摘要:一、計晝名稱:以AAV2病毒載體轉移芳香族L-胺基酸脫羧酵素(AADC)基因治療AADC缺乏 症之Phase I/II臨床試驗二、目的:1.確認以AAV2病毒載體傳送hAADC基因來治療AADC缺乏症的病童是安全的。2.了解使用AAV2載體傳送hAADC基因後,hAADC基因的表現是否可促進左多巴轉 變為多巴胺,以增進病患的運動功能。三、試驗藥物:1.藥名:AAV2-hAADC2.劑型:Aqueous solution, 5x10u - 1x1012 vg/ml3.劑量:1.81x10uvg/case4.用法:Intracerebralinfusion5.藥物作用機轉(如已知):以基因治療補充腦部所缺乏的蛋白質6.藥理分類:none四、藥物發展階段:Phase_I/n 口羾nW □其他五、試驗設計.1.□對照:□安慰劑□有效藥(藥名、劑型、用法)_口其他 _■非對照2.盲性:■開放□評估者盲性□單盲 □雙盲□雙虛擬 □其他 _3.隨機分派:□是■無4.□平行 □交叉 □其他_5.治療期間:一次使用6.劑量調整:□強制性□選擇性■無7.□多國多中心 □台灣多中心 ■台灣單中心六、評估指標:主要評估指標:治療效果評估1.術後一年腦脊髓液神經傳導物質代謝產物HVA或HIAA可以測到2.術後一年PDMS-II評估分數比術前有10分以上的進步次要評估指標:安全性及其他治療效果評估治療安全性評估1.術後未發生需要手術處置之顱内出血2.開顧受術引起之腦脊鑛液渗漏3.術後過動症之嚴重性(是否影響進食而需要安裝鼻胃管)4.其他重大不良事件發生之頻率 次要治療效果評估1.體重之增加2.正子造影中殼核多巴胺訊號強度之增加3.其他發展評估分數之增加 探索性指標1.anti-AAV2抗體效價和治療效果之相關性2.病人的年齡和治療效果之相關性七、參加試驗.主要納入條件1.確診為AADC病患,包括腦脊髓液分析證實神經經傳導物質代謝物HVA和 5-HIAA降低,L-Dopa上升,以及具有一個以上的AADC基因突變。2.具有此疾病的典型臨床表徵,如眼動危象、張力不全及發展遲緩。3.病童年齡需在兩足歲以上,或頭圍夠大適合進行手術。4.參與受試者的病患需完全配合整個試驗過程前後的評估與檢查。5.父母親或監護人需在此受試者同意書中簽字同意。主要排除條件1.明顯腦部結構異常。2.如受試者有任何健康或神經學上的疑慮而可能增加手術的風險則不能參與此項 試驗,計晝主持人有權依據受試者的健康狀況來評估是否適合參加此項試驗。3.因為高量的中和性抗體將會影響基因治療的效果,所以當AAV2的中和性抗體 高於1,200倍,或是酵素免疫分析法分析時吸光值(OD值)>1時,不能參與此試驗。4.參與此項試驗的受試者不能服用任何會影響此臨床試驗的藥物。八、試驗程序.GMP實驗室製造AAV2-hAADC。先進行核磁共振分析腦部構造,放置顱骨上金屬螺釘 後進行電腦斷層分析。結合兩次的影像後定出注射之角度及深度。手術中在頭部兩侧鑽 洞架設定位儀後緩慢注射藥品。每一侧之殼核注射兩次。術後確定無副作用後,即進入 臨床追蹤。九、併用治療:1.允許併用之醫療處置:術前及術後一個月以内可使用AADC治療藥物,包括dopamine agonist, MAO inhibitor, and anti-cholingergic drugs。術後一個月以後可使用 B62.禁止併用之醫療處置:術後一個月以後不可使用 dopamine agonist, MAO inhibitor, or anti-cholinergic drug。十、統計:1.主要試驗假說:■較優性試驗(優於治療前)口不劣於試驗□相等性試驗 口其他 _2.樣本數:納入試驗人數 10_可評估人數 103.療效評估群體:□意圖治療■依計晝書□其他_安全評估群體:□意圖治療■依計晝書□其他_(附註:意圖治療:ITT ;依計晝書:PP )4.療效/安全評估指標所採用之統計方法:一般性分析工具5.期中分析:□有■無
Abstract: . Protocol title: A Phase I/II clinical trial for treatment of aromatic L-amino aciddecarboxylase (AADC) deficiency using AAV2-hAADC. Objectives: This study is to prove the safety and efficacy of AAV2-hAADCtreatment for patients with Aromatic L-amino acid decarboxylase(AADC) deficiency.. Test drug:1.Name: AAV2-hAADC2.Dosage form: Aqueous solution, 5x1011 - 1x1012 vg/ml3.Dose(s): 1.81x1011 vg/case4.Dosing schedule: single dose5.Mechanism of action (if known): supplement a gene defect6.Pharmacological categorynone. Developmental phase: phase Others. Study design:1. Control: placeboactive (please specify name and dosage)otherUncontrolled2. Blinding: open-label evaluator blind single blind double blinddouble dummy other3. Randomized: yes no4. Parallel Cross-over Other5. Duration of treatment: single dose6. Titration: forced optional none7. Multi-national Multi-center(Taiwan) Single center. EndpointsPrimary end points1. Measurable neurotransmitter metabolite HVA or HIAA levels in CSF one yearafter gene therapy. (Done by Medical Neurogenetics, Atlanta, GA, USA, aCLIA certified laboratory)3. Increase of PDMS-II score more than 10 points one year after gene therapySecondary end points1. Safety of the trialPost-surgery intracerebral hemorrhagePost-surgery CSF leakageSeverity of post-gene therapy dyskinesia (if NG tube feeding is required)Frequency of severe adverse reaction2. Other secondary efficacy end pointsBody weight gainIncrease putaminal signal in DOPA-PET studyIncrease of score in other developmental tests3. Exploratory end pointsCorrelation between anti-AAV2 titer and efficacyCorrelation between age and efficacy. Selection criteria:Inclusion Criteria:1. A definitive diagnosis of AADC deficiency, including a CSF study showingdecreased levels of HVA and 5-HIAA, and an elevated L-dopa level, and thepresence of at least one AADC gene pathologic mutation.2. The patient must have clinical symptoms of AADC deficiency, includehypotonia, dystonia, and oculogyric crisis.3. The patient must be older than 24 months of age or has skull bones suitable forsurgery.4. The