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800155000 22300Amx00422 K ࢫࢸ࢟ࢾ࣐ࣈ 2.7.6 ಶࠎࡢヨ㦂ࡢࡲ࡜ࡵ ┠ḟ 2.7.6 ಶࠎࡢヨ㦂ࡢࡲ࡜ࡵ ................................................................................................................ 3 ඲⮫ᗋヨ㦂୍ぴ⾲ ................................................................................................................................ 3 2.7.6.1 ᾏእ⮫ᗋ➨ I ┦ヨ㦂㸦CNTO1275NAP1002 ヨ㦂㸪ཧ⪃㈨ᩱ㸸5.3.1.2.1㸧 ................ 6 2.7.6.2 ➨ III ┦ᅜ㝿ඹྠヨ㦂㸸ᐶゎᑟධヨ㦂㸦CNTO1275CRD3001 ヨ㦂㸪 ホ౯㈨ᩱ㸸5.3.5.1.1㸧 .................................................................................................... 12 2.7.6.3 ➨ III ┦ᅜ㝿ඹྠヨ㦂㸸ᐶゎᑟධヨ㦂㸦CNTO1275CRD3002 ヨ㦂㸪 ホ౯㈨ᩱ㸸5.3.5.1.2㸧 .................................................................................................... 84 2.7.6.4 ➨ III ┦ᅜ㝿ඹྠヨ㦂㸸ᐶゎ⥔ᣢヨ㦂㸦CNTO1275CRD3003 ヨ㦂㸪 ホ౯㈨ᩱ㸸5.3.5.1.3-1㸧 ............................................................................................... 137 2.7.6.5 ᾏእ⮫ᗋ➨ IIa ┦ヨ㦂㸦C0379T07 ヨ㦂㸪ཧ⪃㈨ᩱ㸸5.3.5.1.4㸧 .......................... 385 2.7.6.6 ᾏእ⮫ᗋ➨ IIb ┦ヨ㦂㸦C0743T26 ヨ㦂㸪ཧ⪃㈨ᩱ㸸5.3.5.1.5㸧 .......................... 