Исследование AZD4956 в качестве монотерапии и в комбинации с противоопухолевыми препаратами у пациентов с распространёнными/метастатическими солидными опухолями с дефицитом гомологичной рекомбинации (PARTHENON)
Модульное открытое исследование фазы I/IIa для оценки безопасности, переносимости, фармакокинетики, фармакодинамики и предварительной эффективности возрастающих доз AZD4956 в качестве монотерапии и в комбинации с противоопухолевыми препаратами у участников с распространенными/метастатическими солидными опухолями с дефектом репарации гомологичной рекомбинации
The purpose of this modular, first trial in human study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of ascending dose levels (DLs) of AZD4956 monotherapy and in combination with other anti-cancer agents in participants with advanced/metastatic solid tumours with homologous recombination repair (HRR) deficiencies.
Обзор исследования
Статус
Условия
Вмешательство/лечение
Подробное описание
The study consists of individual modules each evaluating the safety and tolerability of AZD4956 dosed as monotherapy, or with a specific combination partner. There are following 2 modules -
- Module 1: AZD4956 monotherapy
- Module 2: AZD4956 in combination with saruparib
Each module may further contain 2 parts-
- Part A (dose escalation/dose finding): To determine the safety, tolerability, PK, PD, and preliminary efficacy of AZD4956 as monotherapy or in combination.
- Part B (dose expansion): To further evaluate the safety and preliminary efficacy of AZD4956 in combination with other anti-cancer agents.
Тип исследования
Регистрация (Оцененный)
Фаза
- Фаза 2
- Фаза 1
Контакты и местонахождение
Контакты исследования
- Имя: AstraZeneca Clinical Study Information Center
- Номер телефона: 1-877-240-9479
- Электронная почта: information.center@astrazeneca.com
Места учебы
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Melbourne, Австралия, 3000
- Рекрутинг
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Westmead, Австралия, 2145
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Barcelona, Испания, 08036
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Barcelona, Испания, 8035
- Еще не набирают
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Barcelona, Испания, 08023
- Рекрутинг
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Logroño, Испания, 26006
- Еще не набирают
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Pozuelo de Alarcón, Испания, 28223
- Еще не набирают
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Seville, Испания, 41013
- Еще не набирают
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Cambridge, Соединенное Королевство, CB2 0QQ
- Рекрутинг
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London, Соединенное Королевство, SE1 9RT
- Еще не набирают
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Sutton, Соединенное Королевство, SM25PT
- Рекрутинг
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New York
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New York, New York, Соединенные Штаты, 10065
- Рекрутинг
- Research Site
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Rhode Island
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Providence, Rhode Island, Соединенные Штаты, 02903
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Texas
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Houston, Texas, Соединенные Штаты, 77030
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Virginia
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Fairfax, Virginia, Соединенные Штаты, 22031
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Seoul, Южная Корея, 03080
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Seoul, Южная Корея, 120-752
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Chūōku, Япония, 104-0045
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- Research Site
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Kashiwa, Япония, 277-8577
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Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
Принимает здоровых добровольцев
Полы, имеющие право на обучение
Описание
Core Inclusion Criteria:
- Documented locally advanced or metastatic solid tumour malignancy.
- Eastern cooperative oncology group (ECOG) performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to screening and first day of dosing.
- Minimum life expectancy ≥ 12 weeks.
- Adequate organ and marrow function.
- Female participants must not breastfeed and must not donate or retrieve ova for their own use from screening to approximately 6 months after the last dose of study intervention.
Module 1 Inclusion Criteria:
- Demonstrated evidence of disease progression.
- Participants must have advanced or metastatic solid tumours.
- Participants may have received up to one prior line of therapy with a poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi)-based regimen (either as a treatment or as maintenance).
