臨床研究等提出・公開システム

単一群，非盲検

Single Group Assignment Open Label

血友病B患者集団：
・18 歳以上65 歳未満の中等症～重症の血友病B 男性患者（ベースライン来院前の検査でFIX 活性が2%以下）である
・本治験に参加し，予定されている来院，FIX 定期補充療法の治療計画，臨床検査およびその他の治験手順に従う意思および能力を有している
・これまでFIX製剤（遺伝子組換え，血漿由来または半減期延長製剤）を投与した累積日数が50日以上である。
・現在FIX 製剤（遺伝子組換え，血漿由来または半減期延長製剤）による定期補充療を実施している患者は，本治験期間を通じて，定期補充療法を継続する意思を有する
・FIX製剤に対する過敏症の既往がない
・臨床検査に基づく評価または臨床的に，FIX に対するインヒビターの既往歴（力価が0.6 BU/mL以上）がない
血友病A患者集団：
・18 歳以上65 歳未満の中等症～重症の血友病A 男性患者（ベースライン来院前の検査でFVIII 活性が1%以下）である
・本治験に参加し，予定されている来院，FVIII 定期補充療法の治療計画，臨床検査およびその他の治験手順に従う意思および能力を有している
・これまでFVIII製剤（遺伝子組換え，血漿由来または半減期延長製剤）を投与した累積日数が150日以上である。
・現在FVIII製剤（遺伝子組換え，血漿由来または半減期延長製剤）による定期補充療を実施している患者は，本治験期間を通じて，定期補充療法を継続する意思を有する
・FVIII製剤に対する過敏症の既往がない
・臨床検査に基づく評価または臨床的に，FVIII に対するインヒビターの既往歴（力価が0.6 BU/mL以上）がない

Inclusion Criteria:

Hemophilia B Population:
1.Evidence of a signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2.Willing and able to comply with scheduled visits, FIX prophylaxis treatment plan, laboratory tests and other study procedures.
3.Males >= 18 and <65 years of age with moderately severe to severe hemophilia B and documented FIX activity (<=2%) prior to baseline visit.
4.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).
5.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.
6.No known hypersensitivity to FIX replacement product.
7.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.Evidence of a signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
2.Willing and able to comply with scheduled visits, FVIII prophylaxis treatment plan, laboratory tests and other study procedures.
3.Males >=18 and <65 years of age with moderately severe to severe hemophilia A and documented FVIII activity (<=1%) prior to baseline visit.
4.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).
5.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.
6.No known hypersensitivity to FVIII replacement product.
7.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.

・中央測定により，スクリーニング検査でAAV-Spark100 に対する中和抗体を有する血友病B患者およびSB-525キャプシド（AAV6）に対する中和抗体を有する血友病A患者（抗体価が検出可能である患者）
・出血および定期補充療法の実施を記録することが遵守できない患者
・HbsAgが陽性またはHBV-DNAが陽性／検出可能のいずれかである患者
・B 型肝炎に対する抗ウイルス療法を現在受けている患者
・C型肝炎に対する抗ウイルス療法を現在受けている患者
・HCV-RNA量の検査結果が陽性／検出可能であった患者
門脈圧亢進症，脾腫または肝性脳症の既往歴と定義する重大な肝疾患のある患者。
上記に挙げた既往歴のない患者は，スクリーニング前12ヵ月以内に以下の評価を受けていなければならない。受けていない場合，スクリーニング来院時に肝線維化の状態を検査する必要がある。
血清アルブミン値が基準値下限未満または
以下のいずれかの検査により重大な肝線維化が認められる者
・FibroScan（スコア >8 kPa）または
・FibroTest/FibroSURE（>0.48）
・スクリーニング前12 ヵ月以内の検査で，血清学的検査でHIV-1またはHIV-2が検出され，CD4+細胞数が200 mm3 以下の患者。.
・治験責任医師が許容できないリスクと判断する慢性感染症または他の慢性疾患の既往歴がある患者。脳卒中または心筋梗塞を含む（ただしこれらに限定されない）血栓性事象の既往歴がある患者
・本治験組み入れ前3 ヵ月以内または治験期間中に治験薬を使用する他の治験に参加する患者，またはスクリーニング前12 ヵ月以内に遺伝子治療の治験に参加した患者
・今後24 ヵ月以内にFIX（血友病B）またはFVIII（血友病A）手術時補充療法を必要とする外科処置を予定している患者

Exclusion Criteria:

1.Anti-AAV-Spark100 neutralizing antibody titer above the established threshold performed by a central laboratory during screening in hemophilia B subjects or Anti-AAV6 neutralizing antibody titer above the established threshold performed by a central laboratory during screening in hemophilia A subjects.
2.Lack of participant 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 subject would be eligible for the study. Anti-HBc must be obtained in all subjects 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 and if not will need to be tested for liver fibrosis status at 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.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.
8.Any concurrent clinically significant major disease or condition that the investigator deems unsuitable for participation or other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. In addition, any participant with a history of a neoplasm (including hepatic malignancy) that required treatment (eg, chemotherapy, radiotherapy, immunotherapy), is excluded, except for adequately treated basal or squamous cell carcinoma of the skin or a surgically removed benign neoplasm not requiring chemotherapy, radiotherapy and/or immunotherapy. Any other neoplasm that has been cured by resection should be discussed between the investigator and sponsor.
9.Participation in other studies if involving administration of investigational product(s) within the last 3 months prior to study entry and/or during study participation or in a previous gene therapy clinical study within the last 12 months prior to screening.

* Participants already enrolled in this lead-in study (C0371004) may be allowed to participate in the screening and baseline periods of either C0371002 or C3731003 protocols prior to their completion of the end of study visit in this lead-in study.

10.Any participant who previously received fidanacogene elaparvovec (hemophilia B) or giroctocogene fitelparvovec (hemophilia A) or any AAV gene-based therapy.
11.Any participant with a planned surgical procedure requiring FIX (hemophilia B) or FVIII (hemophilia A) surgical prophylactic factor treatment in the next 24 months.
12.Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or participants who are Pfizer employees, including their family members, directly involved in the conduct of the study.

NOTE: The sponsor's medical team should be contacted if there are any questions regarding any of the inclusion or exclusion criteria (Sections: 4.1 and 4.2).

18歳以上

18age old over

64歳以下

64age old under

男性

Male

実施中

progressing