393 1 (1) ࢫࢸ࢟ࢾ࣐ࣈ 2.7.6 ಶࠎࡢヨ㦂ࡢࡲ࡜ࡵ ␎ྕ୍ぴ⾲ ␎ྕཪࡣ␎⛠ ྡ⛠ཬࡧෆᐜ 5-ASA 5-aminosalicylate㸦5-࢔࣑ࣀࢧࣜࢳࣝ㓟㸧 area under the serum concentration versus time curve from time 0 to infinity with AUCinf extrapolation of the terminal phase㸦⤊ᮎ┦ࢆእᤄࡋࡓ 0 ᫬㛫࠿ࡽ↓㝈኱᫬㛫 ࡲ࡛ࡢ⾑Ύ୰⃰ᗘ-᫬㛫᭤⥺ୗ㠃✚㸧 area under the concentration versus time curve from time 0 to last quantifiable AUC last time㸦0 ᫬㛫࠿ࡽ᭱⤊ᐃ㔞ྍ⬟᫬㛫ࡲ࡛ࡢ⾑Ύ୰⃰ᗘ-᫬㛫᭤⥺ୗ㠃✚㸧 BMI body mass index㸦య᱁ᣦᩘ㸧 CDAI Crohn’s Disease Activity Index CDEIS Crohn’s Disease Endoscopic Index of Severity CI confidence interval㸦ಙ㢗༊㛫㸧 CL total systemic clearance㸦඲㌟ࢡࣜ࢔ࣛࣥࢫ㸧 Cmax maximum observed serum concentration㸦᭱㧗⾑Ύ୰⃰ᗘ㸧 CRP C-reactive protein㸦C ཯ᛂᛶࡓࢇⓑ㸧 DMC Data Monitoring Committee㸦ࢹ࣮ࢱࣔࢽࢱࣜࣥࢢጤဨ఍㸧 DNA deoxyribonucleic acid㸦ࢹ࢜࢟ࢩࣜ࣎᰾㓟㸧 GCP Good Clinical Practice㸦་⸆ရࡢ⮫ᗋヨ㦂ࡢᐇ᪋ࡢᇶ‽㸧 HBV hepatitis B virus㸦B ᆺ⫢⅖࢘࢖ࣝࢫ㸧 HCV hepatitis C virus㸦C ᆺ⫢⅖࢘࢖ࣝࢫ㸧 HIV human immunodeficiency virus㸦ࣄࢺච␿୙඲࢘࢖ࣝࢫ㸧 IBDQ Inflammatory Bowel Disease Questionnaire JSEQ Jenkins Sleep Evaluation Questionnaire㸦ࢪ࢙ࣥ࢟ࣥࢫ╧╀ホ౯㉁ၥ⚊㸧 IL interleukin㸦࢖ࣥࢱ࣮ࣟ࢖࢟ࣥ㸧 ITT intent to treat IV intravenous㸦㟼⬦ෆ㸧 LIV liquid in vial㸦ᾮయࣂ࢖࢔ࣝ〇๣㸧 LOR loss of response㸦response ࡢᾘኻ㸧 MCS Mental Component Summary㸦⢭⚄ⓗഃ㠃ࡢ QOL ࢧ࣐࣮ࣜ㸧 MedDRA Medical Dictionary for Regulatory Activities㸦ICH ᅜ㝿་⸆⏝ㄒ㞟㸧 PCS Physical Component Summary㸦㌟యⓗഃ㠃ࡢ QOL ࢧ࣐࣮ࣜ㸧 PDAI Perianal Disease Activity Index QOL quality of life㸦⏕άࡢ㉁㸧 RNA ribonucleic