臨床研究報告
一期、隨機、雙盲、安慰劑對照多劑量治療評估***在健康受試者中安全性、耐受性、藥代動力學的研究
DCR學習代碼：13172
贊助商研究代碼：***-1H-01（SNO-2）
IND號：119145
***：臨床1期研究
研究適應癥：安全性，耐受性，藥代動力學
研究期間：2014年2月16日（篩選出第一個主題）– 2014年11月11日（最新隨訪）
贊助商Nivalis Therapeutics，Inc.（以前為N30 Pharmaceuticals）
3122 Sterling Circle，Suite 200
美國科羅拉多州博爾德市80301
贊助商聯系人Robert Hopkins，DVM，MS
電話：+1（720）945-7716
傳真：+1（303）440-8399
研究者DaVita臨床研究
11750 W. 2nd Place，Suite 300，Lakewood，CO 80228美國
研究人員克里斯·加洛韋（醫學博士）
電話：+1（303）566-3100
傳真：+1（303）542-7300
RN BSN的項目經理Marla Elhard
電話：+1（303）566-3005
傳真：+1（855）544-8170
作者Christopher A. Graybill博士，醫學作家（達維塔）
斯科特·布蘭特利（Scott Brantley）博士，藥代動力學科學家（Nuventra）
Eugene R. Heyman博士，高級生物統計學家（Cardiocore）
醫學博士Daniel B. Goodman，副總裁兼醫療總監
（心臟）
格雷格·吉恩（Greg Ginn），碩士，生物統計學家（DaVita）
這份報告的日期：2015年9月18日
這項研究是遵循良好臨床規范（GCP）的原則進行的，包括基本文件的存檔。 本報告是按照國際協調會議（ICH）指南編寫的。
概要
研究主題：一項1期，隨機，雙盲，安慰劑對照，多劑量評估***在健康受試者中的安全性，耐受性和藥代動力學的劑量研究。
研究代碼
DCR學習代碼：13172
贊助商研究代碼：***-1H-01（SNO-2）
IND號：119145
贊助商：Nivalis Therapeutics，Inc.（以前稱為N30 Pharmaceuticals，Inc.）
3122 Sterling Circle，Suite 200，Boulder，CO 80301美國
贊助者聯系人：Robert Hopkins，DVM，MS
研究中心：DaVita臨床研究
11750 W. 2nd Place，Suite 300，Lakewood，CO 80228美國
項目經理：RN BSN的Marla Elhard
研究者：醫學博士克里斯托弗·加洛韋（Christopher Galloway）
出版：撰寫本報告時無
研究時間：初篩日期至最后隨訪時間：2014年2月16日– 2014年11月11日
臨床階段：I期
目標
主要目標：
?為了評估***在健康受試者劑量遞增中的安全性和耐受性。
次要目標：
?多次服用后評估***及其主要代謝產物N91288的藥代動力學（PK）。
方法
設計：
這計劃作為一項雙盲、隨機、安慰劑對照、多劑量組研究，然而，后續增加了兩個單劑量組，在這個研究的多劑量組中，至少計劃4個遞增組每組8個受試者（6個試驗藥，2個安慰劑），每一個受試者接受篩選（給藥前28天到給藥前3天），如果符合條件，在給藥前一天返回醫院并進行再次確認資格，合格受試者會收到***或安慰劑研究藥物的口服劑量，在研究的第1天到第14天觀察安全性問題，在臨床研究單位的基地直到在第15天沒有變化；藥代動力學來自于研究第1天到第16天的早上。個別特殊的受試者可能持續49天從篩選期到研究結束，一個安全委員會收到每組完成后的安全性數據，來決定是否進入下一個增加劑量組的計劃。改變計劃劑量組，重復劑量組，或者根據協議中概述停止研究。
單劑量組每組也納入8個受試者（6個試驗藥，2個安慰劑），分別評估單劑量組的PK和食物攝入的影響。
治療方法：
?***（10、50、250和500 mg）膠囊，每天口服一次，連續14天（多次劑量組）或一次（單劑量組）
?匹配的安慰劑膠囊，每天口服一次
程序和評估：
資格篩選包括病史，人口統計學信息，既往和伴隨用藥，體格檢查，體格測量（身高，體重，體重指數[BMI]），12導聯心電圖（ECG）評估，48小時動態ECG心律失常（Holter）監測）評估，生命體征測量，臨床實驗室檢查（血清學，血液學，血液化學，尿液分析，婦女妊娠試驗）以及藥物和酒精檢查
PK評估：***和N1979的血液和尿液PK評估
安全性：12導聯心電圖記錄，不良事件（AE）監測，動態心電圖（Holter），臨床安全實驗室測試，伴隨用藥，身體檢查，脈搏血氧飽和度測定血紅蛋白氧飽和度，妊娠試驗，肺活量測定，遙測，生命體征，體重；
納入的主要標準
年齡：18-55歲（含）
體重指數：≥19.5 kg / m2和≤32.0 kg / m2
對象：健康的白人男性和女性對象，無臨床上重要的心臟發現史
研究藥物
活性物質：***
劑型：膠囊
強度/批號：5 mg / N454451
強度/批號：25毫克/ N454891
強度/批號：50毫克/ N456044
制造商：Norwich Pharmaceuticals (Norwich, NY)
名稱：安慰劑
劑型：膠囊
批號：N454450
制造商：Norwich Pharmaceuticals (Norwich, NY)
評估標準/主要結局
藥效學：不適用
藥動學：這是一項雙盲、隨機、安慰劑對照、多劑量組研究。4個遞增劑量10, 50, 250 和500 mg，研究的每個組有8個受試者（6個試驗藥，2個安慰劑），在研究第1天到第14天，每個受試者收到研究藥物的口服劑量，***或者安慰劑，然后追蹤安全性和藥動學評估；
血漿PK：第一天的PK參數取決于第一劑量組***的濃度-時間數據，包括最大濃度值（Cmax），最大濃度值的時間（Tmax），在濃度-時間曲線下計算從0時刻到最后可測量和無窮大下的面積（AUC0-t，AUCinf）；和最終消除半衰期(T?).，另外估計口服清除率(CL/F)和最大表觀分布容積(Vz/F)，包含14天濃度-時間數據中***的穩態PK參數，Cmax, Tmax, t?, AUC0-12, AUC0-τ, CLss/F，以及累計比率(Racc)。
***主要經歷了葡萄糖醛酸化，直至N1979，O-葡萄糖醛酸含量占所測葡萄糖醛酸代謝物總量的> 95％。N91288，酰基-葡糖醛酸苷是次要成分，占總含量的<3％.這代謝物的藥動學參數由N1979和N91288離子體的總血漿濃度決定的，并被稱為N1979,在PK報告和整個文章中的主要代謝物。N1979的在第一劑量組第一天濃度-時間數據包括：Cmax, Tmax, t?, AUC0-24,
AUCinf，原型代謝物與原型的比值（M/P），來自***的14天穩態PK參數濃度-時間數據包括：Cmax, Tmax, t?, AUCtau, Racc, and M/P 比值，通過至少使用3個時間點的對數值（終末期的）血漿濃度對數線性回歸來估計最終消除半衰期
尿PK：隊列2在D1計算***和代謝物N1979PK參數即腎臟清除率（Clt）和累積回收量（Ae0-t）原型
安全性：安全性評估是基于AE報告醫學審查和12導聯ECG測量，動態ECG（Holter），臨床安全性實驗室檢測（包括血液學，CRP臨床化學,尿液分析），伴隨用藥，體格檢查，通過脈搏血氧儀測定的血紅蛋白血樣飽和度，孕檢，肺活量，遙測，生命體征測量，和體重；
統計學方法
樣本量大小測定，這是一個暴露動力學研究，因此對于統計學分析推斷沒有把握度，沒有正式進行樣本量測算；受試者數量的選擇是基于可行性，被認為足以滿足研究主題。
藥動學參數：***和 N1979的PK參數被推導運用WinNonlin軟件6.3版本，估計PK參數來自于使用非房室分析標準方法計算的血漿濃度，使用實際收集時間計算，使用方差分析比較PK參數；
安全性參數：將不良事件列表化；臨床實驗室檢測，12導聯ECG數據、生命體征數據被匯總描述，并描述了與基線相比的變化，ECG的分析數據（在第1-2天和第14-15天的3個時間點進行三次重復測量，以及在其他時間點進行單次測量），包括心率，QRS軸，PR間隔，QRS持續時間，RR間隔和 QT間隔；QTcF被計算。所有的ECG要通過合格的，能集中心臟安全性的心臟病專家進行。
