The Study
SIPPET is an acronym for 'Study on Inhibitors in Plasma-Product Exposed Toddlers'. The SIPPET study, published in The New England Journal of Medicine (NEJM), is a clinical trial conducted on male toddlers under age 6 diagnosed with Factor VIII deficiency with anti-coagulant activity of < 1IU/dl and no inhibitors. The principal investigators were based in Milan, Italy, however this study was conducted (between 2010-2015) in 5 countries (India, Egypt, Iran, USA, other). Prior to this study participants had received either no treatment or minimal treatment with blood products (whole blood, FFP, packed red cells, platelets or cryoprecipitate).
The Products
The Factor products used in this study varied based on what was licensed for use in the country. One plasma-derived (Pd) and 1 recombinant (Re) product was used in each country. Patients were randomly assigned to one or the other product. The Pd products used were: Alphanate and Fanhdi (Grifols), Emoclot (Kedrion Biopharma), and Factane (LFB Biomedicaments ). The Re products were: Recombinate and Advate (Baxalta), Kogenate FS (Bayer AG) and ReFacto AF (Pfizer).
The Study Design
The investigators had determined, based on some statistical analyses, that a sample size of 300 would be sufficient, accounting for a 10% dropout rate. The steering committee overseeing the trial decided to terminate the trial in May 2015. This was done in response to announcement by the World Federation of Hemophilia to consider not using Kogenate FS, for newly diagnosed patients with Hemophilia A, when other, safer, clotting-factor concentrates are available. This was due to higher risk of inhibitors. I assume this put some limits on conducting the trial in certain countries, possibly due to product licensing issues.
Even though they did start with 303 patients assessed for eligibility, 264 were randomized to receive either Pd or Re Factor VIII. A further pared down patient number- 125 in the Pd group and 126 in the Re group were analyzed. The investigators then characterized these patients based on country, age at first treatment, type of mutation, mutation status (null, not-null), family history of hemophilia, family history of inhibitor development, race or ethnic group, previous treatment, type of treatment (on-demand, standard prophylaxis, modified 'once weekly' prophylaxis and brand of Factor VII used. They have further monitored the inhibitor development characteristics based on type of inhibitor ( all, titer- high/low/peak, persistent/transient) and time of development based on exposure days. A data was analyzed for their statistically differences between the two patient groups.
The Results and Interpretations
The results from the analysis of regression models, have lead the authors of this study to conclude that the rate of inhibitor development was 87% higher with recombinant factor VIII than with plasma-derived factor VIII. In the editorial, in the same issue of NEJM, Donna DiMichele MD wrote:
"these data must now be integrated globally into the multifactorial decision-making processes underlying product selection for at-risk children with severe hemophilia A. The results are scientifically compelling. Endocytosis, clearance, and antigen presentation are affected by factor VIII protein glycosylation and von Willebrand factor association. That both glycosylation and association with von Willebrand factor are altered by recombinant technology lends immunologic plausibility to the implication that the product source plays a role in inhibitor generation and provides valuable mechanistic insight into the conundrum of factor VIII immunogenicity."
The following is my interpretation of this quote: The results from this study are compelling. the recommendation is to select the product source carefully before starting to treat at-risk (for inhibitors) children with severe Hemophilia A. Dr. DiMichele refers to an article based on which she surmises that the source of the Factor (in this case Recombinant vs. plasma-derived) could make a difference in the immune response developed to Factor. The chemical structure of recombinant Factor is different from that in plasma-derived. Further, von Willebrand factor is missing in the recombinant product. These chemical differences in the Factor VIII structure may lead the inhibitor development noted in the SIPPET study.
The Study Author's Disclosure
To address potential conflicts of interest, the authors have disclosed that Grifols, Kedrion Biopharma and LFB have provided grants to the Angelo Bianchi Bonomi Foundation. This Foundation is the primary funding agency for this study. However, they had no input in the trial design; protocol preparation; patient recruitment; data collection, handling, and interpretation; or writing of this publication. The full disclosure by corresponding author, Dr. Peyvandi is available for review here.
Coming soon
What does this study result mean to the patient or the caregiver? Has this trial answered any question conclusively or has it opened up new ones? Whom can you look to for answers?
