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The rationale of this study is to further fine-tune and individualize prophylactic treatment of patients with severe Haemophilia A with the goal of keeping the trough FVIII level above 1% between doses. Because trough FVIII levels are likely to be important predictors of the efficacy of prophylaxis, the focus of this study is on pharmacokinetic (PK) data.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Human-cl rhFVIII | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Human cl rhFVIII | Biological |
|
| Measure | Description | Time Frame |
|---|---|---|
| Annualized Total Bleeding Rate of Individually Tailored Prophylaxis | Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis | Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII | 6 months |
| Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Craig M Kessler, MD | Georgetown University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Octapharma Research Site | Sacramento | California | 95817 | United States | ||
| Octapharma Research Site |
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| ID | Title | Description |
|---|---|---|
| FG000 | Human-cl rhFVIII | The study consisted of 3 phases:
All 58 patients were included in the safety (SAF) and the intention-to-treat (ITT) populations. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Pharmacokinetic (PK) Evaluation Phase |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 24, 2019 | Dec 21, 2020 |
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Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII |
| 6 months |
| Median Prophylactic Dosing Interval | Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient | 6 months |
| Mean Prophylactic Dosing Interval | Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient | 6 months |
| AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII | AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
| In-vivo Recovery (IVR) of Human-cl rhFVIII | IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
| Half Life (t1/2) of Human-cl rhFVIII | T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
| Mean Residence Time (MRT) of Human-cl rhFVIII | MRT of Human-cl rhFVIII measured using the one-stage (OS) assay | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
| Clearance (CL) of Human-cl rhFVIII | CL of Human-cl rhFVIII measured using the one-stage (OS) assay | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
| Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII | Vss of Human-cl rhFVIII measured using the one-stage (OS) assay | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
| Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient) | Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment | 6 months |
| Number of Patients With Adverse Events (AEs) | AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria | At each study visit over the study duration (7-9 months) |
| Aurora |
| Colorado |
| 80045 |
| United States |
| Octapharma Research Site | Washington D.C. | District of Columbia | 20057 | United States |
| Octapharma Research Site | Miami | Florida | 33136 | United States |
| Octapharma Research Site | Chicago | Illinois | 60612 | United States |
| Octapharma Research Site | Indianapolis | Indiana | 46260 | United States |
| Octapharma Research Site | Memphis | Tennessee | 38163 | United States |
| Octapharma Research Site | Houston | Texas | 77030 | United States |
| Octapharma Research Site | Salt Lake City | Utah | 84112 | United States |
| Octapharma Research Site | Edmonton | Alberta | T6G1C9 | Canada |
| Octapharma Research Site | St. John's | Newfoundland and Labrador | Canada |
| McMaster University | Hamilton | Ontario | L8N 4K1 | Canada |
| University Hospital Centre Zagreb | Zagreb | Croatia |
| Helsinki University Hospital | Helsinki | 00290 | Finland |
| Centre Régional de Traitement de l'Hémophilie | Bron | 69677 | France |
| CHU Estaing | Clermont-Ferrand | France |
| Centre Hospitalier Universitaire Félix Guyon | La Réunion | 97400 | France |
| Centre Régional de Traitement de l'hémophilie | Nantes | 44093 | France |
| Hôpital Purpan - Centre de Traitment Regional de l'Hemophilie Pole | Toulouse | 31059 | France |
| Nagoya University Hospital | Nagoya | Aichi-ken | Japan |
| Hospital of the Univ of Occupational and Environmental Health | Kitakyushu | Fukuoka | Japan |
| St. Marianna Univ School of Medicine Hospital | Kawasaki | Kanagawa | Japan |
| Nara Medical University Hospital | Kashihara | Nara | Japan |
| Gunma University Hospital | Maebashi | Japan |
| Osaka National Hospital | Osaka | Japan |
| Ogikubo Hospital | Tokyo | Japan |
| Teikyo University Hospital | Tokyo | Japan |
| University Medical Center Groningen | Groningen | 9713 | Netherlands |
| PHI Institute of Transfusion Medicine of Republic of Macedonia | Skopje | North Macedonia |
| University Medical Centre Ljubljana | Ljubljana | Slovenia |
| COMPLETED |
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| NOT COMPLETED |
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| Prophylactic Treatment Phase I |
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| Prophylactic Treatment Phase II |
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| ID | Title | Description |
|---|---|---|
| BG000 | SAF/ITT Population | All patients who received at least one infusion of Human-cI rhFVIII |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| ||||||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Weight | Mean | Standard Deviation | kg |
| ||||||||||||||||||||||
| Body mass index (BMI) | Mean | Standard Deviation | kg/m^2 |
| ||||||||||||||||||||||
| Hemophilia Joint Health Score | Joint health status will be assessed using the Hemophilia Joint Health Score (HJHS), which evaluates six index joints to produce a score between 0-124. Higher scores indicate worse joint health. | Mean | Standard Deviation | units on a scale |
| |||||||||||||||||||||
| Blood group | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Annualized Total Bleeding Rate of Individually Tailored Prophylaxis | Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII | The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment. | Posted | Mean | Standard Deviation | Bleeding events per year (ABR) | 6 months |
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| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis | Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII | The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment. | Posted | Mean | Standard Deviation | Bleeding events per year (ABR) | 6 months |
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| Secondary | Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis | Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII | The analysis population comprised 29 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial at intervals of 2x/week or less. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment. | Posted | Mean | Standard Deviation | Bleeding events per year (ABR) | 6 months |
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| Secondary | Median Prophylactic Dosing Interval | Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient | The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. | Posted | Median | Inter-Quartile Range | hours | 6 months |
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| Secondary | Mean Prophylactic Dosing Interval | Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient | The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. | Posted | Mean | Standard Deviation | hours | 6 months |
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| Secondary | AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII | AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay | The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results. | Posted | Mean | Standard Deviation | hr*IU/mL/(IU/kg) | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
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| Secondary | In-vivo Recovery (IVR) of Human-cl rhFVIII | IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII | The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results. | Posted | Mean | Standard Deviation | % per IU/kg | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
|
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| Secondary | Half Life (t1/2) of Human-cl rhFVIII | T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay | The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results. | Posted | Mean | Standard Deviation | hours | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
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| Secondary | Mean Residence Time (MRT) of Human-cl rhFVIII | MRT of Human-cl rhFVIII measured using the one-stage (OS) assay | The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results. | Posted | Mean | Standard Deviation | hours | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
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| Secondary | Clearance (CL) of Human-cl rhFVIII | CL of Human-cl rhFVIII measured using the one-stage (OS) assay | The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results. | Posted | Mean | Standard Deviation | mL/hr/kg | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
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| Secondary | Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII | Vss of Human-cl rhFVIII measured using the one-stage (OS) assay | The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results. | Posted | Mean | Standard Deviation | mL/kg | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection |
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| Secondary | Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient) | Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment | The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. | Posted | Mean | Standard Deviation | IU/kg per week | 6 months |
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| Secondary | Number of Patients With Adverse Events (AEs) | AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria | The SAF population included 58 patients who received at least one infusion of Human-c1 rhFVIII in the GENA-21b trial | Posted | Count of Participants | Participants | At each study visit over the study duration (7-9 months) |
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At each study visit over the study duration (7-9 months)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | SAF/ITT Population | All patients who received at least one infusion of Human-cI rhFVIII | 0 | 58 | 4 | 58 | 34 | 58 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypokalemia | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Basosquamous carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
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| Large B-cell lymphoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
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| Pyrexia | General disorders | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Subdural haematoma | Blood and lymphatic system disorders | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | Systematic Assessment |
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| Influenza | Infections and infestations | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | Systematic Assessment |
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| Gastritis | Gastrointestinal disorders | Systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Bone pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Pyrexia | General disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Dizziness | Nervous system disorders | Systematic Assessment |
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| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Lymphadenopathy | Blood and lymphatic system disorders | Systematic Assessment |
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| Depression | Psychiatric disorders | Systematic Assessment |
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| Insomnia | Psychiatric disorders | Systematic Assessment |
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Octapharma agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Octapharma supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial. Octapharma also reserves the right to review data prior to publishing and provide comments/changes within a certain time period.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sylvia Werner | Octapharma | 415 260-9577 | sylvia.werner@octapharma.com |
| Prot_002.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 30, 2018 | Dec 21, 2020 | SAP_003.pdf |
| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| Discontinued medication |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| United States |
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| Japan |
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| Finland |
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| North Macedonia |
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| Slovenia |
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| France |
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| Croatia |
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| AB |
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| B |
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| Unknown/missing |
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| Negative binomial regression model | <0.0001 | Rate ratio | 11.89 | 2-Sided | 95 | 7.50 | 18.86 | Other | Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Negative Binomial regression model including a correction for overdispersion. |
| Poisson regression model | <0.0001 | Rate ratio | 10.14 | 2-Sided | 95 | 6.12 | 16.80 | Other | Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Poisson regression model including a correction for overdispersion. |
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