E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately Severe To Severe Adult Hemophilia B Participants (FIX:C≤2%) Who Are Negative For Neutralizing Antibodies (NAb) To Adeno-Associated Virus Vector (AAV) Spark100. Moderately severe to severe hemophilia A adult Participants (FVIII:C≤1%) who are negative for neutralizing antibodies to adeno-associated virus vector 6 (AAV6)
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E.1.1.1 | Medical condition in easily understood language |
Moderately severe to severe Hemophilia B and Hemophilia A
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060614 |
E.1.2 | Term | Hemophilia B (Factor IX) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060613 |
E.1.2 | Term | Hemophilia A (Factor VIII) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To establish prospective efficacy data of: - FIX prophylaxis replacement therapy in the usual care setting of hemophilia B participants, who are negative for nAb to AAV-Spark100. - FVIII prophylaxis replacement therapy in the usual care setting of hemophilia A participants, who are negative for nAb to AAV6.
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E.2.2 | Secondary objectives of the trial |
Evaluate safety (serious adverse events and medically important events of FIX or FVIII inhibitor, thrombotic and factor hypersensitivity reactions) of FIX replacement therapy in hemophilia B participants or FVIII replacement therapy in hemophilia A participants.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Hemophilia B Population: 1.Males >= 18 and <65 years of age with moderately severe to severe hemophilia B and documented FIX activity (≤ 2%) prior to baseline visit. 2.Previous experience with FIX therapy (≥50 documented exposure days to a FIX protein product such as recombinant, plasma-derived or extended half-life FIX product). 3.Participants on FIX prophylaxis replacement therapy (recombinant, plasma-derived or extended half-life FIX product) must have the intention to remain on FIX prophylaxis replacement therapy for the duration of the study. 4.No known hypersensitivity to FIX replacement product. 5.No history of FIX inhibitor (clinical or laboratory-based assessment) defined as a titer > = 0.6 BU/mL, regardless of the laboratory normal range, or any measured Bethesda inhibitor titer greater than the upper limit of normal for the laboratory performing the assay. Clinically, no signs or symptoms of decreased response to FIX administration. Participants will not be required to undergo diagnostic evaluation of inhibitor status to participate in the study. Hemophilia A Population: 1. Males ≥ 18 and <65 years of age with moderately severe to severe hemophilia A and documented FVIII activity (≤ 1 %) prior to baseline visit. 2. Previous experience with FVIII therapy (≥150 documented exposure days to a FVIII protein product such as recombinant, plasma-derived or extended half-life FVIII product). 3. Participants on FVIII prophylaxis replacement therapy (recombinant, plasma-derived or extended half-life FVIII product) must have the intention to remain on FVIII prophylaxis replacement therapy for the duration of the study. 4. No known hypersensitivity to FVIII replacement product 5. No history of FVIII inhibitor (clinical or laboratory-based assessment) defined as a titer ≥ 0.6 BU/mL, regardless of the laboratory normal range, or any measured Bethesda inhibitor titer greater than the upper limit of normal for the laboratory performing the assay. Clinically, no signs or symptoms of decreased response to FVIII administration. Participants will not be required to undergo diagnostic evaluation of inhibitor status to participate in the study
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E.4 | Principal exclusion criteria |
1.Anti AAV Spark100 neutralizing antibody titer above the established threshold performed by a central laboratory during screening in hemophilia B participants or Anti-AAV6 neutralizing antibody titer above the established threshold performed by a central laboratory during screening in hemophilia A participants. 2. Lack of participants compliance with documentation of bleeds and/or prophylaxis replacement therapy administration. 3. If there is no documentation regarding hepatitis status, as defined below, within the last 12 months prior to screening for hepatitis B and 6 months prior to screening for hepatitis C, then participants will be required to have the following hepatitis testing performed at screening: a. Hepatitis B screening (acute and chronic): HBsAg (also referred to as Hepatitis B surface antigen), HBV-DNA viral assay (also referred to as a nucleic acid test for Hepatitis B virus DNA), and Anti-HBc (also referred to as Total Hepatitis B core antibody). -A participant is not eligible if either HbsAg is positive or HBV-DNA is positive/detectable. -Anti-HBc must be obtained in all participants for determination of whether the participant had prior hepatitis B. If the anti-HBc is positive and both HBsAg and HBV DNA are negative this would be consistent with a prior