SIPPET is an acronym for 'Study on Inhibitors in Plasma-Product Exposed Toddlers'. The SIPPET study, published in The New England Journal of Medicine (NEJM), is a clinical trial conducted on male toddlers under age 6 diagnosed with Factor VIII deficiency with anti-coagulant activity of < 1IU/dl and no inhibitors. The principal investigators were based in Milan, Italy, however this study was conducted (between 2010-2015) in 5 countries (India, Egypt, Iran, USA, other). Prior to this study participants had received either no treatment or minimal treatment with blood products (whole blood, FFP, packed red cells, platelets or cryoprecipitate).
The Products
The Factor products used in this study varied based on what was licensed for use in the country. One plasma-derived (Pd) and 1 recombinant (Re) product was used in each country. Patients were randomly assigned to one or the other product. The Pd products used were: Alphanate and Fanhdi (Grifols), Emoclot (Kedrion Biopharma), and Factane (LFB Biomedicaments ). The Re products were: Recombinate and Advate (Baxalta), Kogenate FS (Bayer AG) and ReFacto AF (Pfizer).
The Study Design
The investigators had determined, based on some statistical analyses, that a sample size of 300 would be sufficient, accounting for a 10% dropout rate. The steering committee overseeing the trial decided to terminate the trial in May 2015. This was done in response to announcement by the World Federation of Hemophilia to consider not using Kogenate FS, for newly diagnosed patients with Hemophilia A, when other, safer, clotting-factor concentrates are available. This was due to higher risk of inhibitors. I assume this put some limits on conducting the trial in certain countries, possibly due to product licensing issues.
Even though they did start with 303 patients assessed for eligibility, 264 were randomized to receive either Pd or Re Factor VIII. A further pared down patient number- 125 in the Pd group and 126 in the Re group were analyzed. The investigators then characterized these patients based on country, age at first treatment, type of mutation, mutation status (null, not-null), family history of hemophilia, family history of inhibitor development, race or ethnic group, previous treatment, type of treatment (on-demand, standard prophylaxis, modified 'once weekly' prophylaxis and brand of Factor VII used. They have further monitored the inhibitor development characteristics based on type of inhibitor ( all, titer- high/low/peak, persistent/transient) and time of development based on exposure days. A data was analyzed for their statistically differences between the two patient groups.
The Results and Interpretations
The results from the analysis of regression models, have lead the authors of this study to conclude that the rate of inhibitor development was 87% higher with recombinant factor VIII than with plasma-derived factor VIII. In the editorial, in the same issue of NEJM, Donna DiMichele MD wrote:
"these data must now be integrated globally into the multifactorial decision-making processes underlying product selection for at-risk children with severe hemophilia A. The results are scientifically compelling. Endocytosis, clearance, and antigen presentation are affected by factor VIII protein glycosylation and von Willebrand factor association. That both glycosylation and association with von Willebrand factor are altered by recombinant technology lends immunologic plausibility to the implication that the product source plays a role in inhibitor generation and provides valuable mechanistic insight into the conundrum of factor VIII immunogenicity."
The following is my interpretation of this quote: The results from this study are compelling. the recommendation is to select the product source carefully before starting to treat at-risk (for inhibitors) children with severe Hemophilia A. Dr. DiMichele refers to an article based on which she surmises that the source of the Factor (in this case Recombinant vs. plasma-derived) could make a difference in the immune response developed to Factor. The chemical structure of recombinant Factor is different from that in plasma-derived. Further, von Willebrand factor is missing in the recombinant product. These chemical differences in the Factor VIII structure may lead the inhibitor development noted in the SIPPET study.
The Study Author's Disclosure
To address potential conflicts of interest, the authors have disclosed that Grifols, Kedrion Biopharma and LFB have provided grants to the Angelo Bianchi Bonomi Foundation. This Foundation is the primary funding agency for this study. However, they had no input in the trial design; protocol preparation; patient recruitment; data collection, handling, and interpretation; or writing of this publication. The full disclosure by corresponding author, Dr. Peyvandi is available for review here.
Coming soon
What does this study result mean to the patient or the caregiver? Has this trial answered any question conclusively or has it opened up new ones? Whom can you look to for answers?
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