Clinical trial NCT02856698
Conditions: Acute Pulmonary Edema
Keywords: Acute heart failure morphine midazolam in-hospital mortality
Sponsor: Alberto Dominguez-Rodriguez
Start date: 2017-04-08; Completion date: 2020-12-31
Enrollment: 111 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Acute pulmonary edema (APE) is a common condition in the emergency room, associated with considerable mortality. The use of intravenous morphine in the treatment of APE remains controversial and Benzodiazepines have been suggested as an alternative for morphine to relieving dyspnoea and anxiety in the patients with APE. The MIdazolan versus MOrphine in APE trial (MIMO) is a multicenter, prospective, open-label, randomized study designed to evaluate the efficacy and safety of morphine in patients with APE.

Detailed description:

Arms: arm 1: The dose of midazolam intravenously will be of 1 mg which may be repeated until a total dose of 3 mg. arm 2: The dose of morphine intravenously is of 2-4 mg which may be repeated until a total dose of 8 mg if the patient continue suffering from severe anxiety or distress caused by APE
Interventions: intervention 1: Midazolam intervention 2: Morphine
Intervention descriptions: intervention 1: Dose use according to the product technical sheet intervention 2: Dose use according to the product technical sheet

Protocol documents:
Prot_000.pdf: 
A MULTICENTER, OPEN-LABELED, RANDOMIZED CONTROLLED TRIAL
COMPARING MIDAZOLAM VERSUS MORPHINE IN ACUTE
CARDIOGENIC PULMONARY EDEMA (MIMO TRIAL)
MIMO study
CLINICAL
 
  TRIAL
 
  PROJECT
 
  
VERSION 2
DATE:
July 7, 2016
Protocol Code: MIMO/2016 
EudraCT number: 2016-000884-17
Promoter and Chief Investigator
Dr. Alberto Domínguez-Rodríguez
Hospital 
Universitario 
de
Canarias Ofra s/n. La Cuesta
38320- 
La
Laguna Tenerife
Person authorized by the Promoter fo r t h e management o f
AEMPS, CEIm and centers of investigation:
Dr. Fernando Alberto Hidalgo Figuerola (Hospital Universitario de Canarias)


Estudio MIMO
2
INDEX.

Summary.................................................... ................

General information...................................................

Justification and objectives...........................................

Type and design of the clinical trial.................

Patient selection...............................................

Description of the treatment.........................................

Development of the trial and evaluation of response..

Adverse events..........................................

Ethical aspects...........................................................

Practical considerations.........................................

Statistical analysis......................................................

Publicaction...........................................................

References...................................................................

Annex I.........................................................................

Annex II........................................................................

Annex III.......................................................................

Annex IV.......................................................................


3
Estudio MIMO
A MULTICENTER, OPEN-LABELED, RANDOMIZED CONTROLLED TRIAL
COMPARING MIDAZOLAM VERSUS MORPHINE IN ACUTE
CARDIOGENIC PULMONARY EDEMA (MIMO TRIAL)
I.   SUMMARY
 
 
1.
STUDY PROMOTER: Dr. Alberto Domínguez-Rodríguez.
2. STUDY TITLE: Multicenter, open-labeled, randomized controlled trial
comparing Midazolam versus Morphine in acute cardiogenic pulmonary edema
“MINO trial”
3. PROTOCOL:code:
MIMO/2016
Nº EUDRACT: 2016-00884-17
EXECUTIVE COMMITTEE:
Dr. Alberto Domínguez-Rodríguez (Promoter) / Dr. Guillermo Burillo-Putze / 
Dr. Coral Suero / Dr. Pedro Abreu-González / Dr. Óscar Mirò.
5. CENTERS PARTICIPATING IN THE TRIAL:
It is foreseen that 14 national hospitals will participate in the trial.
6. ETHICAL COMMITTEE OF INVESTIGATION WITH MEDICATIONS
APPROVED BY THE TRIAL: CEIm of the Hospital Universitario de Canarias.
7. PERSONS RESPONSIBLE FOR MONITORING ADVERSE EVENTS: 
Dr. Ana Aldea-Perona / Dr. Patricia Rodríguez-Fortunez / Dr. Consuelo 
Rodríguez -                  Jiménez / Dr. Néstor Baez-Ferrer.
8. GROUP AND PHARMACEUTICALS:
Study drug: MORPHINE HYDROCHLORIDE

Morphine hydrochloride: Presentation: vials of 10 mg/ml (1%), 1 ml vial
containing 10 mg*.
Administration: initial i.v. dose: dilute 1 vial in 9 ml of physiological
serum (1ml = 1 mg). Begin slowly administering 2-3 ml of the i.v.
dilution (2-3 mg) and continue every 5 min with 1 ml (1mg) until
achieving the




Estudio MIMO
desired effect, the appearance of secondary effects or reaching the 
maximum total dose of 8 mg (8 ml).
*Other presentations of morphine hydrochloride with concentrations
of 20 mg/ml should not be used.
GROUP II:

Medication under investigation: MIDAZOLAM HYDROCHLORIDE

Midazolam: Presentation: Midazolam injectable solution 1 mg/ml, 5 ml vial
containing 5 mg**.
Administration: initial i.v. dose of 1 mg (1 ml of the vial) that should be
administered in less than 30 seconds. If there is no clinical
improvement the same dose can be repeated (1 mg) every 10
minutes with the same form of administration until achieving the
desired effects, appearance of secondary effects or  reaching the
maximum total dose of 3 mg.
*Other presentations of midazolam with concentrations of 5 mg/ml
should not be used.
9.
TRIAL PHASE: Phase IV clinical trail
10. PRINCIPAL OBJECTIVE: Evaluate the difference in in-hospital survival
of patients with acute pulmonary edema receiving the usual medical treatment after
the addition of midazolam versus morphine.
11. STUDY DESIGN: P r o s p e c t i v e , m u l t i c e n t 
e r , r a n d o m i z e d , o p e n - l a b e l , p h a s e I V c l i n i c a l t r 
i a l .
12.
DISEASE OR DISORDER UNDER STUDY: Acute pulmonary edema
defined as severe respiratory difficulty which worsens in supine, with clinical and
radiological signs of pulmonary congestion requiring urgent treatment.
13. PRINCIPAL OUTCOME VARIABLE: In-hospital mortality.
14. STUDY POPULATION AND TOTAL NUMBER OF PATIENTS: The
total number of patients is 136 with acute heart failure. Sixty-eight (68)
patients will receive treatment with intravenous morphine added to standard
medical therapy for this disease and will be compared with 68 patients who
will receive treatment with intravenous midazolam.


15. STUDY DURATION: our study lasted 4 years and included only 
111 patients during this period. Two reasons may explain this low 
inclusion rate: a) 667 cases were excluded because of the use of 
morphine by emergency medical services before emergency arrival.
16. CALENDAR AND FORESEEN FINALIZATION DATE:
INITIATION: January 2017
FINALIZATION: December 2020
II.   GENERAL
 
  INFORMATION
 
 
A) IDENTIFICATION OF THE TRIAL:
PROTOCOL CODE: MIMO/2016
EudraCT number: 2016-000884-17.
17.TITLE: Multicenter, open-labeled, randomized controlled trial comparing
Midazolam versus Morphine in acute cardiogenic pulmonary edema “MINO trial”
B) TYPE OF CLINICAL TRIAL:
Multicenter, randomized phase IV clinical trial open to the administration of 
midazolam versus morphine in patients with acute pulmonary edema.
Clinical trial with authorized low level of intervention medications.
C) DESCRIPTION OF THE STUDY PROTOCOL
Experimental
 
  drug:
 
  Intravenous solution of morphine hydrochloride
Mechanism of action and pharmacokineetics: Pentacyclin alkaloid. The
structure of morphine is rigid and T-shaped. It is considered to be derived from 
phenanthrene or as a derivative of 4-phenylpiperidine. It is a powerful agonist of 
opioid µ receptors. From a clinical point of view, stimulation of µ receptors 
produces analgesia, euphoria, circulatory depression, reduction of peristaltism, 
myosis and dependence. Other clinical effects which may be produced by opioids
include suppression of cough, hypotension and nausea/vomiting. Hypotension is 
due to a increase in the release of histamine and depression of the vasomotor 


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center of the medulla. The induction of nausea is the result of direct stimulation of


the vestibular system.
The cardiovascular effects of morphine are complex because of the 
involvement of neurogenic, cardiac and vascular factors as well as the 
physiological status of the person. If pulmonary ventilation is ensured, 
cardiovascular function resists the action of morphine. It can produce bradycardia 
of vagal origin, which is more notable if the administration is intravenous. It also 
induces hypotension due to action on the vasomotor center as well as arterial and 
venous vasodilatation which has repercussion on the reduction of after- and 
preload, respectively. Morphine induces vasodilatation of brain circulation due to 
the increase of pCO2, with elevation of intracranial pressure.
Control
 
  drug:
 
  Intravenous solution of midazolam.
Mechanism of action and pharmacokinetics: Midazolam is a drug with a
short depressive action on the central nervous system with sedative and anxiolytic
properties. The half life of elimination is 1-12 hours, and it is rapidly metabolized in
the liver to 1-hydroxyaceyl midazolam and excreted in the urine. Following
intravenous administration, sedation appears in 3-5 minutes and is maximum at 5-
10 minutes.
The  use of morphine and its analogs is mentioned in the 2008 national
guidelines on the management of heart failure (Dickstein K et al. Guidelines for
Clinical Practice of the European Society of Cardiology (ESC) for the diagnosis and
treatment of acute and chronic heart failure (2008) Rev Esp Cardiol.
2008;61(12):1329.e1-1329.e70) in the initial phases of treatment of patients
hospitalized for acute pulmonary edema (APE), especially in cases presenting
agitation, dyspnea, anxiety or chest pain. In patients with APE, morphine alleviates
dyspnea and other symptoms and can favor patient cooperation during the
application of non invasive ventilation. Nonetheless, the same guideline mentions
that the evidence favoring the use of morphine in APE is scarce. When heart
failure is  a  complication  of  ischemic  cardiopathy  or  the  patient  presents
bradyarrhythmias, the use  of  benzodiazepines  is preferred  to  avoid the
hemodynamic effects  of morphine ( Bosomworth J.  Rural  treatment  of acute


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cardiogenic pulmonary edema:




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applying the evidence to achieve success with failure. Can J Rural Med.
2008;13:121-8 /// Ellingsrud C, Agewall S. Morphine  in the treatment of acute
pulmonary oedema--Why? Int J Cardiol. 2016;202:870-3.)
D) STUDY PROMOTER – CHIEF INVESTIGATOR
Dr. Alberto Domínguez-Rodríguez
Servicio de Cardiología. Hospital Universitario de Canarias. Ofra s/n, 38320 
La Laguna. Tenerife.
Telephone: (922) 679040.
E-mail: adrvdg@hotmail.com
E) MONITOR AND PROMOTER CONTACT FOR PHARMACOVIGILANCE
Dr. Ana Aldea-Perona
Servicio de Farmacología clínica 
Hospital Universitario de Canarias
Teléfono: (922) 67 8117
e-mail: a.aldea@gmail.com
FAX: 922 677284
F) INVESTIGATORS:
See list of investigators attached.
G) CENTERS WHERE THE CLINICAL TRIAL WILL BE PERFORMED:
 Hospital Universitario de Canarias, Hospital de la Axarquia, Hospital Clínico de 
Barcelona, Hospital Universitario Reina Sofía de Córdoba, Hospital Universitario 
Reina Sofía de Murcia, Hospital General de Alicante, Hospital Clínico San Carlos 
de Madrid.
H)
IDENTIFICATION 
OF 
THE 
ETHICAL 
COMMITTEE 
OF
INVESTIGATION WITH DRUGS RECIEVING A FAVORABLE REPORT
FOR PERFORMING THE TRIAL: CEIm DEL HOSPITAL UNIVERSITARIO
DE CANARIAS.


.
I) FORESEEN DURATION OF THE TRIAL
Our study lasted 4 years and included only 111 patients during this period.
Two reasons may explain this low inclusion rate: a) 667 cases were excluded
because of the use of morphine by emergency medical services before emergency
arrival.
III.
   JUSTIFICATION
 
  AND
 
  OBJECTIVES
 
  
Acute cardiogenic pulmonary edema is an acute severe disease requiring
emergency treatment. The treatment of chronic heart failure is well defined in the
guidelines and has demonstrated to improve the life expectancy of affected
patients1,2,3. However, in the case of APE, while the currently available diuretics
and vasodilators are widely used they have not been shown to reduce mortality. In
addition, there are few large clinical trials on the treatment of APE in emergency
departments (EDs) and the recommendations of the current guidelines are
supported by only low levels of evidence1,2. Nonetheless, at present it is widely
accepted that the first step in the treatment of APE is immediate treatment in the
ED4,5
The current focus of treatment in patients with APE in the ED is to improve
the signs and symptoms of patients, correct the volume overload, increase the
perfusion of end organs and improve the hemodynamic status counteracting
neurohormonal hyperactivation which constitutes the principal physiological
mechanism of the disease6. It has been demonstrated that an energetic adequate
approach to the treatment of APE is useful to improve the clinical outcomes of the
patients7.
Diuretics continue to be the cornerstone of APE treatment. The current
international guidelines consider that intravenous loop diuretics are the first line
treatment in patients with APE8.
Vasodilatators together with diuretics are the drugs most commonly used for
APE in the ED. These drugs reduce the preload, the afterload or both by producing
arterial and venous dilatation, thereby reducing the left ventricular filling pressure
and increasing the ejection volume and improving the peripheral oxygen supply9.
International guidelines recommend the use of vasodilators in patients with APE as


