LTFU for Gene Transfer Subjects With Hemophilia B
| Status: | Completed |
|---|---|
| Conditions: | Hematology |
| Therapuetic Areas: | Hematology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 3/14/2019 |
| Start Date: | August 2007 |
| End Date: | December 2017 |
A Long-Term Follow-Up Study in Subjects With Sever Hemophilia B Who Received Adeno-Associated Viral Vectors Expressing Human Factor IX
Several subjects enrolled in a multi-site, gene transfer clinical study to evaluate the
intrahepatic administration of AAV2-hFIX16 vector for the treatment of severe hemophilia B
between 2001 and 2009. As the US FDA has established guidelines for the long-term follow-up
(LTFU) of subjects receiving investigational gene therapy products, this protocol seeks to
characterize the clinical outcome and the type and seriousness of adverse events following
the AAV gene transfer. The primary study tools will consist of annual history/physical
examination and blood tests, as well as periodic liver ultrasound, to characterize clinical
outcomes. Where possible, data will be obtained for up to 15 years following hepatic
AAV2-hFIX16 gene transfer.
intrahepatic administration of AAV2-hFIX16 vector for the treatment of severe hemophilia B
between 2001 and 2009. As the US FDA has established guidelines for the long-term follow-up
(LTFU) of subjects receiving investigational gene therapy products, this protocol seeks to
characterize the clinical outcome and the type and seriousness of adverse events following
the AAV gene transfer. The primary study tools will consist of annual history/physical
examination and blood tests, as well as periodic liver ultrasound, to characterize clinical
outcomes. Where possible, data will be obtained for up to 15 years following hepatic
AAV2-hFIX16 gene transfer.
A prior clinical gene transfer study of intrahepatic adeno-associated virus (AAV) vector
administration of the factor IX gene (AAV2-hFIX16) to adult subjects with severe hemophilia B
enrolled several subjects from 2001 through 2004. These subjects received various doses of
AAV2-hFIX16 manufactured by Avigen, Inc. (Alameda, CA). They were monitored up to at least
one year following vector administration for evaluation of adverse events and for indices of
efficacy. At the time study enrollment was suspended by Avigen, Inc., and IND 9398 under
which the study was conducted was transferred to The Children's Hospital of Philadelphia (May
2005), there were no guidelines for long-term follow-up of the trial subjects. However, in an
unrelated study conducted in France, of pediatric subjects administered integrating
retrovirus vectors for X-linked severe combined immune deficiency (X-SCID), several leukemias
developed years after transfer of the γc common chain gene. The underlying mechanism was
attributed to proviral integration near, and upregulation of, proto-oncogenes such as LMO-2,
coupled with robust expression of the γc common chain, inducing unregulated cellular
proliferation. In response to these events, and in concert with the NIH and gene transfer
scientific community, the U.S. Food and Drug Administration (US FDA) issued guidelines for
the 'long-term follow-up of gene transfer subjects'. Since AAV vectors have a low rate of
genomic integration, the risks of integration are low, but the long-term effect of the
persistence of vector particles in humans is unknown. The investigators plan to enroll
available subjects from the prior intrahepatic AAV gene transfer study to this observational
study to follow them for up to 15 years after gene transfer.
An additional subject received AAV2-hFIX16 vector, manufactured by CCMT at CHOP, via hepatic
artery infusion in January 2009. The study AAV2-hFIX-002, an amendment to the prior Avigen,
Inc. clinical protocol modified to include transient immunomodulation, was conducted under
IND 9398. This subject was monitored for three years following vector administration under
clinical study AAV2-hFIX-002; amendment one of the current protocol transfers his annual
long-term follow-up visits to AAV2-hFIX16-LTFU-01.
Spark Therapeutics will be the study sponsor; prior vector administration sites or
referral/follow up sites will participate as study sites. The long-term follow-up (LTFU)
study will consist primarily of endpoints including annual history, physical examination,
blood tests, urinalysis, and periodic liver ultrasound. Adverse event reporting will focus on
the development of oncologic, hematologic, neurologic and auto-immune events following gene
transfer as specified in the November 2006 FDA Center for Biologics Evaluation and Research
(CBER) guidance document entitled, "Gene Therapy Clinical Trials - Observing Subjects for
Delayed Adverse Events."1 The LTFU study seeks to provide longitudinal information, and
should adverse events occur, more timely discovery and treatment.
administration of the factor IX gene (AAV2-hFIX16) to adult subjects with severe hemophilia B
enrolled several subjects from 2001 through 2004. These subjects received various doses of
AAV2-hFIX16 manufactured by Avigen, Inc. (Alameda, CA). They were monitored up to at least
one year following vector administration for evaluation of adverse events and for indices of
efficacy. At the time study enrollment was suspended by Avigen, Inc., and IND 9398 under
which the study was conducted was transferred to The Children's Hospital of Philadelphia (May
2005), there were no guidelines for long-term follow-up of the trial subjects. However, in an
unrelated study conducted in France, of pediatric subjects administered integrating
retrovirus vectors for X-linked severe combined immune deficiency (X-SCID), several leukemias
developed years after transfer of the γc common chain gene. The underlying mechanism was
attributed to proviral integration near, and upregulation of, proto-oncogenes such as LMO-2,
coupled with robust expression of the γc common chain, inducing unregulated cellular
proliferation. In response to these events, and in concert with the NIH and gene transfer
scientific community, the U.S. Food and Drug Administration (US FDA) issued guidelines for
the 'long-term follow-up of gene transfer subjects'. Since AAV vectors have a low rate of
genomic integration, the risks of integration are low, but the long-term effect of the
persistence of vector particles in humans is unknown. The investigators plan to enroll
available subjects from the prior intrahepatic AAV gene transfer study to this observational
study to follow them for up to 15 years after gene transfer.
An additional subject received AAV2-hFIX16 vector, manufactured by CCMT at CHOP, via hepatic
artery infusion in January 2009. The study AAV2-hFIX-002, an amendment to the prior Avigen,
Inc. clinical protocol modified to include transient immunomodulation, was conducted under
IND 9398. This subject was monitored for three years following vector administration under
clinical study AAV2-hFIX-002; amendment one of the current protocol transfers his annual
long-term follow-up visits to AAV2-hFIX16-LTFU-01.
Spark Therapeutics will be the study sponsor; prior vector administration sites or
referral/follow up sites will participate as study sites. The long-term follow-up (LTFU)
study will consist primarily of endpoints including annual history, physical examination,
blood tests, urinalysis, and periodic liver ultrasound. Adverse event reporting will focus on
the development of oncologic, hematologic, neurologic and auto-immune events following gene
transfer as specified in the November 2006 FDA Center for Biologics Evaluation and Research
(CBER) guidance document entitled, "Gene Therapy Clinical Trials - Observing Subjects for
Delayed Adverse Events."1 The LTFU study seeks to provide longitudinal information, and
should adverse events occur, more timely discovery and treatment.
Inclusion Criteria
-Adult subjects who participated in prior intrahepatic AAV2-hFIX16 gene transfer studies
Exclusion Criteria
- Subjects who will not consent for study
- Subjects who the investigators believe are not capable of performing endpoints of the
study
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