A pilot randomized controlled trial Registry #: NCT 01800887

    Inclusion Criteria Exclusion Criteria Consent Models Central Randomization System (CRS)

 Male and female critically ill adult patients in shock and receiving vasopressors after the early phase of resuscitation.

Patient receiving vasopressors Screen patient for eligibility Record screening info into CRS

 Sites should screen subjects who are admitted to their ICU daily and who are receiving vasopressors

The patient must fulfill all of the following criteria to be included: 1. > 16 years of age at the time of consent; and 2. Under the direct care of the ICU team regardless of location; and

3. Who have receive a minimum of 30 mL/kg of

intravenous fluids (2100 mL for a 70 kg patient) before enrolment OR the most responsible physician has good reasons to believe that more fluid resuscitation is no longer required and could be harmful; and

  The fluid requirement should be determined using ideal body weight (IBW) using a body mass index of 22.

It is preferred to confirm the minimum fluid requirement from the medical chart prior to randomization.

  It may be difficult to get access to the medical chart early on in a patient’s admission, it is permissible to use the opinion of a physician. If the physician believes the patient has been adequately fluid resuscitated, they will be considered to meet this criterion.

4. The treating physician believes will need vasopressors for at least 6 hours once enrolled

We will exclude patients who meet at least one of the following criteria: 1. Have received vasopressors for more than than 24 consecutive hours; if vasopressors are discontinued for > 2 hours, restarting vasopressors will constitute a distinct vasopressor episode and the clock will be reset.

   If vasopressors are started, then stopped, and then started again, the clock for this criterion restarts with the latest initiation of pressors.

If the patient is admitted to the local ED, started on pressors, then transferred to the ICU, the start time for pressors is the actual start time in the ED.

If the patient arrives from a referring hospital on pressors, the start time for vasopressors is the hospital admission time.

2. Are judged by the treating physician to be in obvious cardiogenic shock after an acute myocardial infarction (based on new ST segment elevations on ECG or obvious echocardiographic findings).

3. Have obvious haemorrhagic shock as a consequence of a clearly identified source of blood loss.

4. Require vasopressors after cardiac surgery as a result of cardiopulmonary bypass-induced hypotension.

5. Who have a specific indication for catecholamine therapy other than shock (i.e. angioedema or intracranial hypertension).

6. The attending team has agreed to withhold or withdraw life sustaining treatments.

 The decision to withdraw life-sustaining therapies must be explicitly noted in the patient medical record. A “no code” order does not constitute a withdrawal of life sustaining therapies in and of itself.

7. Concurrent enrollment in interventional trials that do not meet guidelines for co-enrolment (co-enrolment is permissible if there is no potential interaction between the protocols; this will be addressed case by case)

 Studies approved for co-enrollment include: STARRT AKI, ABLE, Towards RECOVER.

8. Prior randomization in this study

 

“Free and informed consent refers to the dialogue, information sharing and general process through which prospective subjects choose to participate in research involving themselves.”

- Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans

 The written informed consent form (ICF) and any other written information given to subjects/SDMs should provide adequate information for the subject/SDM to make an informed decision about participation  All written ICFs and other information documents given to subjects/SDMs must be approved by the local ethics committee prior to use

ICH Good Clinical Practices (4.8.10) outlines the essential elements of informed consent to be as follows:

 Trial involves research     Purpose of the trial Trial treatments and probability for random assignment to treatment Trial procedures to be followed, including all invasive procedures Subject’s responsibilities

        Aspects of the trial that are experimental Reasonably foreseeable risks and inconveniences to the subject Reasonably expected benefits, clarify if no benefit is expected Alternative treatments and procedures available to the subject Compensation in the event of trial injury Payment for participation Anticipated expenses to the subject Voluntary participation, including right to withdraw at any time without any loss of rights or benefits

       Monitor, sponsor, auditor, ethics, regulatory agency access to medical records for purposes of verifying procedures/data Subject confidentiality will be maintained New information will be reported to the subject in a timely manner Contact regarding subject rights or in the event of trial related injury Circumstances why trial or subject participation may be terminated Expected duration of subject participation Approximate number of subjects involved in the trial

 If the subject is not able to grant consent for themselves (e.g. unconscious patient in the ICU or a child) consent must be obtained from a substitute decision maker (SDM) or legally appointed representative  A SDM is usually determined via a hierarchy as permitted by local, provincial/state, national and ethics committee laws and regulations.

 A SDM may be one of the following:       A guardian appointed by the court if the court order authorizes the guardian to make health care decisions for the subject A person with a “power of attorney for personal care” authorizing him or her to make health care decisions for the subject A spouse or partner A child or parent (custodial parent if the patient is a minor) A brother or sister Any other relative

 It is recommended that the site use deferred consent, also known as an

a posteriori

consent, to enter patients into the study. By deferred consent, we mean that the patient can be enrolled into the study, subsequent to enrollment, written consent is sought from the SDM.  Refer to protocol section 2.19 Ethics for the rationale for deferred consent.

 Confirm subject eligibility and appropriateness of enrolment with the site investigator or physician delegate.  Check to see if the subject has refused to participate in research in general on their medical record.

 Randomize the patient, initiate the study intervention and collect data.

 Seek to obtain written informed consent from the SDM (or patient) as soon as possible.

 Familiarize yourself with the patient’s history.

   Approach bedside nursing staff/medical staff for an update on the family’s involvement and their degree of knowledge of the patient’s condition.

Fully inform the SDM (or patient) of all pertinent aspects of research, in non-technical language that is easy to understand. Provide a copy of the consent form to the patient/SDM and allow for ample time to read it and ask questions.

 Ascertain the SDMs (or patient’s) willingness to participate.    Did the patient die before you could obtain a deferred consent?

Were you able to obtain a deferred consent from the SDM (or patient)? Was deferred consent denied by the SDM (or patient)? Ensure you determine:  consent is denied to continue with further participation in the study; and  if data collected to the date of consent being denied can be kept.

 Document the consent process in the patient’s medical chart.

 Provide the SDM with a copy of the signed document.

 File the originally signed ICF in the patient study file. Place a copy in the patient’s medical chart.

  It may also be necessary to use a standard or a priori consent approach from time to time.

In these cases observe local REB approved consent procedures.

 Informed consent is a process, communicate any important new information that becomes available, and that may be relevant to the patient/SDMs.

 If consent was granted by a SDM, assess the subject through the duration of the study for competency to grant consent for themselves.

 Always refer to the local ethics committee concerning procedures and policies to follow concerning informed consent  The ability to use telephone consent, fax consent or verbal consent must be assessed for each trial individually and approval must be granted by the ethics committee to use these methods.

 Enter all patients who are receiving vasopressors at the time of screening into the CRS.

You will note each patient entered into the CRS is issued a screening number. Those patients that are eligible and randomized are issued an randomization number.

Enter the appropriate Inclusion Criteria information.

This is the starting point to entering screening data. If you select ‘no’ this patient will not be saved.

Enter the appropriate Exclusion Criteria information.

If the patient is eligible, you will next see the Pre Enrollment Form.

Indicate if you are using a Deferred or Standard Consent.

Standard Consent – SDM not approached Standard Consent – SDM approached consent denied

Standard Consent – SDM approached consent granted

Deferred Consent– unable to approach SDM (patient) Deferred Consent– consent obtained

Deferred Consent– consent denied

Thank you for taking the time to complete this training module.

Proceed to Module 3: Study Procedures