acid㸦ࣜ࣎᰾㓟㸧 SAE serious adverse event㸦㔜⠜࡞᭷ᐖ஦㇟㸧 SC subcutaneous㸦⓶ୗ㸧 SD standard deviation㸦ᶆ‽೫ᕪ㸧 SF-36 36-item Short-form Health Survey T1/2 half-life㸦ᾘኻ༙ῶᮇ㸧 TB tuberculosis 㸦⤖᰾㸧 TEAEs Treatment Emergent Adverse Events TNF tumor necrosis factor㸦⭘⒆ቯṚᅉᏊ㸧 VAS Visual Analog Scale Vz volume of distribution during the terminal phase㸦⤊ᮎ┦ࡢศᕸᐜ✚㸧 WLQ Work Limitations Questionnaire 2 (2) ࠙ࠬ࠹ࠠ࠿ࡑࡉ (1) 2.7.6 ୘ޘߩ⹜㛎ߩ߹ߣ߼ ో⥃ᐥ⹜㛎৻ⷩ⴫ ⹜㛎ߩ ⹜㛎⇟ภ ⹜㛎ߩਥ⋡⊛ ⹜㛎࠺ࠩࠗࡦ ⵍ㛎⮎෸߮ኻᾖ⮎ ⵍ㛎⠪ᢙ ஜᐽⵍ㛎⠪ ᛩਈᦼ㑆 ⹜㛎ߩ 2.7.6 ⒳㘃 [⹜㛎ႎ๔ᦠ ෸߮ ᛩਈᣇᴺ ෶ߪ ㅴⴕ⁁ᴫ ᷝઃ႐ᚲ] ኻᾖߩ⒳㘃 ᛩਈ⚻〝 ᖚ⠪ߩ⸻ᢿฬ ႎ๔ᦠߩ ⒳㘃 ⮎‛േᘒ CNTO1275NAP1002 ஜᐽⵍ㛎⠪ߦᧄ೷ߩᶧ૕ࡃࠗࠕ࡞⵾ ╙ I ⋧㧘ᄙᣉ⸳౒ห㧘 90 mg/mL LIV ⟲㧦 140 ଀ ஜᐽⵍ㛎⠪ න࿁ ቢੌ [5.3.1.2.1] ೷㧔LIV㧕2 ⵾೷㧔90 mg/mL LIV ෸ ࡜ࡦ࠳ࡓൻ㧘ਗⴕ⟲ Day 1 ߦ㧘ᧄ೷ 90 mg/mL LIV㧔ኻᾖ⮎㧕ࠍ ቢోߥ ߮ 5 mg/mL LIV㧕ࠍ 6 mg/kg ߩ↪㊂ 㑆㧘㕖⋤ᬌ㧘න৻↪ 6 mg/kg ߢන࿁㕒⣂ౝᛩਈ㧔ࡐࡦࡊࠍ૶ ႎ๔ᦠ ߢන࿁㕒⣂ౝᛩਈߒߚߣ߈ߩ⮎‛േ ㊂㧘౉㒮㧛ᄖ᧪ㅢ㒮⹜ ↪㧕 ᘒࠍᲧセߔࠆޕ 㛎 5 mg/mL LIV ⟲㧦 ኻᾖ⮎㧦ᧄ೷ Day 1 ߦ㧘ᧄ೷ 5 mg/mL LIV㧔ⵍ㛎⮎㧕ࠍ 90 mg/mL LIV 6 mg/kg ߢන࿁㕒⣂ౝᛩਈ㧔ࡐࡦࡊࠍ૶ ↪㧕 ᦭ലᕈ CNTO1275CRD3001 1. 1 ೷એ਄ߩ᛫ TNF㧔⣲≌უᱫ࿃ ╙ III ⋧㧘࡜ࡦ࠳ࡓ 0 ㅳ⋡ߦ㧘ࡊ࡜࠮ࡏ㧘ᧄ೷ߩ࿕ቯ↪㊂ 769 ଀ ਛ╬∝߆ࠄ㊀∝ߩ න࿁ ቢੌ ቟ోᕈ [5.3.5.1.1] ሶ㧕⮎ᴦ≮ߢലᨐਇචಽ෶ߪᔋ ൻ㧘ੑ㊀⋤ᬌ㧘ࡊ࡜࠮ 㧔130 mg㧕෶ߪ૕㊀೎↪㊂㧔㨪6 mg/kg㧕ߩ 㧔⹜㛎ౣ㐿ᓟ ᵴേᦼࠢࡠ࡯ࡦ∛ ቢోߥ ኈᕈߩߥ޿ਛ╬∝߆ࠄ㊀∝ߩᵴ ࡏኻᾖ㧘ਗⴕ⟲㑆㧘ᄙ ޿ߕࠇ߆ࠍන࿁㕒⣂ౝᛩਈ ߦ࡜ࡦ࠳ࡓൻ ᖚ⠪ ႎ๔ᦠ േᦼࠢࡠ࡯ࡦ∛ᖚ⠪ߦ߅޿ߡ㧘 ᣉ⸳౒ห⹜㛎 ߐࠇߚⵍ㛎 ᧄ೷ߩ㕒⣂ౝᛩਈߦࠃࠆኡ⸃ዉ ኻᾖ⮎㧦ࡊ࡜࠮ࡏ ⠪㧦741 ଀㧕 ౉≮ᴺߩ clinical response ߢߩ᦭ ലᕈࠍ⹏ଔߔࠆޕ 2. 