The Intensive Care Platform Trial

Официальное название

The Intensive Care Platform Trial (INCEPT)

Обзор

Among critically ill patients, many die, and many of the survivors and their family members struggle for years with reduced quality of life. Critically ill patients are treated in intensive care units (ICUs). Here, they receive life support, e.g., mechanical ventilation and advanced support of the circulation (heart and blood vessels) and kidneys. In addition, ICU patients receive many other treatments. It is, however, uncertain if all the treatments provide value for the patients. The desirable effects of many treatments are uncertain, and some may be wasteful or even harmful. Clinical trials are necessary to validly assess the desirable and undesirable effects of different treatments. However, conventional clinical trials have limitations: * They typically only assess a single question related to a single comparison of treatments at a time. * They are often not very flexible, including with regards to the number of participants needed, and this increases the risk that a trial will end up as inconclusive. * There is no or limited re-use or sharing of infrastructure across trials, leading to duplicate work and resource use. * Trial participants do usually not benefit from the obtained knowledge before the trial concludes. * Involvement of patients, family members, and other stakeholders is typically limited, which may decrease the relevance of the questions addressed. With the Intensive Care Platform Trial (INCEPT), we aim to tackle these challenges by establishing a flexible platform trial that continuously learns from the obtained results. The platform trial may run forever with simultaneous and continuous assessment of many treatments. INCEPT will continuously learn from the accrued data and use these to improve the treatment of both participating and future patients. With INCEPT, we are also building a framework for thorough and extensive involvement of key stakeholders, including patients and family members. INCEPT will improve the way clinical trials are done and increase the probabilities that treatments are improved. This will: * Directly improve outcomes for ICU patients. * Relieve a strained healthcare system by discarding inefficient or harmful treatments. * Ensure that new treatments are beneficial or cost-effective before implementation. * Lower the costs and burdens of assessing more treatments in the critically ill.

Подробное описание

Background:

Randomised clinical trials (RCTs) are the gold standard for evaluating intervention effects, however, conventional RCTs are bureaucratic, costly, inflexible, and often inconclusive. Adaptive platform trials are increasingly used as they can reduce barriers and are more flexible, and thus come with a higher probability of obtaining conclusive results faster at lower costs.

Objectives:

The Intensive Care Platform Trial (INCEPT) will be used to assess the effects of interventions used in adults acutely admitted to the intensive care unit (ICU).

Design:

INCEPT is an investigator-initiated, pragmatic, randomised, embedded, multifactorial, international, adaptive platform trial. INCEPT uses adaptive stopping and arm-dropping rules, as well as fixed and response-adaptive randomisation. Specific domains may be either open label or blinded.

Domains and interventions:

Comparable groups of interventions will be nested in domains, which have conceptual similarities with stand-alone randomised trials. Domains will continuously be added to INCEPT and conducted following domain-specific appendices to the core protocol.

Inclusion and exclusion criteria:

Adults acutely admitted to the ICU will be screened if they are eligible for at least one active domain. The only platform-level exclusion criteria are 1) informed consent after inclusion expected to be unobtainable and 2) patients admitted under coercive measures. Additional inclusion and exclusion criteria will be domain-specific.

Stakeholder involvement:

Stakeholder involvement is central in INCEPT and ensured through a central advisory board comprising various key stakeholders, and consultations with national and international research panels consisting of ICU survivors, family members, clinicians, and researchers. Stakeholders will be involved in the development of the overall platform trial and specific domains with pre-specified minimum requirements for involvement.

Outcomes:

Each domain will use one of the core outcomes (defined elsewhere in the registration) as the primary outcome and the guiding outcome driving all adaptations.

Statistical methods Primary analyses will generally be conducted in the intention-to-treat population of each domain. INCEPT primarily uses Bayesian statistical methods with neutral priors conveying either minimal information or some scepticism, although specific domains may use conventional, frequentist statistical methods. Outcomes will generally be analysed using logistic and linear regression models adjusted for pre-specified anticipated prognostic baseline characteristics, followed by calculation of sample-average estimates and intervention effects using G-computation. Results will be presented for each intervention and comparisons presented on both the absolute (risk differences and mean differences) and relative (risk ratios and ratios of means) scales with 95% credible intervals and probabilities of superiority. INCEPT will generally use constant, symmetric stopping rules for superiority/inferiority based on the guiding outcome; domains may use stopping rules for practical equivalence or futility based on the posterior distribution of the guiding outcome on the absolute scale. All stopping rules will be binding. Response-adaptive randomisation, either with or without restrictions, may be used based on the posterior distribution for the guiding outcome. Missing data will be multiply imputed. Additional secondary analyses (e.g., per-protocol analyses), sensitivity analyses, and analyses of heterogeneity in intervention effects according to pre-defined baseline characteristics may be specified for each domain and undertaken once a domain has stopped. Domains will be designed and evaluated using statistical simulation.