Module 2 Inclusion Criteria:
Part A (AZD4956 in Combination with Saruparib Dose Escalation) and Part A-PD (PD Backfill Cohorts):
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Participants must have one of the following conditions-
- Histologically or cytologically confirmed carcinoma of the breast with recurrent locally advanced or metastatic disease and evidence of a predicted loss of function germline or somatic mutation.
- Histologically or cytologically confirmed advanced ovarian, fallopian tube, or primary peritoneal cancer.
- Histologically or cytologically confirmed adenocarcinoma of the prostate and advanced/metastatic castrate resistant prostate cancer (CRPC).
- Histologically or cytologically confirmed advanced/metastatic pancreatic cancer.
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Participants must have evaluable disease.
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Participants in PD backfill cohorts must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance).
Part A (PD Backfill Cohorts) - Participants Undergoing Paired Biopsies:
- Participants must have a tumour suitable for biopsy.
Part A-Non-PD (Non-PD Backfill Cohorts) and Part B (Dose Expansion Cohorts):
- Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate and advanced/metastatic CRPC.
- Participants must have documented metastatic disease by clear evidence of ≥ 1 bone lesion (defined as one lesion with positive uptake on bone scan) and/or ≥ 1 soft tissue lesion (measurable or non-measurable).
- Participants must have received the prior approved systemic therapies for metastatic prostate cancer.
- Participants must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance).
Core Exclusion Criteria:
- Any significant laboratory finding or any severe and uncontrolled medical condition.
- Participants with any known predisposition to bleeding.
- Spinal cord compression or symptomatic and unstable brain metastases or leptomeningeal disease.
- Allogenic organ transplantation.
- Known to have active infection, including hepatitis B virus (HBV) or hepatitis C virus (HCV).
- Known history of infection with human immunodeficiency virus (HIV).
- Active gastrointestinal disease or other condition that will interfere significantly with the swallowing, absorption, distribution, metabolism or excretion of oral therapy.
- Participants with history of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML.
- Participants with a known hypersensitivity to the investigational product(s) or any of the excipients of the product(s).
- Previous dosing with AZD4956.
Учебный план
Как устроено исследование?
Детали дизайна
- Основная цель: Уход
- Распределение: Рандомизированный
- Интервенционная модель: Последовательное назначение
- Маскировка: Нет (открытая этикетка)
Оружие и интервенции
Группа участников / Армия |
Вмешательство/лечение |
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Экспериментальный: Module 1 Part A: AZD4956 monotherapy (Dose escalation)
Participants will receive AZD4956 as monotherapy at ascending dose levels. |
AZD4956 will be administered orally. |
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Экспериментальный: Module 2 Part A: AZD4956 + saruparib (Dose escalation)
Participants will receive AZD4956 at ascending dose levels in combination with saruparib. |
Saruparib will be administered orally. AZD4956 will be administered orally. |
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Экспериментальный: Module 2 Part A Optional PD backfill cohort: AZD4956 + saruparib
Participants will receive AZD4956 in combination with saruparib. |
Saruparib will be administered orally. AZD4956 will be administered orally. |
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Экспериментальный: Module 2 Part A Optional PD backfill cohort: Saruparib monotherapy
Participants will receive saruparib monotherapy. |
Saruparib will be administered orally. |
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Экспериментальный: Module 2 Part A Optional non-PD backfill cohort: AZD4956 + saruparib
Participants with metastatic castrate resistant prostate cancer (mCRPC) will receive AZD4956 in combination with saruparib. |
Saruparib will be administered orally. AZD4956 will be administered orally. |
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Экспериментальный: Module 2 Part B: AZD4956 + saruparib (Dose expansion)
Participants will receive AZD4956 in combination with saruparib. |
Saruparib will be administered orally. AZD4956 will be administered orally. |
Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
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Parts A and B: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
Временное ограничение: From Screening (Day -28) to follow-up (up to 3.5 years)
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To assess the safety and tolerability of AZD4956 monotherapy and in combination with anti-cancer agent(s). |
From Screening (Day -28) to follow-up (up to 3.5 years)
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Part B: Progression free survival (PFS)
Временное ограничение: Up to 3.5 years
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PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participants withdraw from study treatment or receive another anti-cancer therapy prior to progression. |
Up to 3.5 years
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Part A - Number of participants with dose-limiting toxicities (DLTs)
Временное ограничение: Up to 28 days