1 ೷એ਄ߩ᛫ TNF ⮎ᴦ≮ߢലᨐ ਇචಽ෶ߪᔋኈᕈߩߥ޿ਛ╬∝ ߆ࠄ㊀∝ߩᵴേᦼࠢࡠ࡯ࡦ∛ᖚ ⠪ߦ߅޿ߡ㧘ᧄ೷ߩ㕒⣂ౝᛩਈ ߦࠃࠆኡ⸃ዉ౉≮ᴺߩ቟ోᕈࠍ ⹏ଔߔࠆޕ ᦭ലᕈ CNTO1275CRD3002 1. ਛ╬∝߆ࠄ㊀∝ߩᵴേᦼࠢࡠ࡯ ╙ III ⋧㧘࡜ࡦ࠳ࡓ 0 ㅳ⋡ߦ㧘ࡊ࡜࠮ࡏ㧘ᧄ೷ߩ࿕ቯ↪㊂ 640 ଀㧔⹜㛎 ਛ╬∝߆ࠄ㊀∝ߩ න࿁ ቢੌ ቟ోᕈ [5.3.5.1.2] ࡦ∛ᖚ⠪ߦ߅޿ߡ㧘ᧄ೷ߩ㕒⣂ ൻ㧘ੑ㊀⋤ᬌ㧘ࡊ࡜࠮ 㧔130 mg㧕෶ߪ૕㊀೎↪㊂㧔㨪6 mg/kg㧕ߩ ౣ㐿ᓟߦ࡜ࡦ ᵴേᦼࠢࡠ࡯ࡦ∛ ቢోߥ ౝᛩਈߦࠃࠆኡ⸃ዉ౉≮ᴺߩ ࡏኻᾖ㧘ਗⴕ⟲㑆㧘ᄙ ޿ߕࠇ߆ࠍන࿁㕒⣂ౝᛩਈ ࠳ࡓൻߐࠇߚ ᖚ⠪ ႎ๔ᦠ clinical response ߢߩ᦭ലᕈࠍ⹏ ᣉ⸳౒ห⹜㛎 ⵍ㛎⠪㧦628 ୘ޘߩ⹜㛎ߩ߹ߣ߼ ଔߔࠆޕ ኻᾖ⮎㧦ࡊ࡜࠮ࡏ ଀㧕 2. ਛ╬∝߆ࠄ㊀∝ߩᵴേᦼࠢࡠ࡯ ࡦ∛ᖚ⠪ߦ߅޿ߡ㧘ᧄ೷ߩ㕒⣂ ౝᛩਈߦࠃࠆኡ⸃ዉ౉≮ᴺߩ቟ ోᕈࠍ⹏ଔߔࠆޕ 3 ࠙ࠬ࠹ࠠ࠿ࡑࡉ (2) ⹜㛎ߩ ⹜㛎⇟ภ ⹜㛎ߩਥ⋡⊛ ⹜㛎࠺ࠩࠗࡦ ⵍ㛎⮎෸߮ኻᾖ⮎ ⵍ㛎⠪ᢙ ஜᐽⵍ㛎⠪ ᛩਈᦼ㑆 ⹜㛎ߩ ⒳㘃 [⹜㛎ႎ๔ᦠ ෸߮ ᛩਈᣇᴺ ෶ߪ ㅴⴕ⁁ᴫ ᷝઃ႐ᚲ] ኻᾖߩ⒳㘃 ᛩਈ⚻〝 ᖚ⠪ߩ⸻ᢿฬ ႎ๔ᦠߩ ⒳㘃 ᦭ലᕈ CNTO1275CRD3003 1. ኡ⸃ዉ౉⹜㛎 ╙ III ⋧㧘࡜ࡦ࠳ࡓ ਥⷐߥኻ⽎㓸࿅㧦 1281 ଀㧔⹜㛎 ਛ╬∝߆ࠄ㊀∝ߩ 44 ㅳ㑆 ታᣉਛ ቟ోᕈ [5.3.5.1.3-1] CNTO1275CRD3001 ෶ߪ ൻ㧘ੑ㊀⋤ᬌ㧘ࡊ࡜࠮ ᧄ೷ߦࠃࠆኡ⸃ዉ౉≮ᴺߢ clinical response ౣ㐿ᓟߦ࡜ࡦ ᵴേᦼࠢࡠ࡯ࡦ∛ 㐳ᦼ⛮⛯ (㐳ᦼ⛮⛯ CNTO1275CRD3002 ߢ㧘ᧄ೷ߩ ࡏኻᾖ㧘ਗⴕ⟲㑆㧘ᄙ ߇ᓧࠄࠇߚⵍ㛎⠪ࠍ㧘એਅߩ 3 ⟲ߦ࡜ࡦ࠳ ࠳ࡓൻߐࠇߚ ᖚ⠪ ᛩਈ㧦 ᛩਈᦼ 2.7.6 ) 㕒⣂ౝᛩਈߦࠃࠅ clinical ᣉ⸳౒ห⹜㛎 ࡓൻ ⵍ㛎⠪㧦1255 272 ㅳ⋡߹ ਛ㑆 response ߇ᓧࠄࠇߚ㧘ਛ╬∝߆ ኻᾖ⮎㧦ࡊ࡜࠮ࡏ ࡮ ࡊ࡜࠮ࡏ⊹ਅᛩਈ ଀㧕 ߢ ႎ๔ᦠ ࠄ㊀∝ߩᵴേᦼࠢࡠ࡯ࡦ∛ᖚ⠪ ࡮ ᧄ೷ 90 mg q12w ⊹ਅᛩਈ ࠍኻ⽎ߦ㧘ᧄ೷ߩ⊹ਅᛩਈߦࠃ ߥ߅㧘44 ㅳ⋡ߩ቟ో ࡮ ᧄ೷ 90 mg q8w ⊹ਅᛩਈ ࠆ 2 ߟߩኡ⸃⛽ᜬ≮ᴺߦ߅ߌࠆ ᕈ෸߮᦭ലᕈ⹏ଔ⚳ੌ clinical remission ࠍ⹏ଔߔࠆޕ ᤨߦ⛮⛯ᛩਈ߇᦭⋉ߢ ߘߩઁߩኻ⽎㓸࿅㧦 2. ਛ╬∝߆ࠄ㊀∝ߩᵴേᦼࠢࡠ࡯ ޽ࠆߣ್ᢿߐࠇߚ႐ว ࡮ ࡊ࡜࠮ࡏߦࠃࠆኡ⸃ዉ౉≮ᴺߢ ࡦ∛ᖚ⠪ࠍኻ⽎ߦ㧘ᧄ೷ߩ⊹ਅ ߪ㧘㐳ᦼ⛮⛯ᛩਈᦼߣ clinical response ߇ᓧࠄࠇߚⵍ㛎⠪㧦 ᛩਈߦࠃࠆ 2 ߟߩኡ⸃⛽ᜬ≮ᴺ ߒߡᦨ㐳 272 ㅳ⋡߹ߢ ࡊ࡜࠮ࡏ⊹ਅᛩਈ ߦ߅ߌࠆ቟ోᕈࠍ⹏ଔߔࠆޕ ᧄ⹜㛎ࠍ⛮⛯ ࡮ ᧄ೷ߦࠃࠆኡ⸃ዉ౉≮ᴺߢ clinical response ߇ᓧࠄࠇߥ߆ߞߚⵍ㛎⠪㧦 0 ㅳ⋡ߦᧄ೷ 90 mg ࠍ⊹ਅᛩਈ ψᧄ೷ 90 mg q8w ⊹ਅᛩਈ ࡮ ࡊ࡜࠮ࡏߦࠃࠆኡ⸃ዉ౉≮ᴺߢ clinical response ߇ᓧࠄࠇߥ߆ߞߚⵍ㛎 ⠪㧦 0 ㅳ⋡ߦᧄ೷ 130 mg ࠍ㕒⣂ౝᛩਈ ψᧄ೷ 90 mg q12w ⊹ਅᛩਈ ୘ޘߩ⹜㛎ߩ߹ߣ߼ 4 ࠙ࠬ࠹ࠠ࠿ࡑࡉ (3) ⹜㛎ߩ ⹜㛎⇟ภ ⹜㛎ߩਥ⋡⊛ ⹜㛎࠺ࠩࠗࡦ ⵍ㛎⮎෸߮ኻᾖ⮎ ⵍ㛎⠪ᢙ ஜᐽⵍ㛎⠪ ᛩਈᦼ㑆 ⹜㛎ߩ ⒳㘃 [⹜㛎ႎ๔ᦠ ෸߮ ᛩਈᣇᴺ ෶ߪ ㅴⴕ⁁ᴫ ᷝઃ႐ᚲ] ኻᾖߩ⒳㘃 ᛩਈ⚻〝 ᖚ⠪ߩ⸻ᢿฬ ႎ๔ᦠߩ ⒳㘃 ᦭ലᕈ C0379T07 1. 5-ࠕࡒࡁࠨ࡝࠴࡞㉄㧔ASA㧕ൻ ╙ IIa ⋧㧘ᄙᣉ⸳౒ ਥ⸃ᨆኻ⽎㓸࿅㧔㓸࿅ 1㧕㧦5-ASA ൻว 㓸࿅ 1㧦 ਛ╬∝߆ࠄ㊀∝ߩ ᛩਈᦼ㑆 ቢੌ ቟ోᕈ [5.3.5.1.4] ว‛㧘᛫↢‛⾰㧘ࠦ࡞࠴ࠦࠬ࠹ ห㧘࡜ࡦ࠳ࡓൻ⹜㛎 ‛㧘᛫↢‛⾰㧘ࠦ࡞࠴ࠦࠬ࠹ࡠࠗ࠼෸߮㧛 104 ଀ ᵴേᦼࠢࡠ࡯ࡦ∛ ߪഀࠅઃ ቢోߥ ࡠࠗ࠼෸߮㧛෶ߪ఺∉⺞▵⮎ߦ ኻᾖ⮎㧦ࡊ࡜࠮ࡏ ෶ߪ఺∉⺞▵⮎㧔᛫ TNF ⮎ࠍ฽߻㧕ߦࠃࠆ 㓸࿅ 2㧦 ᖚ⠪ ߌࠄࠇߚ ႎ๔ᦠ 2.7.6 ࠃࠆᴦ≮ࠍฃߌߚߦ߽߆߆ࠊࠄ ᴦ≮ࠍฃߌߚߦ߽߆߆ࠊࠄߕലᨐ߇ᓧࠄࠇ 27 ଀ 㓸࿅෸߮ ߕᜬ⛯ߔࠆ㧘ਛ╬∝߆ࠄ㊀∝ߩ ߥ߆ߞߚᖚ⠪ࠍ㧘એਅߩ 4 ⟲ߦ࡜ࡦ࠳ࡓൻ ᛩਈ⟲ߦ ᵴേᦼࠢࡠ࡯ࡦ∛㨇Crohn̉s · 0㧘1㧘2 ෸߮ 3 ㅳ⋡ߦࡊ࡜࠮ࡏࠍ⊹ਅ ࠃࠅ⇣ߥ Disease Activity Index㧔CDAI㧕 ᛩਈߒ㧘8㧘9㧘10 ෸߮ 11 ㅳ⋡ߦᧄ೷ ࠆޕ ࠬࠦࠕ߇ 220 એ਄ 450 એਅ㨉ᖚ 90 mg ࠍ⊹ਅᛩਈ 㓸࿅ 1㧦 ⠪ࠍኻ⽎ߣߒߡ㧘ࠢࡠ࡯ࡦ∛ߩ · 0㧘1㧘2 ෸߮ 3 ㅳ⋡ߦᧄ೷ 90 mg ࠍ⊹ · 11 ㅳ ᓽ୥෸߮∝⁁ߩ✭๺ߦ߅ߌࠆᧄ ਅᛩਈߒ㧘8㧘9㧘10 ෸߮ 11 ㅳ⋡ߦࡊ 㑆 ೷ߩ᦭ലᕈࠍ⹏ଔߔࠆޕ ࡜࠮ࡏࠍ⊹ਅᛩਈ · 8 ㅳ㑆 2. ࠢࡠ࡯ࡦ∛ᖚ⠪ࠍኻ⽎ߣߒߡ㧘 · 0 ㅳ⋡ߦࡊ࡜࠮ࡏࠍ㕒⣂ౝᛩਈߒ㧘8 ᧄ೷ߩ⊹ਅᛩਈᤨ෸߮㕒⣂ౝᛩ ㅳ⋡ߦᧄ೷ 4.5 mg/kg ࠍ㕒⣂ౝᛩਈ 㓸࿅ 2㧦 ਈᤨߩ቟ోᕈࠍ⹏ଔߔࠆޕ · 0 ㅳ⋡ߦᧄ೷ 4.5 mg/kg ࠍ㕒⣂ౝᛩਈ · 3 ㅳ㑆 ߒ㧘8 ㅳ⋡ߦࡊ࡜࠮ࡏࠍ㕒⣂ౝᛩਈ · 1 ᣣ㑆 㧔0 ㅳ ೽ᰴ⸃ᨆኻ⽎㓸࿅㧔㓸࿅ 2㧕㧦☨࿖ߢߩࠢ ⋡㧕 ࡠ࡯ࡦ∛ߦኻߔࠆᦨᄢᛚ⹺↪㊂෸߮↪ᴺߩ ࠗࡦࡈ࡝ࠠࠪࡑࡉᛩਈࠍฃߌߚ߇㧘ലᨐਇ චಽ෶ߪലᨐࠍ␜ߒߚ߽ߩߩߘߩᓟലᨐ߇ ᶖᄬߒߚᖚ⠪ࠍ㧘એਅߩ 2 ⟲ߦ࡜ࡦ࠳ࡓൻ · 0㧘1㧘2 ෸߮ 3 ㅳ⋡ߦᧄ೷ 90 mg ࠍ⊹ ਅᛩਈ · 0 