結果
受試者分布
總共有49例受試者被隨機安排進入試驗，47例受試者（96%）完成了試驗，2例受試者由于個人原因（與實驗無關）提前終止試驗；總共49例受試者，其中37例男性12例女性，所有受試者均為白種人，受試者平均年齡（±標準差）是39.1 (11.4)歲。
***的暴露
參與試驗受試者的分組與劑量安排如下：
多劑量組（劑量14天），每組6例受試者服用試驗藥，2例受試者服用安慰劑，總共有24例受試者服用N9115,9例服用安慰劑（包括一例替代受試者）。
?第1組: 10 mg
?第 2組: 50 mg
?第3組: 250 mg
?第4組: 500 mg
單劑量組，每組6例受試者服用***，2例受試者服用安慰劑；
?第2a組：50 mg
?第5組：250 mg（高脂餐）
藥代動力學：藥代動力學概述每天口服*** 10至500 mg，共14天，所有劑量組在給藥后2小時內達到峰值濃度，從而迅速吸收。Cmax幾何均值與劑量遞增成比例增加。、AUC0-tau的增加略大于劑量增加比例。高脂餐組250 mg劑量的***Tmax為4小時，而在禁食狀態下為1.5小時，但*** Cmax和AUC0-t相對于禁食狀態的在90％以內，表明食物對*** PK的影響最小。低劑量下末期半衰期（t?）的幾何平均估計值更長，低劑量下為10.5至14.9小時劑量，高劑量組約5個小時，分別為250和500 mg劑量。對于所有劑量組，穩態下的幾何平均清除率范圍在13.9至23.6 L / h之間，線性分析中注意到清除率的劑量依賴性降低。對于所有劑量組，暴露累積率Racc（AUC）和Racc（Cmax）的幾何平均值最小，分別在> 1.2至> 1.33的范圍內。這表明在低劑量每天重復一次后，***表現出最小的積累，而在測試的最高劑量下則沒有積累。
每天口服10至500毫克后，***會通過葡萄糖醛酸化作用快速而廣泛地代謝為兩種非活性代謝物。 代謝物的濃度大約是100％到300％***血漿濃度。 血漿代謝物濃度的總和為N1979（O-葡萄糖醛酸）和N91288（?；咸烟侨┧幔?N1979濃度> 95％，N91288濃度<5％。 因此，據報道代謝物PK值與N1979相同。
N1979出現相對較快，所有隊列的峰值濃度均在不到4.0小時內達到.Cmax和AUCtau值以小于劑量比例的方式增加。 在較低劑量下，末期半衰期（t?）較大（10.4 – 11.6小時），在較高劑量下則較小（?5小時）。 原型和代謝物之間半衰期值的相似性表明，N1979的消除受到形成速率的限制。 暴露累積比率Racc（AUC）和Racc（Cmax）介于0.9到1.3之間，表明多次給藥時代謝產物暴露的累積量可忽略不計。 高脂食品的Tmax為5小時，而禁食狀態的Tmax為3小時。 然而，與禁食狀態相比，N1979 Cmax和AUC0-t值略高（106％-101％），表明食物對N1979 PK的影響最小。
在隊列2的受試者中，在第1天評估了***和N1979（葡糖醛酸苷代謝產物）的尿排泄量。 ***和N1979的腎臟清除率較低，分別為1.31 L / h和3.67L / h。這代表了***和N1979普通健康成年人肌酐清除率的大約20％和50％，
分別。總體而言，***劑量的55％在24小時內排泄在尿液中，其中***占5％，代謝產物占50％（N1979和N91288）。由于***的腎臟清除率較低，且24小時內***的血漿濃度相對較低，因此代謝和/或其他非腎臟清除途徑（可能是膽道清除）似乎是原型藥物總體清除的主要原因。
***血漿藥代動力學在第1天口服***后，血漿***濃度相對較快達到峰值，所有人群的中位Tmax值在1.50至5.00小時之間。在所有受試者中，給藥后24小時血漿中***仍可定量。第2組的受試者在第1天不慎服用了25 mg，而不是計劃的50 mg；因此，添加了同類群組2a以接受單次50 mg劑量。幾何平均Cmax值隨劑量的增加而增加，從10 mg的33.0 ng / mL增加到25 mg的111 ng / mL，245 ng / mL，1810 ng / mL，1600 ng / mL和3840 ng / mL ，50毫克，250毫克（禁食），250毫克（禁食）和500毫克劑量水平。對于10mg至500mg劑量水平，Cmax的幾何平均％CV范圍為14.0％至57.8％。與Cmax相似，AUC值隨劑量增加而增加。幾何平均AUClast值分別為327 h * ng / mL，893 h * ng / mL，1530 h * ng / mL，12000 h * ng / mL，10300 h * ng / mL和32400 h * ng / mL分別為10毫克，25毫克，50毫克，250毫克（禁食），250毫克（禁食）和500毫克劑量。對于10mg至500mg劑量水平，幾何平均AUCinf值的范圍為357h * ng / mL至32500h * ng / mL。
第1天的***暴露參數（Cmax，AUClast和AUCinf）呈線性且略有增加在最大劑量下大于劑量成比例的方式。對于10、25和50 mg劑量水平，***的表觀清除率（CL / F）似乎與劑量無關，但對于250和500 mg劑量水平，其表觀清除率（CL / F）相對較低。高脂餐后5分鐘內給予***的平均Cmax和AUC值比空腹受試者給予***的平均Cmax和AUC值低約15％。
到第7天，除一名受試者外（在50毫克隊列中），所有受試者的劑量前***濃度均可量化。由于與第1天和第14天相比，在第7天收集的血漿樣品相對較少，因此第7天PK參數的估計值較不可靠。因此，第7天PK值應用于定性而非定量目的。
在10到500 mg劑量范圍內，幾何平均Cmax值以略大于劑量比例的方式從67.9 ng / mL增加到6200 ng / mL。對于10到500 mg劑量，最終相半衰期（t?）的幾何平均估計值隨著劑量從8.03小時增加到4.71小時而降低。與Cmax一致，AUC0-tau以大于劑量比例的方式增加，對于10 mg至500 mg組，其幾何平均值為442 h * ng / mL至40800 h * ng / mL。
在第14天。所有受試者能獲得***的濃度。與第一天相比，***的出現更加迅速，所有組的Tmax中位值均小于兩個小時。與第一天相反， Cmax幾何均值增加與劑量成正比，對10mg和500mg組，從84.3 ng/mL 增長到5800 ng/mL。與第一天一致，AUC0-tau以略大于劑量比例的方式增加。在低劑量最終消除半衰期的幾何平均估計值更長，對10 mg和 50 mg 劑量組，值分別為在14.9到10.5；對250和50 0g劑量組的值分別為5.58和5.21。
在低劑量組中較長的半衰期更有可能取決于采樣時間表，因為只有10 mg和 50 mg 劑量組水平采樣時間達到48小時，在穩態狀態下所有劑量組的清除率的幾何均值范圍在13.9-23.6 L/h之間，線性分析中記錄了清除率的劑量依賴性在降低。在10、25、250 mg 組中暴露累計比的幾何均值是大于1.2的，但是500mg組的是1.01。這表明每天重復一次后***展示了在低劑量組很低的累積值，在高劑量組沒有累計值。對于所有劑量組檢測峰濃度的幾何均值累計比(Racc(Cmax)) >1.33，表明每天重復一次劑量，峰濃度增加中等程度。
代謝物N1979血漿藥代動力學，在第1天口服***之后，N1979血漿濃度，無活性代謝物出現相對較快，顯示Tmax值的中位數約為4.0小時。在所有受試者服藥，N1979服藥后24小時血漿中N1979仍然可測量，表明多劑量組中有累積效應。與空腹受試者相比，高脂餐后5分鐘內服用***可使N1979 Cmax的均值和N1979的AUCinf幾何均值值均高出約6％。 空腹狀態下N1979的出現較快， Tmax值中位數比餐后狀態早2.0小時。 總體而言，代謝物與原型的幾何均值比值≥1.40，在較低劑量（10-50 mg）下可見最大比例。
