更新履歴にある更新日が2018/12/15以前である場合、その情報は旧フォーマットに則って作成されています。
If update date in update history is before 2018/12/15, the information was created in accordance with the old format.

更新履歴 / update history information

項目名 / Item 日本語 / Japanese 英語 / English
最新登録日last update registered date 2022/05/30
最新掲載日last update posted date 2022/06/27
初回登録日first registered date 2015/08/28
初回掲載日first posted date 2015/08/31
結果概要初回登録日first registered date for the result 2022/05/30
結果概要初回掲載日first posted date for the result
更新履歴update history 更新日 / updated date 最新照合日 / last reviewed date
2022/06/27 改訂 / revised
2022/05/13 改訂 / revised
2020/10/14 改訂 / revised 2021/10/11
2019/06/03 改訂 / revised 2020/07/03
2018/12/17 JAPICによる結合情報 / merged information by JAPIC
2016/04/13 改訂 概要(英語) / revised summary (EN) 2017/05/22
2016/04/12 改訂 概要(日本語) / revised summary (JA) 2017/05/22
2016/01/27 改訂 概要(英語) / revised summary (EN)
2016/01/27 改訂 概要(日本語) / revised summary (JA)
2015/08/28 改訂 概要(英語) / revised summary (EN)
2015/08/28 新規作成 概要(日本語) / initial created summary (JA)

基本情報 / basic information

項目名 / Item 日本語 / Japanese 英語 / English
JapicCTI-No. JapicCTI-152999
他の登録機関other registries 無 / absence
IPD共有に関する計画plan to share IPD 有 / yes
IPD共有に関する計画の詳細plan description https://www.ono.co.jp/jpnw/rd/policy.html https://www.ono.co.jp/eng/rd/policy.html

試験名 / title for the study

項目名 / Item 日本語 / Japanese 英語 / English
試験の名称scientific title ONO-5371第1相/第2相試験 褐色細胞腫のカテコールアミン過剰に伴う症状を対象とした多施設共同非盲検非対照試験及び付随する継続投与試験(ONO-5371-02) A multicenter, open-label, uncontrolled, phase 1/2 study and extension study of ONO-5371 for symptoms of pheochromocytoma and paraganglioma caused by excess secretion of catecholamines(ONO-5371-02)
簡易な試験の名称public title ONO-5371第1相/第2相試験(ONO-5371-02) ONO-5371 Phase 1/2 Study(ONO-5371-02)

試験に用いる薬剤等 / investigational material

項目名 / Item 日本語 / Japanese 英語 / English
試験対象薬剤等investigational material 医薬品 / medicine
試験対象薬剤等 / investigational material(s)
一般的名称等generic name etc. ONO-5371 ONO-5371
薬剤:試験薬剤INNINN of investigational material metirosine
試験対象品目:薬剤:薬効分類コードinvestigational material:medicine:therapeutic category code 219 /
用法・用量、使用方法dosage and administration for investigational material 経口投与 oral administration
対照薬剤等 / control material(s)
一般的名称等generic name of control material - -
薬剤:対照薬剤INNINN of control material -
試験対象品目の対照:薬剤:薬効分類コードcontrol material:medicine:therapeutic category code
用法・用量、使用方法dosage and administration for control material - -

