有 / presence
|
2018/01/20 |
https://www.jstage.jst.go.jp/article/endocrj/65/3/65_EJ17-0276/_article |
被験者全体の性別の内訳は,男性11/16名(68.8%),女性5/16名(31.3%)であった.同意取得時の年齢の平均値±標準偏差(最小値~最大値)は54.8±24.3歳(12~86歳)であり,65歳未満は9/16名(56.3%),65歳以上は7/16名(43.8%)であった.
褐色細胞腫の診断名別の内訳は,副腎性の褐色細胞腫9/16名(56.3%),副腎外性のパラガングリオーマ7/16名(43.8%)であった.褐色細胞腫の罹病期間(疾患診断日から登録日までの期間)の平均値±標準偏差(最小値~最大値)は,被験者全体で2894.1±4304.9日(12~15719日)であり,慢性例では3550.2±4547.3日(37~15719日),手術例では51.3±34.1日(12~72日)であった.観察期に褐色細胞腫の転移が確認されていた被験者は8/16名(50.0%)であり,8名すべてが慢性例であった.これら8名のほとんどが複数の転移部位を有しており,最も多く報告された転移部位はリンパ節(7名)で,次いで骨(6名),肝(3名),肺及び腹膜(各2名)並びに腎,副腎,胸膜及びその他(各1名)であった.
すべての被験者が何らかの合併症を有していた.
褐色細胞腫の手術歴のある被験者は7/16名(43.8%),放射線外照射療法歴のある被験者は1/16名(6.3%),シクロホスファミド,ビンクリスチン及びダカルバジン併用による化学療法(CVD療法)歴のある被験者は4/16名(25.0%)であり,これらはいずれも慢性例であった.放射線内照射療法歴のある被験者,又はCVD療法以外のがん化学療法歴のある被験者はいなかった.
被験者全体のDay 1の治験薬投与前のeGFRの平均値±標準偏差(最小値~最大値)は,78.599±40.163 mL/min(30.43~184.82 mL/min)であった.腎機能障害の程度別では,腎機能正常(eGFR≧90 mL/min)は5/16名(31.3%),軽度腎機能障害(eGFR≧60 mL/min,<90 mL/min)は6/16名(37.5%),中等度腎機能障害(eGFR≧30 mL/min,<60 mL/min)は5/16名(31.3%)であった.
ベースラインの尿中カテコールアミン及び代謝物の測定のために,観察期に24時間蓄尿を2 回採取した際の平均値±標準偏差(最小値~最大値)は,メタネフリン4.211±12.840 mg/day( 0.05~52.00 mg/day) ,ノルメタネフリン16.367± 29.928 mg/day( 0.44~115.00 mg/day),メタネフリンとノルメタネフリンの合計20.578±31.327 mg/day(1.52~115.39 mg/day),バニリルマンデル酸48.03±58.93 mg/day(5.3~202.5 mg/day),アドレナリン200.36 ± 547.18 μ g/day( 4.1 ~ 2230.0 μ g/day) , ノルアドレナリン3650.75 ±5923.57μg/day(119.0~23600.0μg/day),ドーパミン1391.88±1339.59μg/day(540.0~5500.0μg/day)であった.
ベースライン(Day 1の治験薬投与前)の収縮期及び拡張期血圧の平均値±標準偏差(最小値~最大値)はそれぞれ126.4±16.6 mmHg(96~157 mmHg)及び71.1±16.1 mmHg(39~96 mmHg)であった.なお,16名すべての被験者が,観察期のDay -14より前から少なくとも1剤の降圧薬を継続的に使用していた.また,ベースライン(Day 1の治験薬投与前)の脈拍数の平均値±標準偏差(最小値~最大値)は70.3±16.1回/分(52~110回/分),ベースライン(Day -14~Day 1の治験薬投与前)の左室駆出率の平均値±標準偏差(最小値~最大値)は65.89±7.45%(47.8%~75.0%)であった.ベースラインの収縮期及び拡張期血圧,脈拍数並びに左室駆出率には,手術例(治療期に褐色細胞腫に対する手術を実施した被験者)と慢性例(それ以外の被験者)で大きな違いはなかった.
ベースライン(Day -7~Day 1の治験薬投与前)の血糖値の平均値±標準偏差(最小値~最大値)は,被験者全体で112.9±18.5 mg/dL(81~152 mg/dL)であった.なお,16名のうち5名は,観察期のDay -14より前から糖尿病治療薬を継続的に使用していた.
本治験では「交感神経受容体遮断薬による治療が行われている患者」を選択しており,16名すべての被験者にα1遮断薬が併用された.α1遮断薬以外に併用された降圧薬は,併用した被験者の多い順に,β遮断薬及びカルシウム拮抗薬が各5/16名(31.3%),αβ遮断薬が3/16名(18.8%),アンジオテンシンII受容体遮断薬及び利尿薬が各1/16名(6.3%)であった.
治験薬投与前(Day 1の起床前までに行った,観察期の2回の評価期間のいずれか)に認められた,カテコールアミン過剰に伴う臨床症状では,疲労が最も多く,12/16名(75.0%)に認められ,次いで多く認められた順に,便秘が11/16名(66.8%),動悸及び立ちくらみが各9/16名(56.3%),頭痛,発汗・多汗症,及び浮動性めまい・動揺感が各7/16名(43.8%),下痢及び不安・神経過敏が各6/16名(37.5%),腹痛,紅潮,呼吸困難及び視力障害が各4/16名(25.0%),発熱・熱感が3/16名(18.8%),その他疼痛及び振戦が各2/16名(12.5%),嘔気・悪心,嘔吐,両手足末梢の冷感,両足先の冷感及び両前腕から手の皮フ紫色が各1/16名(6.3%)であった. |
Patients (pts) consisted of 11 men (68.8%) and 5 women (31.3%) of the 16 pts. The mean plus/minus standard deviation (SD) (minimum to maximum) of age at the time of obtaining informed consent was 54.8 plus/minus 24.3 years (12 to 86 years). Nine out of the 16 pts (56.3%) were under 65 years and 7 of the 16 pts (43.8%) were 65 years or older.
The types of pheochromocytoma as diagnosis were adrenal pheochromocytoma in 9/16 pts (56.3%) and extra-adrenal paraganglioma in 7/16 pts (43.8%). The means plus/minus SD (minimum to maximum) of duration of pheochromocytoma/paraganglioma (PPGL) (period from date of diagnosis to date of enrollment) were 2894.1 plus/minus 4304.9 days (12 to 15719 days) for all pts, 3550.2 plus/minus 4547.3 days (37 to 15719 days) for the pts under chronic treatment, and 51.3 plus/minus 34.1 days (12 to 72 days) for the pts under preoperative treatment. Eight out of the 16 pts (50.0%) had been confirmed to have pheochromocytoma with metastasis during an observation period, and all of them were under chronic treatment. Most of these 8 pts had multiple metastatic sites. The most commonly reported metastatic site was lymph node (7 pts) followed by bone (6 pts), liver (3 pts), lung and peritoneum (2 pts each), and kidney, adrenal gland, pleura and other (1 patient each).
ALL pts had some complication.
Seven out of the 16 pts (43.8%), 1/16 pts (6.3%), and 4/16 pts (25.0%) had a history of surgery, external beam radiation therapy, and chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD therapy) for PPGL, respectively. All of them were under chronic treatment. There was no patient with a history of internal radiation therapy or cancer chemotherapy other than CVD therapy.
The mean plus/minus SD (minimum to maximum) of estimated glomerular filtration rate (eGFR) prior to drug administration on Day 1 was 78.599 plus/minus 40.163 mL/min (30.43 to 184.82 mL/min) for all pts. By severity of renal dysfunction, 5/16 pts (31.3%) had normal renal function (eGFR >= 90 mL/min), 6/16 pts (37.5%) mild renal dysfunction (eGFR >= 60 mL/min, < 90 mL/min), and 5/16 pts (31.3%) moderate renal dysfunction (eGFR >= 30 mL/min, < 60 mL/min).
The means plus/minus SD (minimum to maximum) of two 24-h urine samples during the observation period to determine baseline urinary catecholamines (CAs) and their metabolites were as follows: metanephrine (MN), 4.211 plus/minus 12.840 mg/day (0.05 to 52.00 mg/day); normetanephrine (NMN), 16.367 plus/minus 29.928 mg/day (0.44 to 115.00 mg/day); MN + NMN, 20.578 plus/minus 31.327 mg/day (1.52 to 115.39 mg/day); vanillylmandelic acid, 48.03 plus/minus 58.93 mg/day (5.3 to 202.5 mg/day); adrenaline, 200.36 plus/minus 547.18 micro g/day (4.1 to 2230.0 micro g/day); noradrenaline, 3650.75 plus/minus 5923.57 micro g/day (119.0 to 23600.0 micro g/day); dopamine, 1391.88 plus/minus 1339.59 micro g/day (540.0 to 5500.0 micro g/day).
The means plus/minus SD (minimum to maximum) of systolic and diastolic blood pressure at baseline (Day 1, prior to drug administration) were 126.4 plus/minus 16.6 mmHg (96 to 157 mmHg) and 71.1 plus/minus 16.1 mmHg (39 to 96 mmHg), respectively. All of the 16 pts had continually used at least 1 type of antihypertensive agent since before Day -14 in the observation period. The mean plus/minus SD (minimum to maximum) of heart rate at baseline (Day 1, prior to drug administration) was 70.3 plus/minus 16.1/bpm (52 to 110/bpm) and the mean plus/minus SD (minimum to maximum) of left ventricular ejection fraction (LVEF) at baseline (Day -14 to prior to drug administration at Day 1) was 65.89 plus/minus 7.45% (47.8% to 75.0%). There was no significant difference in systolic and diastolic blood pressure, heart rate, or LVEF at baseline between the pts under preoperative treatment (pts receiving the surgery for PPGL during the treatment period) and the pts under chronic treatment (other pts).
The mean plus/minus SD (minimum to maximum) of blood glucose at baseline (Day -7 to prior to drug administration at Day 1) was 112.9 plus/minus 18.5 mg/dL (81 to 152 mg/dL) for all pts. Five out of the 16 pts had continually used diabetes drug since before Day -14 in the observation period.
The study included "the pts on treatment with sympathetic receptor blockers" and concomitantly gave alpha1-blockers to all of the 16 pts. Other concomitant antihypertensive agents except alpha1-blockers were beta-blockers and calcium antagonists in 5/16 pts each (31.3%), alpha,beta-blockers in 3/16 pts (18.8%), and angiotensin II receptor blockers and diuretic drugs in 1/16 pts each (6.3%), in descending order of patient receiving these drugs.
The most common excess CA-induced symptoms reported prior to drug administration (either of 2 assessment sessions in the observation period before wake-up on Day 1) was fatigue in 12/16 pts (75.0%) followed by the following: constipation in 11/16 pts (66.8%); palpitations and dizziness on standing up in 9/16 pts each (56.3%); headache, sweaty/hyperhidrosis, and dizziness/shaky feelings in 7/16 pts each (43.8%); diarrhoea and anxiety/nervousness in 6/16 pts each (37.5%); abdominal pain, flushing, dyspnoea and visual impairment in 4/16 pts each (25.0%); pyrexia/feeling hot in 3/16 pts (18.8%); other pain and tremor in 2/16 pts each (12.5%); sickness/nausea, vomiting, peripheral coldness of extremities, cold feet and purpuric skin in forearms to hands in 1/16 pts each (6.3%). |
16 |
文書同意を取得した日本人褐色細胞腫患者(同意取得集団)は21名であった.このうち,観察期に適格性が確認された被験者(適格例)は16名,不適格例となり観察期から治療期に移行しなかった被験者(観察期脱落例)は5名であった.これら5名の観察期脱落理由は,被験者若しくは代諾者からの治験中止の申出(2名)又は登録基準を満さなくなったため(3名)であった.
治療期に移行した16名すべてに治験薬が1回以上投与された.16名のうち,治療期に褐色細胞腫に対する手術を実施した被験者(手術例)は3名,それ以外の被験者(慢性例)は13名であった.
慢性例13名のうち,9名は治療期を完了し(治療期完了例),4名は治療期を中止した(治療期中止例).これら4名の治療期中止理由は,被験者若しくは代諾者からの治験中止の申出(3名)又は治験責任医師若しくは治験分担医師の判断(死亡のため:1名)であった.
治療期を完了した慢性例9名は継続投与期に移行した.また,手術例3名はいずれも,手術後に実施した尿中メタネフリン2分画の測定の結果が「基準値上限の3倍以上」には該当せず,治験薬の継続投与が不要であったため,継続投与期に移行せずに治験を終了した(手術完了例).
継続投与期に移行した慢性例9名のうち,12カ月データカットオフ時点までに継続投与期を中止した被験者は2名であり(継続投与期中止例),その継続投与期中止理由は,被験者若しくは代諾者からの治験中止の申出(1名)又は治験責任医師若しくは治験分担医師の判断(死亡したため:1名)であった.残りの慢性例7名は,12カ月データカットオフ時点で継続投与期を継続中であった(継続投与期12カ月完了例). |
Twenty-one Japanese pts with PPGL gave their informed consents (the population with informed consent). Of these pts, 16 pts were confirmed to be eligible in the observation period (eligible pts), while 5 pts became ineligible in the observation period and did not proceed to a treatment period (observation-dropout pts). The reasons for observation-dropout for these 5 pts were patient's or patient's legally acceptable representative's request for discontinuation from the study (2 pts) and being not meeting the criteria (3 pts).
All of the 16 pts who had proceeded to the treatment period received at least 1 dose of the investigational drug. The16 pts consisted of 3 pts receiving the surgery for PPGL in the treatment period (pts under preoperative treatment) and other 13 pts (pts under chronic treatment).
Nine out of the 13 pts under chronic treatment completed the treatment period (treatment-completion pts), and the other 4 pts discontinued the treatment period (treatment-discontinuation pts). The reasons for discontinuation of the treatment period for these 4 pts were patient's or patient's legally acceptable representative's request for discontinuation from the study (3 pts) and investigator/subinvestigator's decision (due to death, 1 patient).
The 9 pts under chronic treatment who had completed the treatment period proceeded to a continuation treatment period. All of the 3 pts under preoperative treatment terminated the study without a transition to the continuation treatment period as their urinary metanephrine, 2-fractionation levels measured after the surgery were not ">= 3 times the upper limit of the corresponding normal value", indicating these pts no longer required to continue to take the investigational drug (surgery-completion pts).
Of the 9 pts under chronic treatment who had proceeded to the continuation treatment period, 2 pts discontinued the continuation treatment period by the Month 12 data cutoff point (continuation-discontinuation pts). The reason for discontinuation of the continuation treatment were patient's or patient's legally acceptable representative's request for discontinuation from the study (1 patient) and investigator/subinvestigator's decision (due to death, 1 patient). The other 7 pts under chronic treatment were in the continuation treatment period at the Month 12 data cutoff point (continuation-12 months completion pts). |
SAF16名(慢性例13名,手術例3名)すべての被験者に,有害事象及び副作用が認められた.
12カ月データカットオフ時点までに死亡の原因となった有害事象は,全体で3/16名(18.8%)に認められ,いずれも慢性例であった[3/13名(23.1%)].このうち1/16名(6.3%)では,死亡の原因となった有害事象は副作用と判断された.
重篤な有害事象(死亡の原因となった有害事象を含む)は,全体で6/16名(37.5%)に認められ,いずれも慢性例であった[6/13名(46.2%)].このうち3/16名(18.8%)は,重篤な副作用(死亡の原因となった副作用を含む)と判断された.
投与中止の原因となった有害事象は,全体で1/16名(6.3%)に認められ,当該被験者は慢性例であった[1/13名(7.7%)].当該被験者の投与中止の原因となった有害事象は副作用と判断された. |
All of the 16 pts in the safety set (SAF) (13 pts under chronic treatment, 3 pts under preoperative treatment) experienced adverse event (AE) and adverse drug reaction (ADR).
Adverse events as the cause of death had been reported in 3/16 pts (18.8%) overall, who were under chronic treatment [3/13 pts (23.1%)], by the Month 12 data cutoff point. Of them, 1/16 pts (6.3%) was considered to have an AE as the cause of death as an ADR.
Serious AEs (including AEs as the cause of death) were reported in 6/16 pts (37.5%) overall, who were under chronic treatment [6/13 pts (46.2%)]. Of them, 3/16 pts (18.8%) were considered to have serious ADRs (including ADRs as the cause of death).
An adverse event leading to treatment discontinuation was reported in 1/16 pts (6.3%) overall, who was under chronic treatment [1/13 pts (7.7%)]. The AE leading to treatment discontinuation was considered as an ADR. |
・最終評価時における尿中メタネフリン2分画(メタネフリン又はノルメタネフリンのうち主要評価にて採用された項目)がベースラインから50%以上減少した被験者割合
最終評価時における尿中メタネフリン2分画(メタネフリン又はノルメタネフリンのうち主要評価にて採用された項目)がベースラインから50%以上減少した被験者割合は,被験者全体で31.3%(5/16名),慢性例で23.1%(3/13名),手術例で66.7%(2/3名)であった. |
-- Proportion of pts with 50% or more reduction from baseline in urinary metanephrine, 2-fractionation (either MN or NMN used as the primary measure for efficacy assessment) at the final evaluation time point
The proportion of pts with 50% or more reduction from baseline in the urinary metanephrine, 2-fractionation (either MN or NMN used as the primary measure for efficacy assessment) at the final evaluation time point was 31.3% (5/16 pts) overall, 23.1% (3/13 pts) in the pts under chronic treatment, and 66.7% (2/3 pts) in the pts under preoperative treatment.
[Some results of secondary outcome measures are presented here due to character restrictions]
-- Proportion of pts with 50% or more reduction in urinary metanephrine, 2-fractionation from baseline during the treatment period
- Either MN or NMN used as the primary measure for efficacy assessment
The proportions of pts with 50% or more reduction from baseline in the primary measure for efficacy assessment were 20.0% (3/15 pts overall; 3/13 pts under chronic treatment, 0/2 pts under preoperative treatment) on Day 6 to 8, 35.7% (5/14 pts overall; 3/11 pts under chronic treatment, 2/3 pts under preoperative treatment) on Day 28, 45.5% (5/11 pts overall; 4/10 pts under chronic treatment, 1/1 pts under preoperative treatment) on Day 56, and 40.0% (4/10 pts overall; 3/9 pts under chronic treatment, 1/1 pts under preoperative treatment) on Day 84.
-- Urinary metanephrine, 2-fractionation during treatment period
- Either MN or NMN used as primary measure for efficacy assessment
In the overall population (the number of subjects), the mean plus/minus SD of changing rate from baseline in either MN or NMN used as the primary measure for efficacy assessment was -45.37 plus/minus 18.26% at the final evaluation time point (12 pts), with -27.06 plus/minus 20.43%, -34.65 plus/minus 23.04%, -41.80 plus/minus 16.26%, -42.48 plus/minus 18.61%, -30.41 plus/minus 30.34%, -7.38 plus/minus 57.09%, and -8.42 plus/minus 51.70% on Day 6 to 8 (15 pts), Day 28 (14 pts), Day 56 (11 pts), Day 84 (10 pts), Day 168 (7 pts), Day 252 (7 pts), and Day 336 (7 pts), respectively.
- Metanephrine
The means plus/minus SD of measured values of MN in the overall population (the number of subjects) were 4.211 plus/minus 12.840 mg/day and 0.457 plus/minus 0.641 mg/day at baseline (16 pts) and the final evaluation time point (12 pts), respectively, with the mean plus/minus SD of changing rate at the final evaluation of -46.76 plus/minus 24.34%.
- Normetanephrine
The means plus/minus SD of measured values of NMN in the overall population (the number of subjects) were 16.367 plus/minus 29.928 mg/day and 9.378 plus/minus 22.316 mg/day at baseline (16 pts) and the final evaluation time point (12 pts), respectively, with the mean plus/minus SD of changing rate at the final evaluation of -42.33 plus/minus 17.52%. |
・治療期に尿中メタネフリン2分画がベースラインから50%以上減少した被験者割合
-メタネフリン又はノルメタネフリンのうち主要評価にて採用された項目
主要評価にて採用された項目がベースラインから50%以上減少した被験者割合は,Day 6~8 は20.0%(全体3/15 名;慢性例3/13名,手術例0/2名),Day 28では35.7%(全体5/14名;慢性例3/11名,手術例2/3名),Day 56では45.5%(全体5/11名;慢性例4/10名,手術例1/1名),Day 84では40.0%(全体4/10名;慢性例3/9名,手術例1/1名)であった.
・治験期間中における尿中メタネフリン2分画
‐メタネフリン又はノルメタネフリンのうち主要評価にて採用された項目
被験者全体(対象者数)では,メタネフリン又はノルメタネフリンのうち主要評価にて採用された項目のベースラインからの変化率の平均値±標準偏差は,最終評価時(12 名)に-45.37±18.26%であり,Day 6~8(15 名),Day 28(14 名),Day 56(11 名),Day 84(10 名),Day 168(7 名),Day 252(7 名)及びDay 336(7 名)にそれぞれ-27.06±20.43%,-34.65±23.04%,-41.80±16.26%,-42.48±18.61%,-30.41±30.34%,-7.38±57.09%及び-8.42±51.70%であった.
-メタネフリン
被験者全体(対象者数)でのメタネフリンの実測値の平均値±標準偏差は,ベースライン(16名) 及び最終評価時(12名) にそれぞれ4.211±12.840 mg/day及び0.457±0.641mg/dayであり,最終評価時での変化率の平均±標準偏差は-46.76±24.34%であった.
-ノルメタネフリン
被験者全体(対象者数)でのノルメタネフリンの実測値の平均値±標準偏差は,ベースライン(16名)及び最終評価時(12名)にそれぞれ16.367±29.928 mg/day及び9.378±22.316 mg/dayであり,最終評価時での変化率の平均値±標準偏差は-42.33±17.52%であった.
・血圧,脈拍数,血糖値及び左室駆出率
-血圧(収縮期血圧)
被験者全体(対象者数)での収縮期血圧の実測値の平均値±標準偏差(最小値~最大値)は,ベースライン(16 名)及び最終評価時(13名)にそれぞれ126.4±16.6 mmHg(96~157 mmHg)及び120.6±14.5 mmHg(101~143 mmHg)であり,最終評価時での変化量の平均値±標準偏差(最小値~最大値)は-3.8±22.1 mmHg(-56~16 mmHg)であった.
収縮期血圧の推移に一定の変化は認められなかった.
-血圧(拡張期血圧)
被験者全体(対象者数)での拡張期血圧の実測値の平均値±標準偏差(最小値~最大値)は,ベースライン(16名)及び最終評価時(13名)にそれぞれ71.1±16.1 mmHg(39~96 mmHg)及び69.8±13.8 mmHg(45~90 mmHg)であり,最終評価時での変化量の平均値±標準偏差(最小値~最大値)は0.3±13.7 mmHg(-31~30 mmHg)であった.
拡張期血圧の推移に一定の変化は認められなかった.
-脈拍数
被験者全体(対象者数)での脈拍数の実測値の平均値±標準偏差(最小値~最大値)は,ベースライン(16名)及び最終評価時(13名)にそれぞれ70.3± 16.1回/分(52~110回/分)及び67.4±21.3回/分(34~120回/分)であり,最終評価時での変化量の平均値±標準偏差(最小値~最大値)は0.4±15.5 回/分(-25~38回/分)であった.
脈拍数の推移に一定の変化は認められなかった.
-血糖値
被験者全体(対象者数)での血糖値の実測値の平均値±標準偏差(最小値~最大値)は,ベースライン(16名)及び最終評価時(13名)にそれぞれ112.9±18.5 mg/dL( 81~152 mg/dL)及び111.8±28.7 mg/dL(71~194 mg/dL)であり,最終評価時での変化量の平均値±標準偏差(最小値~最大値)は0.4±20.9 mg/dL(-25~42 mg/dL)であった.
血糖値の推移に一定の変化は認められなかった.
-左室駆出率
被験者全体(対象者数)での左室駆出率の実測値の平均値±標準偏差(最小値~最大値)は,ベースライン(16名)及び最終評価時(11名)にそれぞれ65.89±7.45%(47.8%~75.0%)及び63.97±7.13%(50.0%~75.7%)であり,最終評価時での変化量の平均値±標準偏差(最小値~最大値)は0.04±4.41%(-7.0%~6.0%)であった.
左室駆出率の推移に一定の変化は認められなかった.
・カテコールアミン過剰に伴う症状,全般改善度
カテコールアミン過剰に伴う症状の全般改善度は,各評価時点で治験薬投与前と比較し,7段階(著明悪化,中等度悪化,軽度悪化,不変,軽度改善,中等度改善,著明改善)で評価した.
最終評価時における全般改善度は,医師評価では「著明改善」及び「中等度改善」が各1/13名(7.7%;いずれも慢性例1名),「軽度改善」が5/13名(38.5%;慢性例5名)並びに「不変」が6/13名(46.2%;慢性例3名,手術例3名)であり,患者評価では「軽度改善」が8/13名(61.5%;慢性例8名)及び「不変」が5/13名(38.5%;慢性例2名,手術例3名)であった.医師評価が「著明改善」及び「中等度改善」であった各1名はいずれも,主要評価項目を達成した慢性例であった.主要評価項目を達成した被験者5名の最終評価時における全般改善度は,慢性例3名では医師評価及び患者評価ともに「軽度改善」以上であり,手術例2名では医師評価及び患者評価ともに「不変」であった.
・交感神経受容体遮断薬及び降圧薬の投与量
交感神経受容体遮断薬及び降圧薬については「観察期における検査実施前7 日[あるいは該当する薬剤の消失半減期(活性代謝物が存在する場合はその消失半減期)の5倍以上の期間のうち長い期間]から継続投与期を含めた最終検査が終了するまでは,原則,用法・用量を変更しない」と規定していた.
血圧の低下に関連する理由により交感神経受容体遮断薬又は降圧薬の用法・用量を変更した被験者は,治療期5名及び継続投与期1名であった.
・褐色細胞腫に対する手術関連処置
手術例は3名であり,手術時間の平均値±標準偏差は6.76±1.55時間であった.
-手術中の高血圧クリーゼの発現頻度
手術中に高血圧クリーゼを発現した被験者は2/3名であり,残り1/3名では発現しなかった.
-手術中の高血圧クリーゼに対する降圧処置の頻度
高血圧クリーゼに対する降圧処置は,発現した被験者2名のいずれに対しても行われた.
-昇圧処置が行われた被験者は2/3名であり,残り1/3名に対して昇圧処置は行われなかった.
・薬物動態の結果
腎機能障害の程度が高いほど血中曝露量が上昇することが示唆されたが,腎機能正常被験者に対する軽度腎機能障害被験者における上昇は,個体間のばらつきの範囲内であり,大きな差異はないと考えられた.Tmaxは腎機能の影響を受けないと考えられた.腎機能障害の程度が高いほど消失が遅延することが示唆されたが,腎機能正常被験者に対する軽度腎機能障害被験者における消失の遅延は,個体間のばらつきの範囲内であり,大きな差異はないと考えられた.腎機能正常被験者に比べ,軽度腎機能障害被験者で血中曝露量の上昇が認められたが,個体間のばらつきの範囲内であり,大きな差異はないと考えられた.
ONO-5371-01試験の結果も含めて検討したところ、日本人の健康成人男性又は腎機能障害男性の単回経口投与時の血漿中ONO-5371のCmax及びAUC9hに比べ,褐色細胞腫患者のCmaxは低かったが,AUC9hに大きな差異は認められなかった.単回経口投与時の比較と同様に反復投与時でも,日本人の健康成人男性又は腎機能障害男性の投与7日目(ONO-5371 250 mg朝投与後)の血漿中ONO-5371のCmaxの予測値及びAUC4hの予測値に比べ,褐色細胞腫患者のCmaxは低かったが,AUC4h に大きな差異は認められなかった.
体重とONO-5371の薬物動態及び年齢とONO-5371の薬物動態に明らかな関係はないことが示唆された. |
-- Blood pressure, heart rate, blood glucose, and left ventricular ejection fraction
- Blood pressure (systolic blood pressure)
The means plus/minus SD (minimum to maximum) of measured values of systolic blood pressure in the overall population (the number of subjects) were 126.4 plus/minus 16.6 mmHg (96 to 157 mmHg) and 120.6 plus/minus 14.5 mmHg (101 to 143 mmHg) at baseline (16 pts) and the final evaluation time point (13 pts), respectively, with the mean plus/minus SD of change (minimum to maximum) at the final evaluation of -3.8 plus/minus 22.1 mmHg (-56 to 16 mmHg).
There was no certain change in the course of systolic blood pressure levels.
- Blood pressure (diastolic blood pressure)
The means plus/minus SD (minimum to maximum) of measured values of diastolic blood pressure in the overall population (the number of subjects) were 71.1 plus/minus 16.1 mmHg (39 to 96 mmHg) and 69.8 plus/minus 13.8 mmHg (45 to 90 mmHg) at baseline (16 pts) and the final evaluation time point (13 pts), respectively, with the mean plus/minus SD of change (minimum to maximum) at the final evaluation of 0.3 plus/minus 13.7 mmHg (-31 to 30 mmHg).
There was no certain change in the course of diastolic blood pressure levels.
- Heart rate
The means plus/minus SD (minimum to maximum) of measured values of heart rate in the overall population (the number of responders of the primary endpoint) were 70.3 plus/minus 16.1/bpm (52 to 110/bpm) and 67.4 plus/minus 21.3/bpm (34 to 120/bpm) at baseline (16 pts) and the final evaluation time point (13 pts), respectively, with the mean plus/minus SD of change (minimum to maximum) at the final evaluation of 0.4 plus/minus 15.5/bpm (-25 to 38/bpm).
There was no certain change in the course of heart rate levels.
- Blood glucose
The means plus/minus SD (minimum to maximum) of measured values of blood glucose in the overall population (the number of responders of the primary endpoint) were 112.9 plus/minus 18.5 mg/dL (81 to 152 mg/dL) and 111.8 plus/minus 28.7 mg/dL (71 to 194 mg/dL) at baseline (16 pts) and the final evaluation time point (13 pts), respectively, with the mean plus/minus SD of change (minimum to maximum) at the final evaluation of 0.4 plus/minus 20.9 mg/dL (-25 to 42 mg/dL).
There was no certain change in the course of blood glucose levels.
- Left ventricular ejection fraction (LVEF)
The means plus/minus SD (minimum to maximum) of measured values of LVEF in the overall population (the number of responders of the primary endpoint) were 65.89 plus/minus 7.45% (47.8% to 75.0%) and 63.97 plus/minus 7.13% (50.0% to 75.7%) at baseline (16 pts) and the final evaluation time point (11 pts), respectively, with the mean plus/minus SD of change (minimum to maximum) at the final evaluation of 0.04 plus/minus 4.41% (-7.0% to 6.0%).
There was no certain change in the course of LVEF levels.
-- Excess catecholamine-induced symptoms, Clinical Global Impression of Change
Clinical Global Impression of Change (CGI-C) of excess CA-induced symptoms by a comparison of the impression at each evaluation point with that prior to the first administration of investigational drug was indicated by 7-grade relative estimation (markedly worsened, moderately worsened, mildly worsened, no change, mildly improved, moderately improved, and greatly improved).
The CGI-C at the final evaluation time point included the following grades: the investigator judged change as "greatly improved" and "moderately improved" for 1/13 pts each (7.7%; 1 patient under chronic treatment each), "mildly improved" for 5/13 pts (38.5%; 5 pts under chronic treatment), and "no change" for 6/13 pts (46.2%; 3 pts under chronic treatment, 3 pts under preoperative treatment); the self-assessment by pts reported "mildly improved" for 8/13 pts (61.5%; 8 pts under chronic treatment) and "no change" for 5/13 pts (38.5%; 2 pts under chronic treatment, 3 pts under preoperative treatment). Each patient with "greatly improved" or "moderately improved" judged by the investigator was one under chronic treatment achieving the primary endpoint. For the 5 pts achieving the primary endpoint, at the final evaluation time point, the CGI-Cs for the 3 pts under chronic treatment and the 2 under preoperative treatment were reported as "mildly improved" or better and "no change", respectively, by both the investigator and the self-assessment by pts.
-- Dosage of sympathetic receptor blockers and antihypertensive agents
Sympathetic receptor blockers and antihypertensive agents had been based on the provision that dosage and administration should not be in principle changed from 7 days prior to the tests during the observation period [or the period more than five times an elimination half-life (t1/2) of a relevant agent (t1/2 of its active metabolites, if applicable), whichever was longer] until the completion of last assessment up to the continuation treatment period.
The dosages and administrations of sympathetic receptor blockers or antihypertensive agents were changed for reasons associated with a decreased blood pressure in 5 pts during the treatment period and 1 patient during the continuation treatment period.
-- Surgery-related treatment for PPGL
Three pts underwent the surgery and the mean plus/minus SD of surgical time was 6.76 plus/minus 1.55 hours.
- Frequency of hypertensive crisis during the surgery
Hypertensive crisis occurred in 2/3 pts and not in 1/3 pts during the surgery.
- Frequency of antihypertensive treatment for hypertensive crisis during the surgery
Antihypertensive treatment for hypertensive crisis was given to each of the 2 pts who had the event.
- Vasopressor treatment was given to 2/3 pts and not to 1/3 pts.
-- Pharmacokinetics
The pharmacokinetic (PK) parameters suggested higher renal dysfunction increased blood exposure. However, the levels of increase in blood exposure of the pts with mild renal dysfunction compared to the pts with normal renal function were within a variation between individuals, indicating no significant difference. Time to maximum concentration (Tmax) was unlikely to be affected by level of renal function. The PK parameters suggested higher renal dysfunction delayed elimination. However, the levels of delay in elimination in the pts with mild renal dysfunction compared to the pts with normal renal function were within a variation between individuals, indicating no significant difference. The blood exposure of the pts with mild renal dysfunction increased compared to the pts with normal renal function. However, the levels were within a variation between individuals, indicating no significant difference.
Including the PK in ONO-5371-01 study ,the pts with PPGL had lower Cmax than and little difference in AUC9h from those for plasma ONO-5371 concentration after a single oral dose in the Japanese healthy males or the males with renal dysfunction. For multiple doses, as with the comparison at a single oral dose, the pts with PPGL had lower Cmax than and little difference in AUC4h from the estimated those for plasma ONO-5371 concentration on Day 7 (after a dose of ONO-5371 250 mg in the morning) in the Japanese healthy males or the males with renal dysfunction.
Neither weight nor age was suggested to have any apparent relationship with the PK of ONO-5371. |
本治験では,褐色細胞腫のカテコールアミン過剰に伴う症状を有する患者を対象に,ONO-5371の開始用量を500 mg/日とし,用量調節基準に従って適宜用量調節した1日投与量(最大用量4000 mg/日)を1日1~4回分割経口投与した.ONO-5371-01試験で得られた薬物動態と比較した結果,日本人の健康成人又は腎機能障害者と褐色細胞腫患者で薬物動態に大きな差異はなかった.本治験で用いた用法・用量は当該患者に対して,カテコールアミン過剰分泌の抑制及びカテコールアミン過剰に伴う症状の改善に有効であり,有害事象の多くは安全性担保の上で管理可能なものと考えられた. |
The study used ONO-5371 started at 500 mg/day with daily dosage based on dose-adjustment criteria (up to 4000 mg/day) in divided oral doses 1-4 times daily in PPGL pts with excess CA-induced symptoms. There was no significant difference in PK between PPGL pts and Japanese healthy adults or renal dysfunction pts in comparison to PK in ONO-5371-01. The dose regimen was considered effective for reducing excess CA and improving associated symptoms in the population with most AEs manageable for assured safety. |
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