在第7天，除了1個受試者（50mg組）所有的受試者劑量前N1979濃度均可以被測量，由于在第7天血漿樣本數量相對較少（與第1天和第14天相比），這個PK參數估計與其他天相比可能可靠性較低。基于這個原因，這些值常常用來定性，而不是定量的目的。10和500 mg 組,Cmax值的幾何均值分別以小于劑量比例的方式從359 ng/mL 增加到 9580 ng/mL。末端半衰期的幾何均值估計值在劑量組之前是一致的，值在5.61-6.09小時之間。對于 10 mg,、50 mg,、250 mg、500 mg組，與Cmax一致，AUC0-24比劑量比例增加，其幾何均值分別是2020 h*ng/mL，8950 h*ng/mL, 47200 h*ng/mL, 83400 h*ng/mL。如第一天所見，根據***的低劑量（10 和50 mg），這個代謝物和原型的幾何均值比是更高的。在500mg劑量水平,代謝物與原型Cmax幾何均值比小于這個單位（0.0973），而其余組的比率均大于1。
在第14天，所有受試者均可以在藥物服用前測出N1979濃度。N1979的出現是非?？斓?，所有組中Tmax值的中位數小于4小時。10 mg 到500 mg 組，Cmax值的幾何均值的增加分別小于從389 ng/mL 到 8270 ng/mL的劑量比例。10 mg 到500 mg 劑量組水平，AUCtau的的增加是小于劑量比例的增加，其幾何均值分別為2110 h*ng/mL 和 69600 h*ng/mL。末端半衰期在低劑量組更長，10 mg 和50mg劑量組值分別是11.6和10.4，250mg 和500mg劑量組值分別是5.77和5.74。對于低劑量組更長的半衰期可能取決于采樣時間表，，因為只有10 mg和 50 mg 劑量組水平采樣時間達到48小時。在原型和代謝物半衰期的值相似性表明N1979的消除受形成速率的影響。由于代謝物的末端消除半衰期不應該短于原型的末端消除半衰期，這N1979的末端消除半衰期很有可能在大部分受試者中被低估了。這暴露累計比值Racc(AUC) 的幾何均值范圍從0.88到1.09，表明多次給藥的代謝物積累量可忽略不計。這峰濃度累計率(Racc(Cmax) 范圍從0.907到1.33，進一步表明缺乏累計。在第14天代謝物和原型的Cmax幾何均值比范圍在0.898到2.91，AUCtau幾何均值比范圍在1.22到3.14。表明N1979的全身暴露是***的100% 至300%。
尿液藥代動力學，*** 和 N1979的尿排泄，葡萄糖醛酸代謝物，在第2組受試者的第1天被評估。25 mg ***組的大約有5%（第2組第1天）被清楚，因為尿液中***沒有變化，導致腎清除率低至1.31 L/h，大約是普通健康成人的肌酐清除率的20％。由于***較低的腎清除率和24小時內***的低血漿濃度，它表明代謝和/或其他非腎臟清除途徑（可能是膽汁清除）的清楚是原型藥物的全身清除的主要原因。
尿液中排出的N1979的幾何平均質量為19.1 mg，它代表了25mg劑量組的50%。這N1979的腎臟清除率是3.67 L/h，大約是普通健康成人的肌酐清除率（7.2 L/h）的50％。
這個結果表明與原型藥物相比，N1979主要經歷了腎臟清除，正如表明的那樣通過高劑量組清除和有更大的腎臟清除估計值。
綜合，***劑量的55%在24小時內排除到尿液中，5%是原型，50%是代謝物（N1979 和 N91288）。
安全性：49例受試者中報道中有40名（81.6%）在研究期間至少有1次發生與治療相關的不良事件。在第1組和第4組的所有受試者（這些接受***和 placebo14天的）報道了1個與藥物相關的，而在第2a組（16.7%）和第5組（66.7%）只有很少的受試者報道與藥物相關，可能是由于在這兩組中***的給藥時間更短。***有很好的耐藥性，所有的與藥物相關的嚴重程度為輕度，沒有觀察到與劑量相關的不良時間發生率增加，***沒有比安慰劑更廣泛的事件出現。一個最大耐受劑量是不確定，因為在高劑量試驗中是沒有劑量限制性毒性是確定的。
第1-4組，受試者合并安慰劑治療（14天劑量）
藥物相關報道頻率最多的是接觸性皮炎、頭痛、頭暈。在第1-4組中接受***或安慰劑的所有受試者中均發生接觸性皮炎，在第1組和第2組中有3/6（50%）的受試者發生頭痛，但是在第3組和第4組中，下降到0/6和1/6 (17%)， 1/9 (11%)發生在安慰劑受試者中。在第2組中有2/6(33%)的受試者發生頭暈，且2/9（22%）發生在安慰劑組。在所有被報告的受試者中，對于心電圖導聯來說接觸性皮炎被認為是次要的。由于接觸性皮炎和頭痛的發生頻率，SOC皮膚和皮下組織疾病顯示出TEAE的發生頻率最高，并且SOC神經系統疾病顯示了下一個TEAE最高頻率，所有的TEAEs在嚴重程度上是輕度。
有19例受試者（38.8%）報告了與研究藥物有相關性的TEAEs。在第1、2組（67%）這些事件百分比較第3、4組（33%）更高，在最后兩個組中，發生率低于安慰劑組（56%）。由研究藥物引起的報告最常見的不良事件是，發生頭痛的總共有7個受試者（在第1、2、3、4組中分別是2例[33%],1例[17%],0例,1例[17%]，其中安慰劑1例[11%]）;發生頭暈的總共有4名受試者（在第2組2例[33%]，安慰劑組2例[22%]）。發生口瘡性口炎總共有3例受試者（第1組2例[33%]，安慰劑組1[11%]）;發生便秘的總共有3名受試者（第2組1例[17%],安慰劑1例[11%]）。所有的其他因素相關的不良時間被報告的僅僅只有1人。
這里沒有嚴重不良事件，沒有與藥物相關的不良事件導致試驗中斷和停止，并且沒有不良事件導致死亡。
在12導聯ECT數據、臨床實驗室結果和其他的安全性數據顯示沒有重大臨床意義事件。
第2a組和第5組（單次給藥組）
接觸性皮炎是報告最多的事件，第5組中有4例（67%）受試者發生，安慰劑有1例（25%）受試者發生。只有一個其他事件被報告：在2a組和安慰劑各有一例受試者發生頭痛。
心血管安全，除了對心率的影響很小，ECG數據發現全部為陰性:所有治療組，包括安慰劑，在第14天心率增加。***的500mg劑量組最高的心率和最大的增加是相關的，但是這個增加與其他劑量組和安慰劑沒有明顯差異。隨著***劑量增加或*** or N1979的濃度的增加，更高的變化值沒有一致的趨勢。
沒有AV傳導干擾是和***的給藥有關，在觀察期內腦室內傳導變化不一致。心肌復極不受***給藥的影響，***, N91288, 或 N1979的QTcF和血漿濃度的改變是沒有相關性的。
除了對心率影響很小以外，心電動態檢測儀結果全部是陰性，24小時心率值的均值，最大值，最小值在治療期間沒有改變，雖然所有治療組平均每小時心率值顯示在第1天末與基線相比有微小增加。在第14天，*** 500 mg組的受試者HR每小時值顯示最低高度，但是沒有注意到一致的劑量趨勢，對比安慰劑改變也沒有明顯差異。
新房異位的結果是正常的。這里有少數室上性心動過速發作，
所有22拍或更短的持續時間最大是147 bpm.，在研究中未發現明顯的室性異常，除了在*** 50 mg組第二天單個受試者發生了短暫的心室發作。最大持續時間是6拍，最大總體心率是99bpm。動態心電圖診斷結果不明顯。
QTcF的均值是很窄的范圍從398.5 到 426.8 msec，在觀察的整個試驗中，幾乎沒有發現變化。對所有治療的QTcF的均值變化與基線相比是非常相似的，但是在第1天2-8小時和第14天的4小時確實顯示出更大的減少趨勢，變化的平均值是最小總體范圍從18.6 msec（250 mg組,14天，4小時）到 9.9 msec（10 mg組，10天，服藥前）。沒有明顯的劑量組的趨勢?；貧w分析顯示QTcF的改變和***的濃度，或N1979的濃度沒有關系?；貧w的斜率近似為0.220 和0.235，非顯著性P值為0.71和 0.65。從最低到最高的觀察濃度QTcF預測變化值幾乎相同，-0.7和 0.1 msec,***分別為-0.8和0.1msec，N1979分別為-0.8和0.1msec。
心電圖和動態心電圖檢查結果是互相補充的，在這兩種情況下，在*** 500 mg 治療中顯示心率最小的增加，與安慰劑相比沒有顯著差異。心臟加速的趨勢僅僅與高劑量組有關，在增加時間或劑量趨勢一致的情況下沒有顯示出藥效學的效果。
結論