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To assess the safety and tolerability of AZD4956 monotherapy and in combination with anti-cancer agent(s). |
Up to 28 days
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Вторичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
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Objective response (OR)
Временное ограничение: Up to 3.5 years
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OR is defined as if a participant achieves a best overall response (BOR) of confirmed complete response (CR) or partial response (PR), as assessed by the investigator, according to response evaluation criteria in solid tumours (RECIST) v1.1 criterion. |
Up to 3.5 years
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Duration of response (DoR)
Временное ограничение: Up to 3.5 years
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DoR is defined as the time from the date of first documented OR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by prostate cancer working group 3 (PCWG3), until the date of documented disease progression or death in the absence of disease progression. |
Up to 3.5 years
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Best Overall Response (BOR)
Временное ограничение: Up to 3.5 years
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To assess the preliminary anti-tumour activity of AZD4956 monotherapy and in combination with anti-cancer agent(s). |
Up to 3.5 years
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Time to response (TTR)
Временное ограничение: Up to 3.5 years
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TTR is defined as the time from the date of first dose of study intervention until the date of first documented OR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3, which is subsequently confirmed. |
Up to 3.5 years
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Disease control (DC)
Временное ограничение: Up to 3.5 years
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DC is defined as if a participant has achieved a best OR of confirmed CR or PR or SD as BOR assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3. |
Up to 3.5 years
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Clinical benefit rate (CBR)
Временное ограничение: Up to 3.5 years
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CBR is defined as the percentage of advanced cancer participants who achieve CR, PR, or at least 16 weeks/24 weeks of stable disease, assessed by RECIST v1.1, in the absence of progression on bone scan assessed by PCWG3, as a result of therapy. |
Up to 3.5 years
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Part A: Progression free survival (PFS)
Временное ограничение: Up to 3.5 years
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PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participants withdraw from study treatment or receive another anti-cancer therapy prior to progression. |
Up to 3.5 years
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Percentage change from baseline in tumour size
Временное ограничение: Up to 3.5 years
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The best percentage change from baseline in target lesion (TL) tumour size is the largest decrease (or smallest increase) from baseline for a participant, using RECIST v1.1 assessments. |
Up to 3.5 years
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Number of participants with cancer antigen 125 (CA125) response (for ovarian cancer participants)
Временное ограничение: From baseline up to 3.5 years
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CA125 response is defined as if at least a 50% reduction in CA125 levels from a pre-treatment sample. |
From baseline up to 3.5 years
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Radiological progression free survival (rPFS) (for prostate cancer participants)
Временное ограничение: Up to 3.5 years
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PFS is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participants withdraw from study treatment or receive another anti-cancer therapy prior to progression. |
Up to 3.5 years
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Change from baseline in prostate specific antigen 50 (PSA50) response rate (for prostate cancer participants)
Временное ограничение: From baseline up to 3.5 years
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PSA50 response is defined as if a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later has been achieved. |
From baseline up to 3.5 years
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Change from baseline in PSA90 response rate (for prostate cancer participants)
Временное ограничение: From baseline up to 3.5 years
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PSA90 response is defined as if a ≥ 90% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later has been achieved. |
From baseline up to 3.5 years
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Change from baseline in PSA undetectable rate
Временное ограничение: At 3, 6 and 9 months
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Undetectable PSA is defined as a measurement of < 0.2 ng/mL. |
At 3, 6 and 9 months
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Time to PSA50/90 response (for prostate cancer participants)
Временное ограничение: Up to 3.5 years