ㅳ⋡ߦᧄ೷ 4.5 mg/kg ࠍ㕒⣂ౝᛩਈ ᦭ലᕈ C0743T26 ࠢࡠ࡯ࡦ∛ᴦ≮ߦኻߒߡᛚ⹺ߐࠇߚ ╙ IIb ⋧㧘ᄙᣉ⸳౒ 0 ㅳ⋡ߦ࡜ࡦ࠳ࡓൻߐࠇ㧘ኡ⸃ዉ౉≮ᴺߣ 526 ଀ ਛ╬∝߆ࠄ㊀∝ߩ 16 ㅳ㑆 ቢੌ ቟ోᕈ [5.3.5.1.5] ↪ᴺ࡮↪㊂ߩ 1 ೷એ਄ߩ᛫ TNF ⮎ᴦ ห㧘࡜ࡦ࠳ࡓൻ㧘ੑ㊀ ߒߡࡊ࡜࠮ࡏ㧘⧯ߒߊߪᧄ೷ 1㧘3 ෶ߪ ᵴേᦼࠢࡠ࡯ࡦ∛ ቢోߥ ≮ࠍฃߌߚ߇㧘৻ᰴήലߢ޽ߞߚ ⋤ᬌ㧘ࡊ࡜࠮ࡏኻᾖ㧘 6 mg/kg ߇㕒⣂ౝᛩਈߐࠇߚޕ8 ㅳ⋡ߦ㧘0 ᖚ⠪ ႎ๔ᦠ ߆㧘ೋᦼߦലᨐࠍ␜ߒߚ߽ߩߩߘߩ ਗⴕ⟲㑆㧘↪㊂⸳ቯ⹜ ㅳ⋡ߦኡ⸃ዉ౉≮ᴺߢᧄ೷ߦഀࠅઃߌࠄࠇ ᓟലᨐ߇ᶖᄬߒߚᖚ⠪㧘෶ߪߎࠇࠄ 㛎 ߚⵍ㛎⠪ࠍ㧘6 ㅳ⋡ߩ clinical response ߦၮ ߩᴦ≮ߦኻߒߡᔋኈᕈ߇ߥ޿㧘ਛ╬ ኻᾖ⮎㧦ࡊ࡜࠮ࡏ ߠ߈ౣ࡜ࡦ࠳ࡓൻߒ㧘ኡ⸃⛽ᜬᦼߩᛩਈߣ ୘ޘߩ⹜㛎ߩ߹ߣ߼ ∝߆ࠄ㊀∝ߩᵴേᦼࠢࡠ࡯ࡦ∛ᖚ⠪ ߒߡ 8 ㅳ⋡෸߮ 16 ㅳ⋡ߦᧄ೷㧔90 mg㧕෶ ߦ߅޿ߡ㧘ᧄ೷ߦࠃࠆ clinical ߪࡊ࡜࠮ࡏࠍ⊹ਅᛩਈߒߚޕ response ߩዉ౉ߦ߅ߌࠆ᦭ലᕈ෸߮ ቟ోᕈࠍ⹏ଔߔࠆޕ 5 ࠙ࠬ࠹ࠠ࠿ࡑࡉ 2.7.6 ୘ޘߩ⹜㛎ߩ߹ߣ߼ NAP1002 ⹜㛎 2.7.6.1 ᶏᄖ⥃ᐥ╙ I ⋧⹜㛎㧔CNTO1275NAP1002 ⹜㛎㧘ෳ⠨⾗ᢱ㧦5.3.1.2.1㧕 2.7.6.1.1 ᭎ⷐ (1) ᴦ㛎ታᣉ⸘↹ᦠ⇟ภ CNTO1275NAP1002 (2) ᴦ㛎ߩᮡ㗴 ࠙ࠬ࠹ࠠ࠿ࡑࡉ㧔એਅ㧘ᧄ೷㧕ߩᶧ૕ࡃࠗࠕ࡞ 2 ⵾೷ࠍ㕒⣂ౝන࿁ᛩਈߒߚߣ߈ߩ⮎‛േᘒࠍ Ყセߔࠆ╙ I ⋧㧘࡜ࡦ࠳ࡓൻ㧘㕖⋤ᬌ㧘ਗⴕ⟲㑆Ყセ⹜㛎 (3) ᴦ㛎⺞ᢛකᏧ (4) ᴦ㛎ታᣉක≮ᯏ㑐 3 ᣉ⸳㧔☨࿖㧕 (5) ౏⴫ᢥ₂㧔ᒁ↪ᢥ₂㧕 ߥߒ (6) ᴦ㛎ታᣉᦼ㑆 2014 ᐕ 6 ᦬ᣣ㨪2014 ᐕ 12 ᦬ ᣣ㧔࠺࡯࠲ࡌ࡯ࠬ࿕ቯ㧦20 ᐕ᦬ᣣ㧕 (7) 㐿⊒ߩ⋧ ╙ I ⋧ (8) ⋡⊛ ਥ⋡⊛ ஜᐽⵍ㛎⠪ߦᧄ೷ߩᶧ૕ࡃࠗࠕ࡞⵾೷㧔LIV㧕2 ⵾೷㧔90 mg/mL LIV ෸߮ 5 mg/mL LIV㧕ࠍ 6 mg/kg ߩ↪㊂ߢන࿁㕒⣂ౝᛩਈߒߚߣ߈ߩ⮎‛േᘒࠍᲧセߔࠆޕ ೽ᰴ⋡⊛ ஜᐽⵍ㛎⠪ߦᧄ೷ 6 mg/kg ࠍන࿁㕒⣂ౝᛩਈߒߚߣ߈ߩ቟ోᕈ㧘ᔋኈᕈ㧘෸߮఺∉ේᕈࠍ⹏ଔ ߔࠆޕ 6 㧔1㧕 ࠙ࠬ࠹ࠠ࠿ࡑࡉ 2.7.6 ୘ޘߩ⹜㛎ߩ߹ߣ߼ NAP1002 ⹜㛎 (9) ᴦ㛎ᣇᴺ ᧄ⹜㛎ߪ㧘ᧄ೷ߩ LIV 2 ⵾೷㧔90 mg/mL LIV ෸߮ 5 mg/mL LIV㧕ࠍ㧘ஜᐽⵍ㛎⠪ߦ 6 mg/kg ߩ ↪㊂ߢන࿁㕒⣂ౝᛩਈߒߚߣ߈ߩ⮎‛േᘒࠍᲧセߔࠆ㧘ᄙᣉ⸳౒ห㧘࡜ࡦ࠳ࡓൻ㧘ਗⴕ⟲㑆㧘㕖 ⋤ᬌ㧘න৻↪㊂㧘౉㒮㧛ᄖ᧪ㅢ㒮⹜㛎ߢ޽ࠆޕ ᴦ㛎⮎ࠍᛩਈߔࠆ೨ߦ㧘ⵍ㛎⠪ࠍᧄ೷ߩ 2 ߟߩ LIV ⟲ߩ޿ߕࠇ߆ߦ㧘1㧦1 ߢ࡜ࡦ࠳ࡓߦഀࠅ ઃߌߚޕ 90 mg/mL LIV ⟲㧦Day 1 ߦ㧘ᧄ೷ 90 mg/mL LIV㧔ኻᾖ⮎㧕ࠍ 6 mg/kg ߩ↪㊂ߢන࿁㕒⣂ౝᛩਈ 㧔ࡐࡦࡊࠍ૶↪㧕ߒߚ㧔70 ଀㧕ޕ 5 mg/mL LIV ⟲㧦Day 1 ߦ㧘ᧄ೷ 5 mg/mL LIV㧔ⵍ㛎⮎㧕ࠍ 6 mg/kg ߩ↪㊂ߢන࿁㕒⣂ౝᛩਈ 㧔ࡐࡦࡊࠍ૶↪㧕ߒߚ㧔70 ଀㧕ޕ ߔߴߡߩⵍ㛎⠪ߩᴦ㛎ෳടᦼ㑆ߪ⚂ 20 ㅳ㑆ߢ޽ࠅ㧘ߘߩઁߦᴦ㛎⮎ᛩਈ೨ 4 ㅳ㑆એౝߦࠬࠢ ࡝࡯࠾ࡦࠣߩߚ߼᧪㒮ߒߚޕ ⴊᷡਛ࠙ࠬ࠹ࠠ࠿ࡑࡉỚᐲ᷹ቯ↪෸߮᛫࠙ࠬ࠹ࠠ࠿ࡑࡉ᛫૕ᬌ಴↪ߩⴊᶧᬌ૕ࠍᴦ㛎ታᣉ⸘↹ ᦠߦⷙቯߒߚᤨὐߦណขߔࠆߎߣߣߒ㧘቟ోᕈߪᴦ㛎ᦼ㑆ࠍㅢߒߡ⹏ଔߒߚޕ (10) ⵍ㛎⠪ᢙ㧔⸘↹ᤨ෸߮⸃ᨆᤨ㧕 ⸘↹ᤨ 140 ଀ ⸃ᨆᤨ 140 ଀߇⊓㍳ߐࠇ㧘ో଀ࠍ⮎‛േᘒ⸃ᨆኻ⽎㓸࿅෸߮቟ోᕈ⸃ᨆኻ⽎㓸࿅ߣߒߚޕ (11) ⸻ᢿ෸߮ਥߥㆬᛯၮḰ ᧄ⹜㛎ߩኻ⽎ߪ㧘18 ᱦ㧔෶ߪᴦ㛎߇ታᣉߐࠇࠆ▤ロ࿾ၞߦ߅ߌࠆหᗧขᓧน⢻ߥᴺቯᐕ㦂㧕એ ਄ 55 ᱦએਅߢ㧘૕㊀߇ 50 kg એ਄ 90 kg એਅ㧘૕ᩰᜰᢙ㧔BMI㧕߇ 18.5 kg/m2 એ਄ 29.0 kg/m2 એ ਅߩஜᐽߥ↵ᕈ෶ߪᅚᕈߣߒߚޕ߹ߚ㧘ⵍ㛎⠪ߪ㕖༛ᾍ⠪߆㧘ᴦ㛎ᦼ㑆ਛ 1 ᣣ޽ߚࠅ⚕Ꮞ࠲ࡃࠦ 10 ᧄ㧘෶ߪ⪲Ꮞ 2 ᧄࠍ⿥߃ࠆ༛ᾍࠍߒߥ޿ߎߣߦวᗧߔࠆᔅⷐ߇޽ࠅ㧘⥃ᐥ⊛ߦ㊀ⷐߥౝ⑼⊛∔ ᖚ෶ߪౝ⑼⊛㓚ኂࠍ᦭ߒߡ޿ߥ޿ߎߣߣߒߚޕᅚᕈⵍ㛎⠪ߪ㧘ᅧᇚ㧘᝼੃ᇚ㧘෶ߪᅧᆼࠍ⸘↹ߒ ߡ޿ࠆ⠪ߢߪߥ޿ߎߣߣߒ㧘ࠬࠢ࡝࡯࠾ࡦࠣᦼ㑆෸߮ᴦ㛎⮎ᛩਈᓟᦨૐ 5 ࠞ᦬㑆ࠍ฽߻ᴦ㛎ᦼ㑆 ਛ㧘↢ᱺ⵬ഥක≮ߩ⋡⊛ߢෆ⚦⢩㧔ෆሶ㧘ෆᲣ⚦⢩㧕ࠍឭଏߢ߈ߥ޿ߎߣߣߒߚޕ↵ᕈⵍ㛎⠪ߪ㧘 ᴦ㛎ᦼ㑆ਛ෸߮ᴦ㛎⮎ᛩਈᓟ 5 ࠞ᦬㑆ߪ♖ሶࠍឭଏߢ߈ߥ޿ߎߣߣߒߚޕ (12) ⵍ㛎⮎㧘↪㊂෸߮ᛩਈᣇᴺ㧘ࡠ࠶࠻⇟ภ ᧄ೷ 5 mg/mL LIV ߪ㧘30 mL ࠟ࡜ࠬࡃࠗࠕ࡞㨇26 mL ߦ࠙ࠬ࠹ࠠ࠿ࡑࡉ㧔ㆮવሶ⚵឵߃㧕 130 mg ࠍ฽᦭㨉ߦలႯߐࠇߚන࿁ᛩਈ↪㧘ή⩶ᶧ೷ߣߒߡଏ⛎ߐࠇ㧘ⵍ㛎⠪ߦ㕒⣂ౝᛩਈ㧔ࡐ ࡦࡊࠍ૶↪㧕ߐࠇߚޕᧄᶧ೷ߪ㧘1 mL ޽ߚࠅ࠙ࠬ࠹ࠠ࠿ࡑࡉ㧔ㆮવሶ⚵឵߃㧕5 mg ࠍ฽᦭ߔࠆ 㧔ࡠ࠶࠻⇟ภ㧦 㧕ޕ 7 㧔2㧕 ࠙ࠬ࠹ࠠ࠿ࡑࡉ 2.7.6 ୘ޘߩ⹜㛎ߩ߹ߣ߼ NAP1002 ⹜㛎 (13) ኻᾖ⮎㧘↪㊂෸߮ᛩਈᣇᴺ㧘ࡠ࠶࠻⇟ภ ᧄ೷ 90 mg/mL LIV ߪ㧘2 mL ࠟ࡜ࠬࡃࠗࠕ࡞ߦలႯߐࠇߚන࿁ᛩਈ↪㧘ή⩶ᶧ೷ߣߒߡଏ⛎ߐ ࠇ㧘ⵍ㛎⠪ߦ㕒⣂ౝᛩਈ㧔ࡐࡦࡊࠍ૶↪㧕ߐࠇߚޕᧄᶧ೷ߪ㧘1 mL ޽ߚࠅ࠙ࠬ࠹ࠠ࠿ࡑࡉ㧔ㆮ વሶ⚵឵߃㧕90 mg ࠍ฽᦭ߔࠆ㧔ࡠ࠶࠻⇟ภ㧦 㧕ޕ (14) ᛩਈᦼ㑆 ߔߴߡߩⵍ㛎⠪ߩᴦ㛎ෳടᦼ㑆ߪ⚂ 20 ㅳ㑆ߢ޽ࠅ㧘ߘߩઁߦᴦ㛎⮎ᛩਈ೨ 4 ㅳ㑆એౝߦࠬࠢ ࡝࡯࠾ࡦࠣߩߚ߼᧪㒮ߒߚޕDay 1 ߩᦺߦᴦ㛎⮎ࠍᛩਈߒ㧘Day 4 ߹ߢ౉㒮ߒߚᓟ㧘ⵍ㛎⠪ߪ Day 6 ෸߮ 8 ߦᄖ᧪ㅢ㒮ߔࠆߎߣߣߒߚޕ߹ߚ㧘ߘߩᓟ㧘቟ోᕈߩㅊ〔⺞ᩏߣ⮎‛േᘒ↪ߩណⴊ ߩߚ߼㧘ᴦ㛎⮎ᛩਈᓟ 16 ㅳ㑆ߪ㧘1 ㅳ㑆෶ߪ 2 ㅳ㑆ߦ 1 ࿁ߩᄖ᧪ㅢ㒮߇ᔅⷐߣߐࠇߚޕᄖ᧪ㅢ㒮 ߦࠃࠆᦨ⚳ߩㅊ〔⺞ᩏߪ Day 113 ߦⴕ߁ߎߣߣߒߚޕⵍ㛎⠪ߩ቟ోᕈߩᦨ⚳⺞ᩏߪ㧘ᴦ㛎⮎ᛩਈ ߩ 20 ㅳ㑆ᓟ㧔Day 141㧕ߦ㧘ᴦ㛎ታᣉක≮ᯏ㑐ߩᜂᒰ⠪ߦࠃࠆ㔚⹤⏕⹺ߦࠃࠅⴕߞߚޕ (15) ⹏ଔ㗄⋡ ⮎‛േᘒ ⴊᷡਛ࠙ࠬ࠹ࠠ࠿ࡑࡉỚᐲߩ᷹ቯ෸߮᛫࠙ࠬ࠹ࠠ࠿ࡑࡉ᛫૕ߩᬌ಴ߩߚ߼㧘ߔߴߡߩⵍ㛎⠪߆ ࠄ㕒⣂ⴊࠍណขߒߚޕ ࠙ࠬ࠹ࠠ࠿ࡑࡉߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲ߪ㧘ⴊᷡਛ࠙ࠬ࠹ࠠ࠿ࡑࡉỚᐲ-ᤨ㑆ߩ࠺࡯࠲ࠍ↪޿㧘 ࡁࡦࠦࡦࡄ࡯࠻ࡔࡦ࠻⸃ᨆߦࠃࠅ▚಴ߒߚޕᧄ೷ߩන࿁㕒⣂ౝᛩਈᓟߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲ߣߒ ߡ㧘ᦨ㜞ⴊᷡਛỚᐲ㧔Cmax㧕㧘⚳ᧃ⋧ࠍᄖᝌߒߚ 0 ᤨ㑆߆ࠄή㒢ᄢᤨ㑆߹ߢߩⴊᷡਛỚᐲ-ᤨ㑆ᦛ ✢ਅ㕙Ⓧ㧔AUCinf㧕㧘0 ᤨ㑆߆ࠄᦨ⚳ቯ㊂น⢻ᤨὐ߹ߢߩⴊᷡਛỚᐲ-ᤨ㑆ᦛ✢ਅ㕙Ⓧ㧔AUClast㧕㧘 ᶖᄬඨᷫᦼ㧔T1/2㧕㧘ోりࠢ࡝ࠕ࡜ࡦࠬ㧔CL㧕㧘⚳ᧃ⋧ߩಽᏓኈⓍ㧔Vz㧕╬ࠍ▚಴ߒߚޕ ఺∉ේᕈ ߔߴߡߩⵍ㛎⠪ߩⴊᷡᬌ૕ࠍ↪޿ߡ㧘᛫࠙ࠬ࠹ࠠ࠿ࡑࡉ᛫૕ࠍ⹏ଔߒߚޕ ቟ోᕈ ቟ోᕈ෸߮ᔋኈᕈߦߟ޿ߡߪ㧘り૕ᚲ⷗㧘ࡃࠗ࠲࡞ࠨࠗࡦ㧘ࠗࡦࡈࡘ࡯࡚ࠫࡦ࡝ࠕ࡚ࠢࠪࡦ㧘 ᔃ㔚࿑㧔ࠬࠢ࡝࡯࠾ࡦࠣᤨ㧘ࡌ࡯ࠬ࡜ࠗࡦᤨ㧘෸߮ᦨ⚳᧪㒮ᣣߩߺ㧕㧘⥃ᐥᬌᩏ୯㧔ⴊᶧቇ⊛ᬌ ᩏ㧘ⴊᷡ↢ൻቇᬌᩏ㧘෸߮ዩᬌᩏ㧕㧘᦭ኂ੐⽎෸߮㊀◊ߥ᦭ኂ੐⽎㧔SAE㧕ࠍ⹏ଔߒߚޕ߹ߚ㧘 ࠬࠢ࡝࡯࠾ࡦࠣᤨߦ㧘ࡅ࠻఺∉ਇో࠙ࠗ࡞ࠬ㧔HIV㧕㧘B ဳ⢄Ἳ࠙ࠗ࡞ࠬ㧔HBV㧕෸߮ C ဳ⢄Ἳ ࠙ࠗ࡞ࠬ㧔HCV㧕ᬌᩏ㧘ਗ߮ߦ QuantiFERON-Tuberculosis㧔TB㧕Gold ߦࠃࠆ⚿ᩭᬌᩏࠍታᣉߒ ߚޕ 8 㧔3㧕 ࠙ࠬ࠹ࠠ࠿ࡑࡉ 2.7.6 ୘ޘߩ⹜㛎ߩ߹ߣ߼ NAP1002 ⹜㛎 (16) ⛔⸘ᚻᴺ ⵍ㛎⠪ᢙߩ⸳ቯ ᧄ⹜㛎ߢߪᱜᑼߥ઒⺑ᬌቯߪⴕࠊߥ߆ߞߚߚ߼㧘ᱜᑼߥⵍ㛎⠪ᢙ෸߮ᬌ಴ജߩ⸳ቯߪⴕࠊߥ߆ ߞߚޕᧄ⹜㛎ߩⵍ㛎⠪ᢙߦߟ޿ߡ㧘ஜᐽⵍ㛎⠪ߦන࿁ᛩਈᓟߩ↢‛ቇ⊛ห╬ᕈߩ⸃ᨆࠍⴕߞߚ㓙 ߩᬌ಴ജࠍ⹏ଔߒߚޕ ⮎‛േᘒ ዋߥߊߣ߽ 1 ߟߩ⮎‛േᘒࡄ࡜ࡔ࡯࠲ߩᱜ⏕ߥ▚಴߇น⢻ߥⴊᷡਛ࠙ࠬ࠹ࠠ࠿ࡑࡉỚᐲ-ᤨ㑆 ࡊࡠࡈࠔࠗ࡞ࠍ᦭ߔࠆⵍ㛎⠪ࠍ⮎‛േᘒ⸃ᨆኻ⽎㓸࿅ߣቯ⟵ߒߚޕⴊᷡਛ࠙ࠬ࠹ࠠ࠿ࡑࡉỚᐲߪ㧘
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