***-1H-01 (SNO-2)臨床研究的主要目的是評估在健康受試者中每日一次口服膠囊14天評估***的安全性和耐受性。第二個目的是評估在健康受試者中***的藥代動力學。36個受試者被隨機分配服用***，所有受試者被納入***及其代謝物N1979的藥代動力學分析中。
***血漿PK結論
每日一次以10, 50, 250, 和500 mg劑量口服***膠囊14天，N9115的藥代動力學結果如下：
?***經歷了快速吸收，所有組的Tmax均小于2小時。
?在10 mg至500 mg組中Cmax幾何均值按劑量比例增加。
?同樣，對于10 mg至500 mg組，穩態時AUCtau幾何均值以略大于劑量比例的方式增加。
?較低劑量下末期半衰期的幾何平均估計值（t?）更長，10和50 mg劑量組分別為14.9和10.5，而250和500 mg劑量分別為5.58和5.21。
?***在第14天之前（可能在第7天或之前）達到穩定狀態。
?所有劑量組在穩態下的幾何平均清除率范圍在13.9至23.6 L / h之間，清除率與劑量有關，可能由于新陳代謝的飽和而降低。
?在低劑量每天重復一次之后，***顯示出最小的累計（Racc（AUC）> 1.2），而在測試的最高劑量下則無累計。
?同樣，所有試驗劑量組的幾何平均峰濃度累積比（Racc（Cmax））> 1.33，這表明，每天重復一次給藥，峰濃度會略有增加。
?在高脂餐中服用250 mg ***不會影響平均Cmax和AUC值，這比空腹受試者的水平低約15％。
血漿代謝物N1979藥代動力學結論
每天一次口服10、50、250和500 mg ***藥物，共14天，導致其通過葡萄糖醛酸化作用快速和廣泛地代謝為兩種非活性代謝物，主要代謝為O-葡糖醛酸N1979（總代謝物的含量> 95％），并在較小程度上（總含量的<5％）轉化為N91288的?；咸侨┧彳?。多次口服10 至500 mg劑量N9115后主要代謝物N1979的要藥代動力學的總結如下：
?N1979的較快的出現，所有組的Tmax值中位數小于4小時。
?所有組中，Cmax幾何均值以低于劑量比例方式增加，表明代謝可能達到飽和。
?類似的，AUCtau幾何均值隨著劑量的遞增以低于劑量比例方式增加。
? N1979末端半衰期幾何均值估計隨著劑量遞減而減??；
?原型與代謝物相似的半衰期值表明劑量的增加限制了N1979的形成速率。
?通過累計暴露比值的幾何均值(Racc(AUC) 和 Racc(Cmax))顯示N1979展示的多次暴露累積曝光量可忽略不計。
?Cmax 和 AUCtau代謝物和原型的幾何均值比隨著***劑量的增加而減少，范圍是***.的300% 到 100%。
*** 和代謝物 N1979 尿液藥代動力學
*** 和 N1979的尿液排泄，在第2組第1天受試者葡萄糖醛酸代謝物被評估。
?***的腎臟清除率低至1.17 L/h,，這大約是健康受試者肌酐清除率的20％，并且24小時內***低血漿濃度表明，對于原型藥物總體清除率，代謝和/或其他非腎臟清除率是主要原因。
???N1979腎臟清除率幾何均值是3.67 L/h。
? ***的25 mg劑量（第2組第1天）約1.17 mg的***，大約5%未改變的原型藥物通過尿液排出。
?被排除的N1979的幾何平均質量是19.1 mg，大約是25mg劑量組的50%。
?25 mg劑量組55%（第2組，第1天）被排除在尿液中，50%是N1979，5%是沒有變化的原型藥物；
?這些結果表明***到N1979經歷了廣泛的新陳代謝，隨后被排出在尿液中，約占劑量的50%。
安全性結論：
?多次遞增劑量的***在普通健康志愿者中有很好的耐受性；
?頻數最多的不良事件是接觸性皮炎（38例受試者），頭痛（8例受試者），和頭暈（4例受試者）。SOC皮膚和皮下組織疾病的發生率最高，接觸性皮炎事件是被認為與心電圖和遙測評估相關的導線放置有關，SOC神經系統疾病顯示出下一個最高的不良事件發生頻率。
?這里沒有嚴重不良事件，或與研究藥物相關的不良事件導致停止和中斷，所有的不良事件在研究完成之前被解決。
?心電圖和動態心電圖檢查結果是互補的，在兩種情況下，*** 500 mg試驗中顯示出輕微的心率增加，與安慰劑組沒有明顯差異。心臟加速的趨勢僅僅與高劑量組有關，在增加時間或劑量趨勢一致的情況下沒有顯示出藥效學的效果。
?總體而言， ***-1H-01（SNO-2）心電圖和動態心電圖結果證明***具有強大的心臟安全性。
?在平均QTcF值變化中未發現劑量組趨勢，回歸分析顯示QTcF改變與***濃度或代謝物N1979濃度無關。
?臨床實驗室結果，肺活量測定，生命體征或體格檢查數據無臨床上顯著趨勢。
后記：我此時此刻是翻譯官，我此時此刻只能做翻譯。沒有什么是不可能的，保持專注度；我目前的翻譯速度一篇文獻的前幾篇是8小時1頁，主要耗時在專業名詞上，在累計了專業名詞后翻譯速度是在8小時3頁。
2021年5月13日星期四
專業名詞積累
P3
1、 medical review錯誤的翻譯為醫藥回顧，正確的是醫學審查，
2、12-lead ECG measurements，12導聯ECG測量。
3、ambulatory：move
4、Hematology：blood
5、urinalysis:bladder（toilet,body）, the waste liquid that collects in the bladder and that you pass from your body，analysis of urine, urinalysis;
6、concomitant：merge
7、hemoglobin oxygen saturation by pulse oximetry, 有沒有認識的，oxygen，pulse
Hemoglobin：blood red egg white；
Saturation：飽和度
Oximetry：血氧儀
8、spirometry
9、telemetry：the process of using special equipment to send, receive and measure scientific data over long distances。
P3
10、inferential statistical analyses
11、Formal ；猜測正式的
12、performed，do
13、feasibility：likely to be achieved；this plan is feasibility.
14、sufficient,錯譯為有效性，正譯為足夠的；
15、derived: 推導
16、noncompartmental methods：非房室模型方法
17、plasma concentrations：血漿濃度
P3
18、Intensive：repeat
19、Triplicate：一式三份
20、Centralized：集中的
21、Cardiac：心臟病
22、cardiologists：心臟病專家
23、Prematurely：in advance
24、Caucasian ：White people
25、Cohort：group
26、each comprising:each group
P4
Pharmacokinetics resulted in rapid absorption
27、Oral:drink
28、Indicated:show
29、Peak：high
30、Rapid：quickly
31、post dose：
P5
32、the appearance of :……的出現
33、cohorts：group
34、In contrast to Day 1：compare
35、in geometric mean：trangal and square are geometric
36、roughly：
37、proportional：ration
38、terminal：end
P6
dependent upon the sampling chedule翻譯錯誤，正確為取決于采樣時間表
P7
likely owing to the shorter duration of *** administration in these 2 cohorts.