Вмешательства

• Препарат Albumin
  Albumin should be used for the following indications: 1. During circulatory failure in addition to crystalloids (resuscitation). 2. For substitution in case of: suspected or overt albumin loss OR P-albumin levels below or equal to 25 g/L. Decisions around timing, volume, and concentration of albumin, and its use for other indications, are at the clinician's discretion. P-albumin should be measured according to local practice.
• Другое No albumin use
  Albumin should not be used. In case of the following special circumstances, albumin may be considered: 1. Large ascites drainage (i.e., equal to or more than 1 L tapped) 2. Spontaneous bacterial peritonitis 3. Hepatorenal syndrome.
• Препарат LMWH in weight-adjusted dose
  Patients with indication for thromboprophylaxis receive low-molecular-weight heparin (LMWH) in a weight-adjusted dose during their ICU stay. The treating clinician may decide to adjust or withhold one or more doses in case of acute and/or chronic kidney injury, renal replacement therapy, thrombocytopenia, invasive procedures, use of thrombolysis, and active (major) bleeding.
• Препарат LMWH in fixed low dose
  Patients with indication for thromboprophylaxis receive low-molecular-weight heparin (LMWH) in a fixed low dose during their ICU stay. The treating clinician may decide to adjust or withhold one or more doses in case of acute and/or chronic kidney injury, renal replacement therapy, thrombocytopenia, invasive procedures, use of thrombolysis, and active (major) bleeding.
• Препарат LMWH in fixed intermediate dose
  Patients with indication for thromboprophylaxis receive low-molecular-weight heparin (LMWH) in a fixed intermediate dose during their ICU stay. The treating clinician may decide to adjust or withhold one or more doses in case of acute and/or chronic kidney injury, renal replacement therapy, thrombocytopenia, invasive procedures, use of thrombolysis, and active (major) bleeding.

Первичные конечные точки

• One of the INCEPT core outcomes (varying between domains) [Срок оценки: From randomisation to 30-180 days after randomisation.]
• Days alive without life support at day 30 (Albumin domain) [Срок оценки: From randomisation to 30 days after randomisation.]
• Days alive and out of hospital at day 30 (Thromboprophylaxis domain) [Срок оценки: From randomisation to 30 days after randomisation.]

Вторичные конечные точки (12)

• All-cause 30-day mortality [Срок оценки: 30 days after randomisation.]
• All-cause 90-day mortality [Срок оценки: 90 days after randomisation.]
• All-cause 180-day mortality [Срок оценки: 180 days after randomisation.]
• Days alive without life support at day 30 [Срок оценки: From randomisation to 30 days after randomisation.]
• Days alive without life support at day 90 [Срок оценки: From randomisation to 90 days after randomisation.]
• Days alive out of hospital at day 30 [Срок оценки: From randomisation to 30 days after randomisation.]
• Days alive out of hospital at day 90 [Срок оценки: From randomisation to 90 days after randomisation.]
• Days free of delirium at day 30 [Срок оценки: From randomisation to 30 days after randomisation.]
• EQ-5D-5L index values (Health-Related Quality of Life) at day 180 [Срок оценки: 180 days after randomisation (+/- 14 days).]
• EQ VAS (Health-Related Quality of Life) at day 180 [Срок оценки: 180 days after randomisation (+/- 14 days).]
• Cognitive function at day 180 [Срок оценки: 180 days after randomisation (+/- 14 days).]
• Thromboprophylaxis domain specific secondary outcomes [Срок оценки: 30 days (matching the primary and guiding outcome) and 90 days (matching the maximum intervention period).]

Критерии участия

The general eligibility criteria below apply to INCEPT as a whole and thus to all domains. Domains may impose domain-specific eligibility criteria that restrict the population eligible for that domain further, but domains are not allowed to broaden the general eligibility criteria. Domain-specific eligibility criteria always apply to all arms in a domain.

PLATFORM INCLUSION CRITERIA:

• Adult patient (≥18 years old) acutely admitted to the ICU. This includes ICU admissions after emergency surgery, unplanned ICU admissions after elective surgery, and prolonged ICU admissions due to complications after elective surgery (i.e., admissions occurring or being prolonged due to an unexpected, worsened condition, but excluding planned ICU admissions after elective surgery without clinical deterioration).
• Eligible for at least one active domain.

PLATFORM EXCLUSION CRITERIA:

• Informed consent following inclusion expected to be unobtainable (e.g., known previous objections to participation).
• Patient is under coercive measures (e.g., ongoing involuntary hospital stay or under the jurisdiction of correctional authorities).

Patients who have previously been included in INCEPT may only be included again during new ICU admissions but may only be randomised to domains in which they have not previously been randomised.

DOMAIN-SPECIFIC ELIGIBLE CRITERIA:

Each domain may have additional eligibility criteria. Refer to the study website for more information (www.incept.dk).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Дания · 21 центр

• Anaesthesia, Hospital Sønderjylland — Aabenraa
• Department of Anaesthesia and Intensive Care, Aalborg University Hospital — Aalborg
• Department of Intensive Care Nord , Aarhus University Hospital — Aarhus
• Department of Intensive Care Øst, Aarhus University Hospital — Aarhus
• Department of Cardiothoracic Anaesthesia and Intensive care, Copenhagen Universisty Hospit — Copenhagen
• Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet — Copenhagen
• Neuroanaesthesiology, Copenhagen University Hospital - Rigshospitalet — Copenhagen
• Department of anesthesiology and intensive care, Bispebjerg-Frederiksberg Hospital — Copenhagen
• … и ещё 13 центров

Идентификаторы

NCT: NCT06667999 · RH-ITA-2024-516208-41-00 · 2024-516208-41-00 · U1111-1313-8171

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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