Estudio MIMO
an adjuvant to diuretic treatment for rapid resolution of the congestive symptoms of
normotensive or hypertensive patients who do not present severe obstructive valve
disease. The vasodilators most commonly used in the treatment of APE are
nitroglycerine and nitroprusiate2.
The use of morphine in the treatment of APE is uncertain. The use of
opioids is contemplated in the Spanish and European guidelines2,3 , in the initial
phase of treatment of patients hospitalized for APE, especially in cases presenting
agitation, dyspnea, anxiety or chest pain. In patients with APE, morphine alleviates
dyspnea and other symptoms and favors patient cooperation during the application
of non invasive ventilation. However, it has been described that morphine reduces
the preload and the heart rate and has sedative properties. On some occasions,
benzodiazepines are used to avoid the hemodynamic effects of morphine10. The
net effect of morphine is a reduction of myocardial oxygen demand11. While the
ESC suppports the use of opioids in the treatment of APE, the same cannot be
said of the American Heart Association12. The guideline  of  the  Heart  Failure
Society of America makes no formal recommendation with regard to morphine, but
does state that it should be used with caution1.
The most common adverse effects of morphine are constipation and
nausea. While constipation is not especially important in the acute medical
context, it has been described that 25-35% of patients report nausea with the
use of morphine13. The European regulations recommend the addition of 10
mg of metoclopramide to counteract  nausea if morphine is administered  2.
Nausea in APE is an unfavorable secondary effect due to subjective malaise
and because  nausea  produces  the  release  of  catecholamines,  and  thus,
increases the afterload13.
A terrible secondary effect of morphine is respiratory depression.
Morphine acts directly on opioid µ receptors located in neurons of nuclei with
bulbous protuberances which participate in the function of the respiratory
center. In humans it especially depresses the respiratory rate, slowing it until
apnea is produced with very high doses or it favors the onset of abnormal
respiratory rates. In addition, morphine produces a loss of sensitivity to CO2 in the
respiratory center while, on the other hand, maintaining sensitivity to hypoxia.
The grade of respiratory depression depends on not only the dose but also the


pathway, being maximum when administered intravenously and minimum when
given orally or by epidural injection14,15.
A recent observational analysis of the ADHERE registry reported that the use
of morphine is associated with a worse clinical evolution, including the need for
mechanical ventilation, longer hospitalization, more admissions to an intensive
care unit and greater risk-adjusted mortality16. It is therefore of interest to perform a
prospective randomized trial to evaluate survival following the use of morphine in
patients with APE.
OBJECTIVE:
1.
Principal objective: Evaluate the difference in in-hospital survival of
patients with acute pulmonary edema who receive the usual medial therapy
and the addition of midazolam versus morphine.
2.
Secondary objectives: 30-day all-cause mortality, use of invasive 
mechanical ventilation and length of hospital stay (from emergency department arrival to
final discharge, either home or due to death). The reporting of adverse event was 
considered the main safety endpoint. A composite endpoint formed by 30-day mortality 
and serious adverse event.
IV.
  TYPE
 
  AND
 
  DESIGN
 
  OF
 
  THE
 
  CLINICAL
 
  TRIAL
 
  
a) Design of the clinical trial
This will be a multicenter, randomized study open to the administration of
morphine  in  patients  with  a  diagnosis  of  acute  pulmonary  edema  requiring
treatment in a hospital emergency department.
Group I: Will receive morphine hydrochloride

Administration: intravenous.

Presentation: 10 mg/ml (1%) vials, vial of 1 ml containing 10 mg*.

Dose and administration: initial i.v. dose: dilute 1 vial in 9 ml of
physiological serum (1ml = 1 mg). Begin administering 2-3 ml (2-3 mg) of
the i.v. dilution slowly and continue every 5 min with 1 ml (1 mg) until


Estudio MIMO
achieving the desired effects, the appearance of secondary effects or until
reaching the maximum total dose of 8 mg.

*Other presentations of morphine hydrochloride with concentrations of 20
mg/ml should not be used.
Group II: Will receive midazolam hydrochloride

Administration: intravenous.

Presentation: injectable 1 mg/ml solution, 5 ml vial containing 5 mg**.

Dose and administration: initial i.v. dose of 1 mg (1 ml of the vial) which
should be administered in at least 30 seconds. If no clinical improvement is
observed the same dose (1 mg) can be repeated every 10 minutes with the
route of administration until achieving the desired effects, the appearance of
secondary effects or until reaching the total maximum dose of 3 mg.

** Other presentations of midazolam with concentrations of 5 mg/ml should
not be used
In addition, both groups will receive the usual systematic treatment for acute
pulmonary edema (diuretics, vasodilators and oxygen therapy).
b) Randomization procedure
At emergency department arrival eligible patients were randomized in a 1:1
ratio to either midazolam (administered intravenously at a dosage of 1 mg, up to a
maximum dose of 3 mg) or morphine (administered intravenously at a dosage of 2-
4 mg, up to a maximum dose of 8 mg) via a password-protected encrypted website
that uses a computer-generated minimization algorithm to ensure balance between
the treatment groups.
c) Blinding process
The administration of the two drugs is not blinded since the administration
dose is different.
V.
  PATIENT
 
  SELECTION 
 
 
A. INCLUSION CRITERIA
A priori all patients attending the emergency departments of the participating


hospitals with a diagnosis of acute pulmonary edema and fulfill the following
conditions will be included in the study:

Age more than 18 years

Symptoms of anxiety and/or acute dyspnea

Consent to participate in the study.
B. EXCLUSION CRITERIA PRIOR TO INCLUSION IN THE STUDY:
Patients with acute pulmonary edema who fulfill any of the following criteria 
will not be included in the study:

Patients receiving kidney dialysis

Severe concomitant disease with short-term prognosis.

Inability to provide informed consent.

Participation in another study.
C. CALCULATION OF SAMPLE SIZE
In a study of a historical cohort of patients included in the ADHERE14 registry
it has been demonstrated that the mortality of patients receiving morphine
compared to those not receiving this drug was 13% versus 2.4%, respectively.
To calculate the sample size of this clinical trial we have assumed the
results of the ADHERE14registry, and thus, for a power of 80% and accepting an
alpha risk of 0.05 and a beta risk of 0.2 in one-sided contrast, 68 subjects are
required for the group receiving morphine and 68 in the group with midazolam to
detect  statistically significant  differences  between  two  proportions,  which  is
expected to be of 13% for group 1 and 2.4% for group 2. A 0% loss to follow-up is
estimated. This sample size allows detecting statistical significance with a p < 0.05.
On the other hand, the participation of the patients in this study is voluntary,
and they can refuse to participate or withdraw from the study whenever they so
wish without this affecting future medical care. Their evolution will be evaluated in
a strict and  fully  complete  manner. After  having  accepted  to  participate,  this
evolution will be immediately registered throughout hospital stay and at the time of
hospital discharge. The participation of patients in this study will not induce added
costs. Likewise, the Principal Investigator of the study can withdraw the patient


Estudio MIMO
without need  for  consent  for any  reason  considered  appropriate,  such  as an
adverse effect which may place the patient at risk of additional complications,
among others.
D. STUDY DURATION
Our study lasted 4 years and included only 111 patients during this period.
Two reasons may explain this low inclusion rate: a) 667 cases were excluded
because of the use of morphine by emergency medical services before emergency
arrival
Recruitment period: January 2017. 
Finalization of the study: December 2020.
VI.
   DESCRIPTION
 
  OF
 
  THE
 
  TREATMENT
 
  
A. STUDY DRUG AND DOSE:
Experimental
 
  drug:
 
  Intravenous solution of morphine hydrochloride
Mechanism of action and pharmacokinetics: Pentacyclic alkaloid. The 
structure of morphine is rigid and T-shaped. It may be considered as derived from 
phenanthrene or as a derivative of 4-phenylpiperidine. It is a powerful agonist of 
opioid µ receptors. From a clinical point of view, stimulation of µ receptors 
produces analgesia, euphoria, circulatory depression, reduction of peristaltism, 
myosis and dependence. Other clinical effects which may be produced by opioids 
include suppression of cough, hypotension and nausea/vomiting. Hypotension is 
due to a increase in the release of histamine and depression of the vasomotor 
center of the medulla. The induction of nausea is the result of direct stimulation of 
the vestibular system.
The cardiovascular effects of morphine are complex because of the 
involvement of neurogenic, cardiac and vascular factors as well as the 
physiological status of the person. If pulmonary ventilation is ensured, 
cardiovascular function resists the action of morphine. It can produce bradycardia
of vagal origin, which is more notable if the administration is intravenous. It also 
induces hypotension due to action on the vasomotor center as well as arterial and
venous vasodilatation which has repercussion on the reduction of after- and 
preload, respectively. Morphine induces vasodilatation of brain circulation due to 


the increase of pCO2, with elevation of intracranial pressure.

Presentation: 10 mg/ml (1%) vials, vial of 1 ml containing 10 mg*.

Dose and administration: initial i.v. dose: dilute 1 vial in 9 ml of
physiological serum (1ml = 1 mg). Begin administering 2-3 ml (2-3 mg) of
the i.v. dilution slowly and continue every 5 min with 1 ml (1 mg) until
achieving the desired effects, the appearance of secondary effects or until
reaching the maximum total dose of 8 mg.
B. CONTROL DRUG AND DOSE
C. Control
 
  drug:
 
  Intravenous solution of midazolam.
D. Mechanism of action and pharmacokinetics: Midazolam is a drug with
a short depressive action on the central nervous system with sedative
and ansiolytic properties. The half life of elimination is 1-12 hours, and it
is rapdily metabolized in the liver to 1-hydroxyaceyl midazolam and
excreted in the urine. Following intravenous administration, sedation
appears in 3-5 minutes and is maximum at 5-10 minutes.
Presentation: injectable 1 mg/ml solution, 5 ml vial containing 5 mg**.
Dose and administration: initial i.v. dose of 1 mg (1 ml of the vial) which
should be administered in at least 30 seconds. If no clinical improvement is
observed the same dose (1 mg) can be repeated every 10 minutes with the
route of administration until achieving the desired effects, the appearance of
secondary effects or until the total maximum dose of 3 mg is reached.
. C. OTHER TREATMENTS
The patients will be treated according to the recommendations of the Spanish 
and European Society of Cardiology for patients with acute pulmonary 
edema2.
The clinical decisions related to the therapeutic management of the patients
will be left to the criteria of the attending physician.
VII.
 
  DEVELOPMENT
 
  OF
 
  THE
 
  TRIAL
 
  AND
 
  EVALUATON
 
  OF
 
  RESPONSE
 
 


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At the beginning of the study informed consent will be obtained from all the
patients, and the demographic data of the patients will be registered.
A. EVALUATION OF EFFICACY
The primary end point for comparing midazolam and morphine was in-
hospital all-cause mortality. The secondary end points were 30-day all-cause
mortality, use of invasive mechanical ventilation and length of hospital stay (from
emergency department arrival to final discharge, either home or due to death).
The final adjudication of outcomes was performed at a local level by the principal
investigator  of  the  center  because  of  the  objectivity  of  the  endpoints.  The
reporting  of  adverse  event  was  considered  the  main  safety  endpoint.  A
composite endpoint formed by 30-day mortality and serious adverse event.
B. STUDY FOLLOW-UP
Patients of both sexes will be included. 
The design of the study is summarized in Annex I.
VIII.
 
 ADVERSE
 
  EVENTS
 
 
A. DEFINITIONS
An adverse event (AE) will be defined as any event that occurs during the
clinical study whether it be an intercurrent or incidental disease and alters the well-
being of the patient. An AE may also be considered as a laboratory abnormality.
The term AE does not imply any causal relationship with the study treatment.
All the AE, including intercurrent diseases will be notified and registered as
described below.
The AEs will be divided into categories of severe and non severe, which will
determine the procedure to follow for the notification and reporting of the same.
An adverse reaction will be defined as any harmful and non 
intentional reaction to the drug under study, independently of the dose 
administered. An adverse reaction will be considered as unexpected if its nature 


or severity does not correspond with the product information (Summary of Product
Characteristics and the study drug file).


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Diseases or medical conditions present prior to initiating the study will only
be considered as AE if they worsen following the initiation of treatment.
Abnormal laboratory values or results will only be considered as AE if they
cause clinical signs or symptoms or require treatment. Whenever possible, each
AE will also be described based on:
      The grade of severity (mild, moderate and severe).
       The relationship with the study drug (suspected/not suspected).
      The actions taken and, if relevant, the result.
Special attention should be given to withdrawal from treatment due to AE
and, if adequate, perform statistical analyses.
B. SEVERE ADVERSE EVENTS OR ADVERSE REACTIONS
A severe adverse event or adverse reaction is defined as:
-
Any event causing death or threatening the life of the patient.
-
Any event producing permanent discapacity.
-
Any event requiring or prolonging hospitalization.
-
Any event involving cancer, congenital abnormalities or that is the
consequence of an overdose (administration of a dose greater than stipulated).
Hospitalization occurring under the following circumstances will not be
considered as severe adverse events: programmed before including the patient in
the study, related to the treatment, occurs in an out-patient emergency regimen
without the need for admission (provided that the previous criteria are met) or
make up part of the normal treatment or monitoring of the indication studied and
are not associated with worsening of the disease.
C. NON SEVERE ADVERSE EVENTS OR ADVERSE REACTIONS.
Adverse events or adverse reactions that do not pertain to any of the above 
mentioned categories will be classified as non severe.


D. CLASSIFICATION OF THE INTENSITY AND 
RELATIONSHIP WITH THE TREATMENT
Classification of intensity
Regardless of whether the adverse event is classified as severe or
non severe (see previous sections), the intensity will be evaluated as mild,
moderate or severe according to exclusively medical criteria.
- Mild: Does not impede routine activities
- Moderate: Interferes with routine activities
- Severe: Makes routine activities impossible
It should be taken into account that a severe adverse event may not
necessarily be severe and that a severe adverse event is not always, by
definition, severe.
All severe adverse events, regardless of their severity, will be
registered as described below.
Relationship with treatment
The investigator should attempt to explain and evaluate the
relationship of every adverse event with the study treatment (probable,
possible, no relationship). The criteria to establish the relationship between
adverse clinical reactions and the study drug include:
Probable:
An adverse event is considered to have a probable relationship with
the drug if it fulfills the following 3 criteria:
 There is a reasonable temporal relationship between administration of the 
drug and the presentation of the adverse event and
2.
It fulfills any of the following criteria:
The adverse event is a typical example of a known adverse reaction to 
the drug so that:
-
If treatment is continued, the adverse event will persist.


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-
If drug administration is discontinued, the adverse event will disappear.
-
In the case of re-exposure to the drug, the adverse event will reappear.
3. In the case of another explanation for the adverse event (concomitant
treatment, intercurrent disease), this explanation is less probable as a cause of the
adverse event.
Possible:
An adverse reaction is considered to possibly be related to the drug if 
it fulfills the two following criteria:
1. There is a reasonable temporal relationship between the administration of
the drug and the adverse event.
2.
None of the criteria established in previous point 2 (probable) are met 
or there is another alternative more plausible explanation for the adverse event.
No relationship:
An adverse event will be classified as having no relationship with the 
drug if it fulfills any of the following requisites:
1.
There is no reasonable temporal relationship between 
administration of the drug and the onset of the adverse reaction.
2. A causal relationship between the drug and the adverse event is 
not plausible from a biological point of view.
3. There is a more plausible alternative explanation for the appearance of
the adverse event.
E. MONITORING, NOTIFICATION AND REGISTRATION OF THE
ADVERSE EVENTS AND ADVERSE REACTIONS.
Monitoring
All the patients presenting adverse events related or not to the study drug
will be  monitored  until  the  disappearance  of  the  symptoms,  laboratory
abnormalities have returned to the baseline values or until there is a satisfactory
explanation for the changes observed.


Actions to carry out in response to an adverse event
The measures to be taken on the appearance of an adverse event are
described on a numerical scale from 0 to 5 covering different possibilities. One or
more possibility should be selected.
Grade  1  Mild;  asymptomatic  or  mild  symptoms;  clinical  or  diagnostic
observations only; intervention not indicated. Grade 2 Moderate; minimal, local or
noninvasive intervention indicated; limiting age appropriate instrumental activities
of daily living. Grade 3 Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling;
limiting self care activities of daily living. Grade 4 Life-threatening consequences;
urgent intervention indicated. Grade 5 Death related to adverse events.
Notification and registration:
Adverse events which develop during the trial will be classified as severe 
and non severe because this classification will determine the procedure to follow 
for the notification and registration of these events.
Diseases or medical conditions present prior to initiating the study treatment
will only be considered as adverse events if they worsen after beginning the
treatment.
Abnormal laboratory values or test results will only be considered as
adverse events if they cause clinical signs or symptoms or require treatment.
Whenever possible, each adverse event will also be described based on:
      - Duration (date of initiation and finalization)
- The grade of severity (mild, moderate and severe).
- The relationship with the study drug (suspect/ not suspected).
- The action(s) taken, and, if relevant, the result.
- Special attention should be given to the withdrawal of treatment 
due to adverse events and, if appropriate, statistical analyses will 
be performed.
Severe and unexpected adverse events and adverse reactions:


Estudio MIMO
All severe adverse events must be reported within 24 hours to the Chief
Investigator of the study, Dr. Alberto Domínguez-Rodríguez, at the email address
adrvdg@hotmail.com. The initial communication will be followed by a detailed
written report.
In the initial reporting and in that of the follow-up, each study subject will be
identified by a specific code number.
In the case of death of a study participant, the investigator will provide the
promoter and the Ethical Committees of Clinical Investigation involved with all the
complementary information requested.
The Coordinator will notify the Spanish Agency of Medication and Health
Care Products and the Center of Pharmacovigilance of Canarias (authority of the
Autonomous Community), of all suspicions of a severe adverse reaction and, in
turn, unexpected adverse events associated with the study drug during the trial.
The maximum notification time will be of 15 days from the time the Promoter was
notified of the suspicion of an adverse reaction. If the suspected and unexpected
adverse event  leads to  the  death  of  the  subject  or  threatens  the  life  of  the
participant, the Promoter will inform the Spanish Agency of Medication and Health
Care Products within a maximum time of 7 days from the time at which the
Promoter is made aware of the case. This information will be completed as far as
possible within the following 8 days.
The Coordinator will maintain a detailed registry of all the adverse events
reported by the investigators. These registries will be presented to the Spanish
Agency of Medication and Health Care Products upon request.
The periodic safety report will be presented annually to the Spanish Agency
of Medication and Health Care Products and the Center of Pharmacovigilance of
the Canarias (competent organ of the Autonomous Community) and to the CEIm
involved in the study until the end of the trial and whenever requested by the health
care authorities or the ethical committees involved in the study.
The Coordinator will continuously evaluate the safety of the study drug using
all the information available. Likewise, any relevant information involving the safety
of the study drug will be reported without delay to the   Spanish Agency of
Medication and Health Care Products and the Center of Pharmacovigilance of


Canarias (competent organ of the Autonomous Community) and to the CEIm.
The investigators will also be informed about any subject related to the
safety of the study drug and the risk/benefit ratio.
Non severe adverse events or adverse reactions:
These events will be reported in the “adverse events” sheet of the “Data
Collection Notebook” and it will not be necessary to follow any special notification
procedure. Nonetheless, these adverse events or adverse reactions will be
reported in the periodic safety report.
F. CONTACT ADDRESSES FOR THE NOTIFICATION 
OF ADVERSE EVENTS.
All investigators will notify the Chief-Investigator (Dr.Alberto Domínguez-
Rodríguez) of severe adverse events within 24 hours:
adrvdg@hotmail.com
Telephone number: 922679040
Fax number: 922677284
The coordinator will report all suspicions of severe and unexpected adverse
reactions to the health care authorities according to the previously established
times and procedures.
Notification to the Spanish Agency of Medications will be made using the
FAX number +34 918 225 076.
Notification to the corresponding Center of Pharmacovigilance can be made
by fax or by post.
IX.
  ETHICAL
 