試験の概要 / brief summary

項目名 / Item 日本語 / Japanese 英語 / English
試験の目的objective 治療 / treatment
試験のフェーズphase フェーズ1・2 / phase1・2
試験の種類study type 介入試験 / interventional study
第1被験者登録・組み入れ日date of first enrolment 2015/10/26
予定試験期間expected duration of study 2015/09/01 ~ 2019/07/31
目標症例数target sample size 10
試験の概要brief summary 褐色細胞腫のカテコールアミン過剰に伴う症状に対するONO-5371の有効性及び安全性,並びに褐色細胞腫患者における薬物動態を確認する. To examine the efficacy and safety of ONO-5371 for symptoms of pheochromocytoma and paraganglioma caused by excess secretion of catecholamines as well as the pharmacokinetics of ONO-5371 in patients with pheochromocytoma and paraganglioma
試験のデザインstudy design 多施設共同非盲検非対照試験及び付随する継続投与試験 A multicenter, open-label, uncontrolled study and extension study
試験実施国・地域countries / regions of recruitment 日本 / Japan
適格基準inclusion criteria 1. 性別:不問
2. 年齢:12歳以上
3. 褐色細胞腫と診断された患者
4. 尿中メタネフリン又はノルメタネフリンのいずれかが基準値上限の3倍以上の患者
5. 交感神経受容体遮断薬による治療(α1遮断薬が最大投与量以上あるいは最大忍容量投与されている,あるいは忍容性及び安全性の点から投与できない)が行われている患者
6. カテコールアミン過剰に起因する血圧高値(収縮期血圧140mmHg以上,又は拡張期血圧90mmHg以上),糖代謝異常,頭痛,動悸,発汗,便秘,頻脈,振戦などのいずれかの臨床症状を有する患者
1. Sex: Male or female patients
2. Age: 12 years of age and older
3. Patients given a diagnosis of, pheochromocytoma and paraganglioma
4. Patients with either urinary metanephrine or normetanephrine is ≥3 times the upper limit of normal
5. Patients undergoing treatment with adrenergic blocking agent (patients receiving alpha 1 blockers at the maximum dose or more or at the maximum tolerated dose, or being unable to receive the agents due to the tolerability and safety)
6. Patients experience any one of these clinical symptoms caused by excess secretion of catecholamines: high blood pressure (with a systolic blood pressure of >=140 mmHg, or with a diastolic blood pressure of >=90mmHg), glucose metabolism disorder, headache, palpitation, perspiration, constipation, tachycardia, or tremor, etc.
適格基準:年齢(下限)minimum age 12 歳 / year
適格基準:年齢(上限)maximum age 制限なし / no limitation
適格基準:性別gender 両方 / both
除外基準exclusion criteria 1. 治験参加の検査実施前90日以内にがん化学療法による治療を受けた患者,治験期間中にがん化学療法による治療を予定している患者
2. 治験参加の検査実施前90日以内に放射線外照射療法を受けた患者,治験期間中に放射線外照射療法を予定している患者
3. 治験参加の検査実施前180日以内に放射線内照射療法を受けた患者,治験期間中に放射線内照射療法を予定している患者
4. 食物,経口剤の経口摂取,消化吸収ができない又は影響する疾患を合併する患者
5. 高度及び末期腎不全の腎機能障害(eGFR<30 mL/分)を有する患者
6. 左室駆出率が40%未満の患者
7. 重篤なアレルギー既住のある患者
8. 妊娠中,授乳中並びに妊娠している可能性のある患者,又は治験期間中に妊娠を希望している患者
9. 他のすべての未承認薬の投与終了後から治験参加の検査実施前までに120日を経過していない患者
10.過去にONO-5371(metirosine)を投与されたことがある患者
1. Patients underwent treatment with cancer chemotherapy within 90 days prior to the examination for the enrollment in the study and patients who will be receiving treatment with cancer chemotherapy during the study period
2. Patients underwent treatment with external radiation therapy within 90 days prior to the examination for the enrollment in the study and patients who will be receiving treatment with external radiation therapy during the study period
3. Patients underwent treatment with internal radiation therapy within 180 days prior to the examination for the enrollment in the study and patients who will be receiving treatment with internal radiation therapy during the study period
4. Patients with complicated diseases that affect or cause inability to intake, digestion and absorption of foods and oral agents
5. Patients with renal dysfunction (eGFR <30ml/min.) derived from severe and end-stage renal failure
6. Patients with <40% of left ventricular ejection fraction
7. Patients with history of severe allergy
8. Pregnant or lactating patients, patients who may be pregnant, patients wish to become pregnant during the study period
9. Patients with >=120 days elapsed between the completion of administration of all other unapproved drugs and the examination for the enrollment in the study
10. Patients have had prior therapy with the investigational medicinal product of ONO-5371 (metirosine)
疾患名health condition or problem studied 褐色細胞腫のカテコールアミン過剰に伴う症状 Symptoms of pheochromocytoma and paraganglioma caused by excess secretion of catecholamines
評価項目・方法:主要な評価項目 / primary outcome
評価項目・方法:主要な評価項目primary outcome 安全性 / safety
有効性 / efficacy
薬物動態 / pharmacokinetics
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)がベースラインから50%以上減少した患者割合 The proportion of patients with
50% or more reduction from baseline in urinary metanephrine or urinary normetanephrine at the final evaluation
評価項目・方法:副次的な評価項目 / secondary outcome
評価項目・方法:副次的な評価項目secondary outcome 安全性 / safety
有効性 / efficacy
薬物動態 / pharmacokinetics
副次的な評価項目には以下が含まれる。
・治療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)、尿中バニリルマンデル酸、尿中カテコールアミン3分画(アドレナリン、ノルアドレナリン又はドーパミン)がベースラインから50%以上減少した患者割合
・カテコールアミン分泌過剰に伴う症状の変化
・血圧、脈拍数、血糖値、左室駆出率の変化
The secondary efficacy endpoints included
-The proportions of patients with 50% or more reduction from baseline in urinary metanephrine, urinary normetanephrine, urinary vanillylmandelic acid, urinary adrenaline, urinary noradrenaline and urinary dopamine during the treatment period
-Clinical Global Impression of Change (CGI-C)
of excess catecholamine-induced symptoms
-Changes in blood pressure, pulse rate, blood glucose, and left ventricle ejection fraction(LVEF)
試験実施施設examination facility
試験の現状study status 試験完了 / completed
被験者募集状況recruitment status 参加募集終了 / completed
試験終了日または中止日completion date or terminated date 2019/07/25

IRB等に関する事項 / information about IRB(s)

注意:『IRB等に関する事項』にある機関等への問合せはご遠慮ください。また、IRBが複数存在する場合、一部のIRB情報のみが公開されている場合があります。
    問合せに関しては、項目『問合せ先』(参照:項目『IRB等に関する事項』から3件下にある項目)にある会社または機関へご連絡ください。
項目名 / Item 日本語 / Japanese 英語 / English
IRB等に関する情報
名称name of IRB - -
住所address of IRB - -
電話番号phone number of IRB
Eメールアドレスe-mail address of IRB
審査の状況status of IRB review 承認 / approved
承認日date of approval by IRB 2015/09/01

試験実施組織 / organizations

資金提供組織 / monetary sponsor

項目名 / Item 日本語 / Japanese 英語 / English
組織名称 / name of monetary sponsor
組織名称name of funding organization - -
研究費の名称name of research funding - -

問合せ先 / contact information

項目名 / Item 日本語 / Japanese 英語 / English
一般的な問合せ先 / public queries
会社名・機関名contact name for public queries 小野薬品工業株式会社 ONO PHARMACEUTICAL CO.,LTD.
問合せ部署名department name for contact くすり相談室 Medical Information Center
連絡先住所address
連絡先電話番号phone number 0120-626-190(受付時間:土・日・祝日を除く9:00−17:00)
連絡先Eメールアドレスe-mail address clinical_trial@ono.co.jp clinical_trial@ono.co.jp
科学的な問合せ先 / scientific queries
会社名・機関名contact name for scientific queries 小野薬品工業株式会社 ONO PHARMACEUTICAL CO.,LTD.
問合せ部署名department name for contact 開発本部 Development Headquarters
連絡先住所address
連絡先電話番号phone number
連絡先Eメールアドレスe-mail address kawata@ono.co.jp kawata@ono.co.jp

その他 / other

項目名 / Item 日本語 / Japanese 英語 / English
関連の試験番号とその名称related study ID number and its name
その他other 本試験は承認取得後,製造販売後臨床試験として実施することになった。
ONO-5371-02
This study was to be conducted as a post-marketing clinical study after approval.
ONO-5371-02
関連情報(既存薬の添付文書、審査報告書、新薬承認情報集等) / related information(e.c. package insert for existing medicine)
名称name
URL
上記情報の簡易的な説明brief description

試験結果の概要 / result summary

項目名 / Item 日本語 / Japanese 英語 / English
出版物の掲載posting of journal publication 有 / presence
初回の出版物の掲載日date of the first journal publication of results 2018/01/20
結果および出版物に関するURLURL hyperlink(s) related to results and publications https://www.jstage.jst.go.jp/article/endocrj/65/3/65_EJ17-0276/_article
試験の対象者に関する背景情報baseline characteristics 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%).
実際の症例数actual enrolled number 16
試験の対象者のフローparticipant flow 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).
有害事象に関するまとめadverse events 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.
主要評価項目の解析結果primary outcome measures ・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%.
副次的評価項目の解析結果secondary outcome measures ・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.
簡潔な要約brief summary 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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