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Time to PSA50/90 response is defined as the time from the date of first dose of study intervention until the date of first documented PSA response (≥ 50%/90% decrease in PSA from baseline) that is confirmed by a second consecutive PSA assessment at least 3 weeks later. |
Up to 3.5 years
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Time to PSA progression (for prostate cancer participants)
Временное ограничение: Up to 3.5 years
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Time to PSA progression is defined as the time from date of first dose of study intervention until the date of first documented PSA progression or the last PSA result in the absence of progression. |
Up to 3.5 years
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PSA PFS at 6 months (PSA-6)
Временное ограничение: At 6 months
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PSA progression is defined as an increase in PSA of ≥ 25% from the nadir and an absolute increase of at least 2 ng/mL above nadir beyond 12 weeks. To assess the preliminary anti-tumour activity of AZD4956 monotherapy and in combination with anti-cancer. agent(s) |
At 6 months
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Area under the concentration-time curve (AUC)
Временное ограничение: From date of first dose of study intervention up to 59 days after first dose
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To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
From date of first dose of study intervention up to 59 days after first dose
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Maximum concentration (Cmax)
Временное ограничение: From date of first dose of study intervention up to 59 days after first dose
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To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
From date of first dose of study intervention up to 59 days after first dose
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Time to maximum concentration (Tmax)
Временное ограничение: From date of first dose of study intervention up to 59 days after first dose
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To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
From date of first dose of study intervention up to 59 days after first dose
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Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe(t1-t2))
Временное ограничение: From date of first dose of study intervention up to 16 days after first dose
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To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
From date of first dose of study intervention up to 16 days after first dose
|
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Renal clearance (CLR)
Временное ограничение: From date of first dose of study intervention up to 16 days after first dose
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To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
From date of first dose of study intervention up to 16 days after first dose
|
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Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae(t1-t2))
Временное ограничение: From date of first dose of study intervention up to 16 days after first dose
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To characterise the pharmacokinetics (PK) of AZD4956 when given orally as monotherapy and in combination with anti-cancer agent(s). |
From date of first dose of study intervention up to 16 days after first dose
|
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Change in amount of KRAB-associated protein-1 phosphorylated on serine 824 [pKAP1 (Ser824)] biomarker in tumour cells at baseline and during treatment
Временное ограничение: From Baseline up to 3.5 years
|
To evaluate PD of AZD4956 in tumour cells when given orally as monotherapy and in combination with anti-cancer agent(s). |
From Baseline up to 3.5 years
|
Соавторы и исследователи
Спонсор
Даты записи исследования
Изучение основных дат
Начало исследования (Действительный)
Первичное завершение (Оцененный)
Завершение исследования (Оцененный)
Даты регистрации исследования
Первый отправленный
Впервые представлено, что соответствует критериям контроля качества
Первый опубликованный (Действительный)
Обновления учебных записей
Последнее опубликованное обновление (Действительный)
Последнее отправленное обновление, отвечающее критериям контроля качества
Последняя проверка
Дополнительная информация
Термины, связанные с этим исследованием
Ключевые слова
Другие идентификационные номера исследования
- D8570C00001
- 2025 (Грант/контракт NIH США)
- 2025-524171-22-00 (Идентификатор реестра: CTIS (EU))
Планирование данных отдельных участников (IPD)
Планируете делиться данными об отдельных участниках (IPD)?
Описание плана IPD
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Сроки обмена IPD
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Критерии совместного доступа к IPD
When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.
Информация о лекарствах и устройствах, исследовательские документы
Изучает лекарственный продукт, регулируемый FDA США.
Изучает продукт устройства, регулируемый Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов США.
Эта информация была получена непосредственно с веб-сайта clinicaltrials.gov без каких-либо изменений. Если у вас есть запросы на изменение, удаление или обновление сведений об исследовании, обращайтесь по адресу register@clinicaltrials.gov. Как только изменение будет реализовано на clinicaltrials.gov, оно будет автоматически обновлено и на нашем веб-сайте. .