parents of study participants must agree to comply in good faith with therequired baseline and follow-up assessments.5. The parents or guardians must understand and sign their child’s informedconsent form.Exclusion criteria1. Other significant medical or neurological conditions which would create anunacceptable operative risk. Each case will be individually reviewed and thefinal decision shall rest with the Primary Investigator.2. Preexisting immunity to AAV may limit AAV-mediated gene delivery. Patientswith anti-AAV2 antibody titer higher than 1.0 OD will be excluded.3. The patient cannot take medicines that will alter the effect of this clinical trial.. Study procedures:AAV2-hAADC will be made by a GMP laboratory. An MRI will be performed todefine the brain structure, and then metal nails will be fixed on the skull and a CT willbe performed. The two images will be confined and the direction and depth ofinfusion will be determined. During the surgery, a stereotactic device will beimplanted on both sides of the brain on a bur hole. Each putamen will be injected fortwo times. If there is no complication from the surgery, the patients will enter thefollow up period.. Concomitant treatment:1. Permitted: Before and until one month after gene therapy, drugs treating AADCdeficiency including dopamine agonist, MAO inhibitor, and anti-cholingergicdrugs can be used. After one month post-gene therapy, vitamin B6 can be used.2. Prohibited: After one month post-gene therapy, drugs treating AADC deficiencyincluding dopamine agonist, MAO inhibitor, and anti-cholingergic drugs cannotbe used.. Statistics:1. Primary hypothesis: superiority non-inferiorityequivalence other2. Sample size: enrolled 10evaluable 103. Efficacy population: ITT PP otherSafety population: ITT PP other4. Statistical method(s) for efficacy/safety evaluations:Regular tools5. Planned interim analysis: yes noXI . Please attach flow chart and/or assessment schedule, if available.Enrollment (-6m) -- baseline study (-1m) -- surgery -- Safety of surgery (1w) --efficacy monitoring (1y)Enrollment tests CSF neurotransmitter metabolites AADC gene mutation analysis Anti-AAV2 antibody (within 6 months) Brain MRI for brain status (within 6 months) CT scan for skull bone thickness (within 6 months)Baseline study Recording for oculogyric crisis (daily from one month before and to 12 monthsafter gene therapy) Neurological examination Sleep oxygen saturation recording and 24-hr ECG Motor developmental evaluation Blood chemistry and anti-AAV2 antibody (around 10 cc venous blood) CSF neurotransmitter metabolites, protein, cell 6-[18F]fluorodopa PETSurgery and gene delivery phase2 MRI localization Placement of fiducials CT localization Surgery and infusion CT scan immediately after surgery to check hemorrhage MRI 3-7 days after surgery to check brain structurePost-surgery, 6th month Blood and urine virus excretion Blood chemistry and anti-AAV2 antibody (around 10 cc venous blood) Neurological examination, motor development evaluation Sleep oxygen saturation recording and 24-hr ECGPost-surgery, 3rd and 9th month Blood and urine virus excretion Blood chemistry and anti-AAV2 antibody (around 10 cc venous blood) Neurological examination, motor development evaluationPost-surgery, 12th month Blood and urine virus excretion Blood chemistry and anti-AAV2 antibody (around 10 cc venous blood) Neurological examination, motor development evaluation Sleep study and 24-hr ECG CSF neurotransmitter metabolites, protein, cell 6-[18F]fluorodopa PET Brain MRIPost-surgery, after 12th month Motor development evaluation every 6 months (suggested) CSF neurotransmitter metabolites every year (suggested) 6-[18F]fluorodopa PET every year (take inspection 2 and 5 years after genetherapy)