Duration:during
Owing：歸咎于
and no events emerged that were more prevalent on *** than placebo
并且沒有事件出現更加廣泛在***超過安慰劑。
The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is
formation rate-limited with increase in dose.
附上原文：
CLINICAL STUDY REPORT
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of *** in Healthy Subjects
DCR study code: 13172
Sponsor study code: ***-1H-01 (SNO-2)
IND number: 119145
***: Clinical Phase 1 Study
Indication studied: Safety, tolerability, pharmacokinetics
Studied period: 16 February 2014 (first subject screened) – 11 November 2014 (last follow-up)
SPONSOR Nivalis Therapeutics, Inc. (formerly N30 Pharmaceuticals)
3122 Sterling Circle, Suite 200
Boulder, CO 80301, USA
Sponsor’s Contact Robert Hopkins, DVM, MS
Phone: +1 (720) 945-7716
Fax: +1 (303) 440-8399
INVESTIGATOR DaVita Clinical Research
11750 W. 2nd Place, Suite 300, Lakewood, CO 80228 USA
Investigators Chris Galloway, MD
Phone: +1 (303) 566-3100
Fax: +1 (303) 542-7300
Project Manager Marla Elhard, BSN, RN
Phone: +1 (303) 566-3005
Fax: +1 (855) 544-8170
AUTHORS Christopher A. Graybill, PhD, Medical Writer (DaVita)
Scott Brantley, PhD, Pharmacokinetic Scientist (Nuventra)
Eugene R. Heyman, PhD, Senior Biostatistician (Cardiocore)
Daniel B. Goodman, MD, Vice President and Medical Director
(Cardiocore)
Greg Ginn, MS, Biostatistician (DaVita)
Date of this report: 18 September 2015
This study was performed in compliance with the principles of Good Clinical Practice
(GCP), including the archiving of essential documents. This report was written in
compliance with the International Conference on Harmonization (ICH) guidelines.
CLINICAL STUDY REPORT
Nivalis Therapeutics, Inc.; ***-1H-01 (SNO-2)
18 September 2015
Confidential
2 SYNOPSIS
Study Title A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending
Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of *** in
Healthy Subjects
Study Code
DCR study code: 13172
Sponsor study code: ***-1H-01 (SNO-2)
IND number: 119145
Sponsor: Nivalis Therapeutics, Inc. (previously known as N30 Pharmaceuticals, Inc.)
3122 Sterling Circle, Suite 200, Boulder, CO 80301 USA
Sponsor’s Contact: Robert Hopkins, DVM, MS
Study Center: DaVita Clinical Research
11750 W. 2nd Place, Suite 300, Lakewood, CO 80228 USA
Project manager: Marla Elhard, BSN, RN
Investigator: Christopher Galloway, MD
Publication: None at time of writing this report
Study Period: Date of first screening to last follow-up: 16 February 2014 – 11 November 2014
Clinical Phase: Phase 1
Objectives
Primary Objective:
? To assess the safety and tolerability of escalating, multiple doses of *** in healthy subjects.
Secondary Objective:
? To assess the pharmacokinetics (PK) of *** and its primary metabolite, N91288, following multiple doses.
Methodology
Design:
This was planned as a double-blind, randomized, placebo-controlled, multiple ascending dose study; however, two single dose cohorts were also added. In the multiple ascending dose portion of the study, at least 4 ascending cohorts were planned with 8 subjects per cohort (6 active, 2 placebo). Each subject underwent screening (Day -28 to Day -3) and, if eligible, returned to the unit on Day -1 and eligibility was reconfirmed. Eligible subjects received an oral dose of investigational medicinal product (IMP), ***, or placebo once daily on Study Days 1 through 14 and were followed for safety while housed in the clinical research unit (CRU) until they were discharged on Day 15. Pharmacokinetics were followed from Study Day 1 through the morning of Study Day 16.Participation of an individual subject may have lasted approximately 49 days from the time of screening until the end-of-study follow-up call. A Safety Monitoring Committee (SMC) reviewed the safety data after completion of each cohort and decided whether to proceed to the next planned ascending dose cohort, modify the planned dose,repeat a dose, or stop the study according to the stopping rules outlined in the protocol.
The single dose cohorts also included 8 subjects per group (6 active, 2 placebo) and assessed single dose PK and effects of food intake, respectively.
Treatments:
? *** (10, 50, 250, and 500 mg) capsules, administered orally once daily for either 14 days (multiple dose cohorts) or one time (single dose cohorts)
? Matched placebo capsules, administered orally once daily
Procedures and Assessments:
Eligibility screening
Consisting of medical history, demographic information, prior and concomitant medications, physical examination, physical measurement (height, weight, body mass index [BMI]), 12-lead electrocardiogram (ECG) evaluation, 48-hour ambulatory ECG arrhythmia (Holter monitoring) assessment, vital signs
measurements, clinical laboratory tests (serology, hematology, blood chemistry,
urinalysis, pregnancy test for women), and drug and alcohol screen
PK assessments:
PK assessments of blood and urine for *** and N1979
Safety: 12-lead ECG recordings, adverse event (AE) monitoring, ambulatory ECG
(Holter), clinical safety laboratory tests, concomitant medications, physical
examinations, hemoglobin oxygen saturation by pulse oximetry, pregnancy testing,
spirometry, telemetry, vital signs, weight
Main Criteria for Inclusion
Age: 18-55 years, inclusive
BMI: ≥ 19.5 kg/m2 and ≤ 32.0 kg/m2
Subjects: Healthy Caucasian male and female subjects without a history of clinically
significant cardiac findings
Study Medication
Active substance: ***
Dosage form: Capsules
Strength/Lot number: 5 mg/N454451
Strength/Lot number: 25 mg/N454891
Strength/Lot number: 50 mg/N456044
Manufacturer: Norwich Pharmaceuticals (Norwich, NY)
Name: Placebo
Dosage form: Capsules
Lot number: N454450
Manufacturer: Norwich Pharmaceuticals (Norwich, NY)
Criteria for Evaluation/Endpoints
Pharmacodynamics: Not applicable.
Pharmacokinetics: This was a double-blind, randomized, placebo-controlled, multiple ascending dose study. Four ascending dose, 10, 50, 250 and 500 mg cohorts were studied with 8 subjects per cohort (6 active, 2 placebo).Each subject received an oral dose of investigational medicinal product (IMP), ***, or placebo once daily on
Study Days 1 through 14 and was followed for safety and pharmacokinetic (PK) assessments.
Plasma PK The Day 1 PK
parameters determined from the *** concentration-time data for the first dose included maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), area under the concentration-time curve calculated from time 0 to the last quantifiable concentration (AUC0-t) and to infinity (AUCinf), and terminal elimination half-life (T?). Additionally, oral clearance (CL/F) and apparent volume of distribution (Vz/F) were estimated. The steady-state PK parameters from the
*** on Day 14 concentrationtime data included: Cmax, Tmax, t?, AUC0-12, AUC0-τ, CLss/F, and accumulation ratio (Racc) were calculated.
*** undergoes glucuronidation, primarily to N1979, the O-glucuronide representing >95% of total glucuronide metabolites measured. N91288, the acyl-glucuronide was a minor component representing <3% of total. The metabolite pharmacokinetic parameters were determined from the total N1979 and N91288 plasma concentrations and are referred to as N1979, the primary metabolite in the SNO-2 PK report and throughout this document. The N1979 concentration-time data for the first dose on Day 1 included: Cmax, Tmax, t?, AUC0-24, AUCinf, and metabolite to parent (M/P) ratio. The steady-state PK parameters from the N1979 Day 14 concentration-time data included: Cmax, Tmax, t?, AUCtau, Racc, and M/P ratio. The terminal elimination half-life was estimated by log-linear regression of the plasma concentrations during the terminal phase on a logarithmic scale, using at least three time points.
Urine PK *** and metabolite (N1979) PK parameters derived from Cohort 2 on Day 1 were renal clearance (CLr) and cumulative amount of study drug recovered in urine (Ae0-t). In addition, combined parent and metabolite results are reported as total percent of dose excreted in urine.