infection and the participant would be eligible for the study. Anti-HBc must be obtained in all participants to discriminate between those with no prior hepatitis B and those with prior infection in the event of reactivation. FDA has noted reactivation of hepatitis B virus exists. -One documented negative HBV-DNA viral load is sufficient to assess eligibility. A participant who is currently undergoing anti-viral therapy for hepatitis B is not eligible. b. Hepatitis C (acute or chronic): -A participant who is currently undergoing anti-viral therapy for chronic hepatitis C is not eligible. -Participants treated with anti-viral therapy for chronic hepatitis C, must have completed anti-viral therapy at least 6 months prior to screening and have a negative HCV-RNA at least 6 months prior to screening. -All participants (who are not currently undergoing anti-viral therapy for chronic hepatitis C) must have a single HCV-RNA load assay (also referred to as a nucleic acid test [NAT] for HCV RNA) obtained during the 6 months preceding screening. This includes participants with prior known chronic hepatitis C who have completed treatment with anti-viral therapy. -A participant is not eligible if his HCV-RNA load assay result is positive/detectable. 4. Currently on antiviral therapy for hepatitis B or C. 5. Significant liver disease, as defined by pre-existing diagnosis of portal hypertension, splenomegaly, or hepatic encephalopathy. All participants who do not have the listed pre-existing diagnoses above must have the following assessments performed within the last 12 months prior to screening:a serum albumin level below normal limits and/or significant liver fibrosis by any of the following diagnostic modalities: FibroScan score >8 kPa units OR FibroTest/FibroSURE >0.48*. * NOTE: If there is concern regarding the validity of any of the liver fibrosis test results please contact the medical monitor to discuss whether any additional testing needs to be performed (ie, either repeating any test or performing another fibrosis test). Also, note, if a participant has a known history of Gilbert's syndrome, a FibroTest cannot be used for fibrosis testing. 6. Documented serological evidence of human immunodeficiency virus HIV-1 or HIV-2 with Cluster of Differentiation 4 positive (CD4+) cell count ≤200 mm3 within the last 12 months prior to screening. Participants who are HIV positive and stable, have an adequate CD4 count (>200/mm3 ) and undetectable viral load (<50 gc/mL) documented within the preceding 12 months, and are on an antiretroviral drug regimen are eligible to enroll. Participants who have not been tested within the prior 12 months of screening will need to be tested for HIV status at screening 7. Any participant who previously received fidanacogene elaparvovec (hemophilia B) or giroctocogene fitelparvovec (hemophilia A) or any AAV gene-based therapy. 8. Any participant with a planned surgical procedure requiring FIX (hemophilia B) or FVIII (hemophilia A) surgical prophylactic factor treatment in the next 24 months. 9. History of chronic infection or other chronic disease that the investigator deems an unacceptable risk. In addition, any participant with conditions associated with increased thromboembolic risk such as known inherited or acquired thrombophilia, or a history of thrombotic events including but not limited to stroke, myocardial infarction, and/or venous thromboembolism, is excluded.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Endpoints: - Annualized bleeding rate (ABR) in hemophilia B participants. - Annualized bleeding rate (ABR) in hemophilia A participants.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy analysis population is defined as participants identified as NAb negative during screening and have prospective data collection.
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E.5.2 | Secondary end point(s) |
Efficacy Endpoints: Annualized number of infusions (AIR) in hemophilia B participants. Annualized number of infusions (AIR) in hemophilia A participants. Safety Endpoints: - Incidence of serious adverse events in hemophilia B participants. - Incidence of serious adverse events in hemophilia A participants. - Events of Special Interest in hemophilia B participants: FIX inhibitor; Thrombotic events; Factor hypersensitivity events. - Events of Special Interest in hemophilia A participants: FVIII inhibitor Thrombotic events; Factor hypersensitivity events.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy analysis population is defined as participants identified as NAb negative during screening and have prospective data collection. Safety Endpoints: From Screening visit: Day - 42 to Day -1 till End of Study / Early Termination Visit
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
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E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
Israel |
Japan |
Korea, Democratic People's Republic of |
Saudi Arabia |
Taiwan |
United States |
European Union |
Turkey |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |