse Events.
Time frame: 5 days to approximately 11 months. All routine lab parameters and vital signs were measured at various times, until end of PK and also monthly during daily prophylaxis.)
Secondary
Safety: Change in Aspartate Transaminase (AST)
Aspartate transaminase (AST) compared to baseline, measured in U/l. Number of Participants with changes in AST that were considered as Adverse Events.
Time frame: 5 days to approximately 11 months
Secondary
Safety: Change in Hemoglobin
Number of Participants with changes in hemoglobin levels that were considered as Adverse Events.
Time frame: 5 days to approximately 11 months. All routine lab parameters and vital signs were measured at various times, until end of PK and also monthly during daily prophylaxis.)
Secondary
Safety: OCTA12 Plasma Levels
OCTA12 plasma levels during daily dosing (cohorts 1, 2, 3 and 6).
Time frame: 3 months; maximally 6 months for cohort 6