Safety: Safety assessments were based on medical review of AE reports and the results of 12-lead ECG measurements, ambulatory ECG (Holter), clinical safety laboratory tests (including hematology, clinical chemistry with CRP, and urinalysis), concomitant medications, physical examinations, hemoglobin oxygen saturation by pulse oximetry, pregnancy testing, spirometry, telemetry, vital sign measurements, and weight.
Statistical Methods
Sample Size Determination: This was an exploratory PK study and, therefore, was not powered for inferential statistical analyses. Formal sample size calculations were not performed. The number of subjects was chosen based on feasibility and was considered sufficient to meet the study objectives.
Pharmacokinetic Parameters: PK parameters for *** and N1979 were derived using noncompartmental methods employing WinNonlin? Phoenix version 6.3 (Pharsight, St. Louis, MO). The PK parameters were estimated from the plasma concentrations using standard methods of noncompartmental analysis and were
calculated using actual collection times, and PK parameters were compared using analysis of variance.
Safety Parameters: AEs were tabulated; clinical laboratory tests, 12-lead ECG data, vital signs data, and physical examinations data were summarized descriptively and changes from Baseline were described. Analysis of ECG data (with intensive, triplicate measurements at 3 timepoints on Days 1-2 and Days 14-15 in addition to single measurements at other timepoints) included heart rate rhythm, QRS axis, PR interval, QRS duration, RR interval, and QT interval; QTcF was calculated. All ECGs were evaluated by qualified, centralized cardiac safety cardiologists.
Results
Subject Disposition
A total of 49 subjects were randomized into the study, and 47 subjects (96%) completed the study. Two subjects discontinued the study prematurely for personal reasons (unrelated to the study). Of the 49 total subjects, 37 were male and 12 were female. All subjects were Caucasian. The mean age (±SD) of subjects was 39.1 (11.4) years.
*** Exposure
The following describes the assignment of study subjects to cohort and dose:
Multiple-dose (14 days of dosing) cohorts, each comprising 6 subjects on active *** and 2 subjects on placebo, with a total of 24 subjects dosed with ***, and 9 with placebo (including 1 replacement subject).
? Cohort 1: 10 mg
? Cohort 2: 50 mg
? Cohort 3: 250 mg
? Cohort 4: 500 mg
Single dose cohorts, each comprising 6 subjects on active *** and 2 subjects on placebo:
? Cohort 2a: 50 mg
? Cohort 5: 250 mg (dosed with high-fat meal)
Pharmacokinetics
Pharmacokinetics Summary Oral administration of *** from 10 to 500 mg once daily for 14 days resulted in rapid absorption as indicated by the peak concentrations achieved within 2 hours post dose for all dose groups.
The geometric mean Cmax values increased in a roughly dose proportional manner. Similarly, the AUC0-tau increased in a slightly greater than dose proportional manner. Administration of 250 mg dose of *** with high-fat food resulted in a Tmax of 4 hours relative to 1.5 hours in fasted state. However, *** Cmax and AUC0-t values relative to those at fasted state were within 90%, indicating minimal effects of food on *** PK.Geometric mean estimates of the terminal phase half-life (t?) were longer at lower doses with values of 10.5 to 14.9 hours for the low doses, and approximately 5 hours of the high dose groups, 250 and 500 mg doses. The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance noted in the linearity analysis. The geometric mean of the exposure accumulation ratios, Racc(AUC) and Racc(Cmax), was minimal, ranging >1.2 to >1.33, respectively for all dose groups. This indicates
that *** displays minimal accumulation following repeat once-daily dosing at low doses and no accumulation at the highest dose tested.
*** underwent rapid and extensive metabolism via glucuronidation to two inactive metabolites, following oral administration of 10 to 500 mg once daily. The metabolite concentrations were approximately 100% to 300% of *** plasma concentrations. Plasma metabolite concentrations were measured as a sum of N1979, the O-glucuronide, and N91288, the acyl glucuronide. N1979 concentrations were >95% and N91288 concentrations were <5% of the total sum. Therefore, the metabolite PK values are reported as that of N1979.
N1979 appearance was relatively rapid, with peak concentrations reached in less than 4.0 hours for all cohorts.
The Cmax and AUCtau values increased in a less than dose proportional manner. The terminal phase half-life (t?) was larger (10.4 – 11.6 hours) at lower doses, and smaller (~5 hours) for the high doses. The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited. The
exposure accumulation ratios, Racc(AUC) and Racc(Cmax), ranged from 0.9 to 1.3, indicating negligible accumulation of metabolite exposure with multiple dosing. High-fat food resulted a Tmax of 5 hours relative to 3 hours in fasted state. However, N1979 Cmax and AUC0-t values were slightly greater (106% - 101%) relative to those at fasted state, indicating minimal effects of food on N1979 PK.
The urinary excretion of *** and N1979, the glucuronide metabolite, were evaluated on Day 1 in Cohort 2 subjects. *** and N1979 exhibited a low renal clearance of 1.31 L/h and 3.67L/h, respectively. This represents roughly 20% and 50% of the creatinine clearance of an average healthy adult for *** and N1979,
respectively. Overall, 55% of the *** dose was excreted in the urine over 24 hours, 5% as *** and 50% as metabolites (N1979 and N91288). Due to the low renal clearance of *** and the relatively low plasma concentrations of *** at 24 hours, it appears that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug. *** Plasma Pharmacokinetics Following oral administration of *** on Day 1, plasma *** concentrations peaked relatively rapidly with median Tmax values ranging between 1.50 and 5.00 hours across all cohorts. *** remained quantifiable in plasma 24 hours post-dose in all subjects. Subjects in Cohort 2 were inadvertently dosed 25 mg on Day 1 instead of planned 50 mg; therefore, Cohort 2a was added to receive a single 50 mg dose. The geometric mean Cmax values increased with an increase in dose from 33.0 ng/mL at 10 mg, to 111 ng/mL, 245 ng/mL, 1810 ng/mL, 1600 ng/mL, and 3840 ng/mL at the 25 mg, 50 mg, 250 mg (fasted), 250 mg (fed), and 500 mg dose levels, respectively. The geometric mean %CV for Cmax ranged from 14.0% to 57.8%, for the 10 mg to 500 mg dose levels. Similarly to Cmax, AUC values increased with an increase in dose. The geometric mean AUClast values were 327 h*ng/mL, 893 h*ng/mL, 1530 h*ng/mL, 12000 h*ng/mL, 10300 h*ng/mL, and 32400 h*ng/mL for the 10 mg 25 mg, 50 mg, 250 mg (fasted), 250 mg (fed), and 500 mg dose levels, respectively. The geometric mean AUCinf values ranged from 357 h*ng/mL, to 32500 h*ng/mL for the 10 mg to 500 mg dose levels.*** exposure parameters on Day 1 (Cmax, AUClast, and AUCinf) increased in a linear and slightly greater than dose proportional manner at the highest dose. The apparent clearance (CL/F) of *** appeared to be relatively
independent of dose for the 10, 25, and 50 mg dose levels but was slightly lower for the 250 and 500 mg dose levels. Administration of *** within 5 minutes of a high-fat meal resulted in mean Cmax and AUC values roughly 15% lower than those when *** was administered to fasting subjects.
By Day 7, all but one subject (in the 50 mg Cohort) had quantifiable pre-dose *** concentrations. Day 7 PK parameter estimates are less reliable since relatively fewer plasma samples were collected on Day 7 compared to Days 1 and 14. Therefore, the Day 7 PK values should be used for qualitative, rather than quantitative, purposes.
The geometric mean Cmax values increased in a slightly greater than dose proportional manner from 67.9 ng/mL to 6200 ng/mL over the 10 to 500 mg dose range. Geometric mean estimates of the terminal phase half-life (t?) decreased with increasing dose from 8.03 to 4.71 hours for the 10 to 500 mg doses. Consistent with Cmax, AUC0-tau increased in a greater than dose-proportional manner, with geometric means of 442 h*ng/mL to 40800 h*ng/mL for the 10 mg to 500 mg cohorts.
By Day 14, all subjects had quantifiable pre-dose *** concentrations. Compared to Day 1, the appearance of *** was more rapid, with median Tmax values less than 2.0 hours for all cohorts. In contrast to Day 1, the increase in geometric mean Cmax values was roughly dose proportional from 84.3 ng/mL to 5800 ng/mL for the 10 mg to 500 mg cohorts. Consistent with Day 1, the AUC0-tau increased in a slightly greater than dose proportional manner. Geometric mean estimates of the terminal phase half-life (t?) were longer at lower doses with values of 14.9 and 10.5 for the 10 and 50 mg doses, respectively, and 5.58 and 5.21 for the 250 and 500 mg doses, respectively. The longer half-lives at the lower dose groups are likely dependent upon the sampling schedule as the 10 and 50 mg dose levels were the only ones sampled out to 48 hours. The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance noted in the linearity analysis. The geometric mean of the exposure accumulation ratios (Racc(AUC)) was >1.2 for the 10, 25, and 250 mg cohorts, but was 1.01 for the 500 mg cohort. This indicates that *** displays minimal accumulation following repeat once-daily dosing at low doses and no accumulation at the highest dose
tested. The geometric mean peak concentration accumulation ratios (Racc(Cmax)) were >1.33 for all doses tested,indicating that peak concentrations increased to modest extent with repeat once-daily dosing.N1979 Metabolite Plasma Pharmacokinetics Following oral administration of *** on Day 1, plasma
concentrations of N1979, the inactive metabolite, appeared relatively rapidly with median Tmax values around 4.0 hours. N1979 remained quantifiable in plasma 24 hours post-dose in all subjects, indicating the potential for accumulation with multiple dosing. Administration of *** within 5 minutes of a high-fat meal resulted in roughly 6% higher mean N1979 Cmax and approximately equal mean N1979 AUCinf values compared to the values for fasting subjects. Appearance of N1979 was quicker in the fasted state, with a median Tmax value 2.0 hours earlier than the fed state. Overall, the geometric mean metabolite to parent ratios were ≥ 1.40, with the largest ratios seen at the lower (10-50 mg) doses.
By Day 7, all but one subject (in the 50 mg Cohort) had quantifiable pre-dose N1979 concentrations. Due to the relatively small (compared to Days 1 and 14) number of plasma samples on Day 7, the PK parameter estimates are likely less reliable than those on other days. For this reason, these values should be used for qualitative, rather? than quantitative, purposes. The geometric mean Cmax values increased in a less than dose proportional manner from 359 ng/mL to 9580 ng/mL for the 10 and 500 mg cohorts, respectively. Geometric mean estimates of the terminal phase half-life (t?) were consistent between doses, with values between 5.61 and 6.09 hours. Consistent with Cmax, AUC0-24 increased than dose-proportional manner, with geometric means of 2020 h*ng/mL,8950 h*ng/mL, 47200 h*ng/mL, and 83400 h*ng/mL for the 10 mg, 50 mg, 250 mg, and 500 mg Cohorts,respectively. As seen on Day 1, the geometric mean metabolite to parent ratios were higher following the lower (10 and 50 mg) doses of ***. The geometric mean metabolite to parent ratio for Cmax at the 500 mg dose level was less than unity (0.973), whereas the remainder of the ratios were greater than 1.
By Day 14, all subjects had quantifiable pre-dose N1979 concentrations. The appearance of N1979 was relatively rapid, with median Tmax values less than 4.0 hours for all cohorts. The increase in geometric mean Cmax values was less than dose proportional from 389 ng/mL to 8270 ng/mL for the 10 mg to 500 mg cohorts, respectively. AUCtau increased in a less than dose proportional manner with geometric mean values of 2110 h*ng/mL to 69600 h*ng/mL for the 10 to 500 mg dose levels, respectively. Geometric mean estimates of the terminal phase half-life (t?) were larger at lower doses with values of 11.6 and 10.4 at 10 and 50 mg doses, respectively, and 5.77 and 5.74 at the 250 and 500 mg doses, respectively. The longer half-lives for the lower dose groups are likely dependent upon the sampling schedule as the 10 and 50 mg dose levels were the only ones sampled out to 48 hours. The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited.
Since the terminal elimination half-life of a metabolite should not be shorter than the terminal elimination half-life of the parent, the terminal elimination half-life of N1979 is likely underestimated in many subjects. The geometric means of the exposure accumulation ratios (Racc(AUC)) ranged from 0.880 to 1.09, indicating negligible
accumulation of metabolite exposure with multiple dosing. The peak concentration accumulation ratios (Racc(Cmax)) ranged from 0.907 to 1.33, further indicating the lack of accumulation. The geometric mean metabolite to parent ratios on Day 14 ranged between 0.898 and 2.91 for Cmax and between 1.22 and 3.14 for AUCtau, indicating systemic exposure to N1979 is between 100% and 300% of that of ***.
Urine Pharmacokinetics The urinary excretion of *** and N1979, the glucuronide metabolite, was evaluated on Day 1 in Cohort 2 subjects. Approximately 5% of the 25 mg *** dose (Cohort 2, Day 1) was eliminated as unchanged *** in the urine, resulting in a low renal clearance of 1.31 L/h, which is roughly 20% of the creatinine clearance of an average healthy adult. Due to the low renal clearance of *** and the relatively low plasma concentrations of *** at 24 hours, it appears that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug.
A geometric mean mass of N1979 excreted in the urine was 19.1 mg, which represents approximately 50% of the 25 mg dose. The geometric mean renal clearance of N1979 was 3.67 L/h that is roughly 50% of the creatinine clearance of an average healthy adult (7.2 L/h).These results suggest that N1979 primarily undergoes renal clearance, as indicated by the high percent of dose eliminated and the greater renal clearance estimates as compared to those of the parent drug.
Overall, 55% of the *** dose was excreted in the urine over 24 hours, 5% as parent and 50% as metabolites (N1979 and N91288).
Safety
Adverse Events Forty (40) of 49 total subjects (81.6%) reported at least 1 TEAE during study participation. All subjects (those receiving *** and placebo for 14 days) in Cohorts 1 through 4 reported a TEAE, whereas fewer subjects in Cohort 2a (16.7%) and Cohort 5 (66.7%) reported TEAEs, likely owing to the shorter duration of *** administration in these 2 cohorts. *** was well tolerated, all TEAEs were mild in severity, no dose related increases in the incidence of adverse events were noted, and no events emerged that were more prevalent on *** than placebo. A maximum tolerated dose was not identified because no dose limiting toxicities were identified at the highest dose tested.Cohorts 1 – 4 and combined placebo treated subjects (14-day dosing) The most frequently reported TEAEs were contact dermatitis, headache, and dizziness. Contact dermatitis occurred in all subjects who received *** or placebo in Cohorts 1 through 4; headache occurred in 3/6 (50%) subjects in Cohorts 1 and 2 but decreased to 0/6 and 1/6 (17%) in Cohorts 3 and 4 compared with 1/9 (11%) subjects on placebo; dizziness occurred in 2/6 (33%) subjects in Cohort 2 and 2/9 subjects on placebo (22%). Of note, the contact dermatitis was considered to be secondary to the ECG leads in all subjects in which it was reported. Due to the frequency of contact dermatitis and headache, the SOC Skin and Subcutaneous Tissue Disorders displayed the highest frequency of TEAEs, and the SOC Nervous System Disorders displayed the next highest frequency of TEAEs. All TEAEs were mild in severity.Nineteen subjects (38.8%) reported TEAEs that were causally related to the study drug. A higher percentage of these events were observed in Cohorts 1 and 2 (67%) than in Cohorts 3 and 4 (33%). In the latter two cohorts, the incidence was less than on placebo (56%). The most frequently reported adverse events that were attributed to study drug were: headache occurring in a total of 7 subjects (2 [33%], 1 [17%], 0, 1 [17%], in Cohorts 1, 2, 3, and 4, respectively, and 1 [11%] on placebo); dizziness occurring in a total of 4 subjects (2 [33%] in Cohort 2 and 2 [22%] on placebo); aphthous stomatitis occurring in 3 subjects (2 [33%] in Cohort 1 and 1 [11%] on placebo); and constipation occurring in 2 subjects (1 [17%] in Cohort 2 and 1 [11%] on placebo). All other causally related TEAEs were reported by only 1 subject. There were no SAEs, no TEAEs resulting in study drug discontinuation or interruption, and no AEs resulting in death.
There were no clinically significant trends in 12-lead ECG data, clinical laboratory results, or other safety data. Cohorts 2a and 5 (single dose administration) Contact dermatitis was the most frequently reported event, occurring in 4 (67%) subjects in Cohort 5 and 1 (25%) subject on placebo. The only other event reported was headache occurring in 1 subject each in Cohort 2a and on placebo.
Cardiovascular Safety Findings for ECG data were uniformly negative, with the exception of a minimal effect on heart rate (HR): all treatment groups, including Placebo, had increases of HR on Day 14. The 500 mg dose of *** was associated with the highest HRs and greatest increases, but the increases were not markedly different from the other dose groups or Placebo. There were no consistent trends for higher values of change with increasing dose of *** or increasing concentrations of *** or N1979.No disturbance of AV conduction was associated with administration of ***. There were no consistent trends of intra-ventricular conduction to vary over the observation period. Cardiac repolarization was not affected by administration of ***. There was no relationship between change of QTcF and plasma concentrations of ***, N91288, or N1979.
Holter monitoring findings were consistently negative, again with the exception of a minimal effect on heart rate. Mean, maximum, and minimum 24-hour HR values were unchanged during treatment, although mean hourly HR values showed minor increases from Baseline late on Day 1 for all treatment groups. On Day 14, hourly values of HR showed minimal elevation for subjects in the *** 500 mg group, but no consistent dose trends were noted and changes were not clearly different from Placebo.
Findings for atrial ectopy were normal. There were a small number of supraventricular tachycardia episodes, all 22 beats or fewer in duration with a maximum rate of 147 bpm. Significant ventricular ectopy was not noted during the study, with the exception of 2 brief episodes of ventricular runs in a single subject on *** 50 mg on Day 2. The maximum duration was 6 beats and maximum overall heart rate was 99 bpm. Holter diagnostic findings were unremarkable.
Mean QTcF values were in a narrow range of 398.5 to 426.8 msec. Little variation was noted across the time course of observations. Mean changes of QTcF from Baseline were quite similar for all treatments, but did show a tendency to greater decreases on Day 1 Hour 2 to Hour 8 and on Day 14 Hour 4. The mean values of change were minimal overall ranging from -18.6 msec (250 mg group, Day 14, Hour 4) to 9.9 msec (10 mg group, Day 10, predose). No dose group trends were seen. Regression analysis showed no relationship of change of QTcF with concentration of *** or, separately, with the concentration of N1979. The slopes of the regressions were nearly flat, 0.220 and 0.235, and had non-significant p-values of 0.71 and 0.65. Value of predicted change of QTcF for the lowest to highest observed concentration were nearly identical, -0.7 and 0.1 msec, respectively for *** and from -0.8 and 0.1 msec, respectively for N1979.
The ECG and Holter heart rate findings were complementary and, in both cases, showed minor increases of heart rate during *** 500 mg treatment, not clearly different from placebo. The trend for the cardiac acceleration was associated solely with the highest dose without indication of a pharmacodynamic effect either for timing of the increases or for a consistent dose trend.
Conclusions
The primary objective of Clinical Study ***-1H-01 (SNO-2) was to evaluate the safety and tolerability of *** administered as a once daily oral capsule for 14 days in healthy subjects. A secondary objective was to evaluate the PK of *** in this subject population. Of the 36 subjects who were randomized to receive ***,
all were included in the PK analysis of *** and its metabolite, N1979.
*** Plasma PK Conclusions
The oral administration of *** at 10, 50, 250, and 500 mg once daily for 14 days results in the following *** PK:
? *** undergoes rapid absorption as indicated by a Tmax of less than 2 hours for all cohorts.
? The geometric mean Cmax values increased roughly dose proportional for the 10 mg to 500 mg cohorts.
? Similarly, the geometric mean AUCtau at steady state increased in a slightly greater than dose proportional manner for the 10 mg to 500 mg cohorts.
? Geometric mean estimates of the terminal phase half-life (t?) were longer at lower doses with values of 14.9 and 10.5 for the 10 and 50 mg doses, respectively, and 5.58 and 5.21 for the 250 and 500 mg doses, respectively.
? *** reached steady state before Day 14, possibly before or by Day 7.
? The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance, possibly due to saturation of metabolism.
? *** displays minimal accumulation (Racc(AUC) >1.2) following repeat once-daily dosing at low doses and no accumulation at the highest dose tested.
? Similarly, the geometric mean peak concentration accumulation ratios (Racc(Cmax)) were >1.33 for all doses tested, indicating that peak concentrations increased slightly with repeat once-daily dosing.
? Administration of 250 mg of *** with a high-fat meal did not affect the mean Cmax and AUC values, which were roughly 15% lower than the levels in fasting subjects.
N1979 Metabolite Plasma PK Conclusions
The oral administration of *** at 10, 50, 250 and 500 mg once daily for 14 days resulted in the rapid and extensive metabolism of *** via glucuronidation to two inactive metabolites, mainly to O-glucuronide N1979 (>95% of total metabolite) and, to a lesser extent (<5% of total), to N91288, the acyl glucuronide. The PK values for
the primary metabolite N1979 following repeat oral dosing of *** at 10 to 500 mg are summarized below.
? The appearance of N1979 was relatively rapid, with median Tmax values less than 4.0 hours for all cohorts.
? The geometric mean Cmax values increased in a less than dose proportional manner for all cohorts, suggesting possible saturation of metabolism.
? Similarly, the geometric mean AUCtau increased in a less than dose proportional manner with increase in dose.
? N1979 geometric mean estimates of the terminal phase half-life (t?) decreased with increase in dose.
? The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited with increase in dose.
? N1979 shows negligible accumulation of exposure with multiple dosing as shown by the geometric means of the exposure accumulation ratios (Racc(AUC) and Racc(Cmax)).
? The geometric mean metabolite to parent ratios for Cmax and AUCtau decreased with an increase in N911115 dose, ranged from 300% to 100% of that of ***.
*** and N1979 Metabolite Urine PK The urinary excretion of *** and N1979, the glucuronide metabolite, was evaluated on Day 1 in Cohort 2 subjects.
? Renal clearance of *** was low 1.17 L/h, which is roughly 20% of the creatinine clearance in healthy subjects and the relatively low plasma concentrations of *** at 24 hours suggest that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug.
? The geometric mean renal clearance of N1979 was 3.67 L/h.
? Approximately 1.17 mg of ***, approximately 5% of the 25 mg of *** dose (Cohort 2, Day 1) was eliminated unchanged parent drug in the urine
? The geometric mean mass of N1979 excreted was 19.1 mg, which represents approximately 50% of the 25 mg dose.
? A total of 55% of the 25 mg dose (Cohort 2, Day 1) was eliminated in the urine, with 50% as N1979 and 5% as unchanged parent drug.
? These results suggest that *** undergoes extensive metabolism to N1979 which was subsequently eliminated in the urine, representing approximately 50% of the dose.
Safety Conclusions
? Multiple, ascending doses of *** were well tolerated in normal healthy volunteers.
? The most frequently reported TEAEs were dermatitis contact (38 subjects), headache (8 subjects), and dizziness (4 subjects). The SOC Skin and Subcutaneous Tissue Disorders displayed the highest frequency of TEAEs, where contact dermatitis events were thought to be related to the lead placement associated with ECG and telemetry assessments, and the SOC Nervous System Disorders displayed the next highest frequency of TEAEs.
? There were no SAEs or TEAEs resulting in study drug discontinuation or interruption. All TEAEs were resolved prior to study completion.
? The ECG and Holter heart rate findings were complementary and, in both cases, showed minor increases of heart rate during *** 500 mg treatment, not clearly different from placebo. The trend for the cardiac acceleration was associated solely with the highest dose without indication of a pharmacodynamic effect either for timing of the increases or for a consistent dose trend.
? Overall, Protocol ***-1H-01 (SNO-2) ECG and Holter results demonstrated robust cardiac safety for ***.
? No dose group trends were seen in change in mean QTcF values. Regression analysis showed no relationship of change of QTcF with concentration of *** or, separately, with the concentration of N1979.
? There were no clinically significant trends in clinical laboratory results, spirometry, vital sign, or physical examination data.
Date of report: 18 September 2015