  ASPECTS
 
 
The trial will be performed according to the principles of the Declaration of
Helsinki adopted by the 18th World Medical Assembly, Helsinki, Finland in 1964 
and amended in Tokyo (1975), Venecia (1983), Hong Kong (1989), South Africa 


Estudio MIMO
(1996), Edinburg (2000), Washington (2002), Tokyo (2004), Seoul (2008)and 
Brazil (2013); the Norms of Good Clinical Practice of the International 
Harmonization Conference (CPMP/ICH/135/95) and the laws and regulation 
prevailing in Europe and Spain.
The Coordinating Principal Investigator has presented the protocol to the
pertinent Ethical Committee of Investigation of Medication and the trial has been
approved.  Likewise, approval from the health care authorities will be requested
prior to initiation of the trial.
Patients should be adequately informed of the trial and must provide written
informed consent. In particular, the following points should must be explained to
the patients: Study objective, therapeutic actions and possible secondary effects,
duration of the study, potential benefits, other possible therapeutic alternatives,
freedom of the patient to choose to participate or not in the trial and decide to
prematurely withdraw at any time without this representing any negative
consequence to the patient.
All the participants in the trial, the objective and the study content will be
managed with confidentiality. The clinical trial will be performed respecting the
rights of the subjects and the ethical postulates affecting biomedical investigation
in humans. The physical and mental of the subject will be particularly safeguarded
as well as their privacy and the protection of their data according to Organic Law
15/1999, of December 13, on the Protection of Data of Personal Nature. Informed
consent will be obtained and documented from each of the study subjects, being
freely provided prior to inclusion in the study under the terms foreseen in Article 4
of Royal Decree 1090/2015.
X.
   PRACTICAL
 
  CONSIDERATIONS
 
  
RESPONSIBILITIES
A) RESPONSIBILITIES OF THE INVESTIGATOR
Approval of this protocol by the Principal Investigator and collaborating
investigators will be confirmed by their corresponding signatures (Annex II).
Prior to the inclusion of a patient, the investigator should provide the


Spanish Agency  of  Medications and  Health  Care  Products  with  the  following
documents (copies of which should be maintained by the investigator in the files
which will include):
- Signed copy (original) of the approved protocol
- Completed and signed declaration of the investigator.
- Copy of the approval document signed by the Ethical Committee of 
Clinical Investigation.
- Conformity of the Director of the Center.
- Sample of informed consent document to be used.
- List of normal laboratory values of the center in question.
All the information indicated in this protocol will be carried out in accordance
with the Norms of Good Clinical Practice. This includes the possibility of inspection
at any time by representatives of the health care authorities. The investigators will
provide their conformity with the inspection of the study documents by
representatives of the health care authorities.
In addition to all the local regulations applicable, the investigator should
respect the following principles:
1*     Declaration of Helsinki
2*
Spanish Law of Medication
3*
Local norms
4*
European norms of Good Clinical Practice
B) OTHER RESPONSIBILITIES OF THE 
COORDINATING INVESTIGATOR
All the Data Collection Notebooks and crude data will be conserved in the
Work Center, under the custody of the Principal Investigator during a 
minimum of 10 years after study finalization. The data will be conserved 
while the product remains authorized. In the case of expiry of product 
commercialization, the final report of the trial will be conserved by the 
promoter during an additional 5-year period. The informed consent 
documents of the patients will be conserved by the investigators for an 
equal period of time.


Estudio MIMO
DATA REGISTRY AND TREATMENT
This will be performed following the norms of Royal Decree 1090/2015,
which establishes the requisites for performing clinical trials with medications.
A) REPORTING IN THE DATA COLLECTION 
NOTEBOOKS, SIGNATURE AND FILING
The Data Collection Notebooks will be supplied by the Promoter-Principal
Investigator. These documents will be used to report all the information collected
along the development of the study to the health care authorities. All the Data
Collection Notebooks should be completed by machine or with capital letters in
black ink. Corrections should be made by simply crossing out incorrect data with a
line and writing the new data alongside. All the corrections should be initialed by
the person who made them together with the date and the reason for correction.
The corrected data should not be crossed out so that it is impossible to
read and neither should corrector fluid or an eraser be used.
A copy of the Data Collection Notebook of each patient can be sent to the
General Pharmacy Administration before finalizing the study, when required by the
health care authorities. The investigator will conserve the original notebook.
Likewise, the investigator or the person designated by the investigator will be
responsible for noting all the data in the Data Collection Notebooks, and will be
certified by their signature and date on the opportune pages.
B) SOURCE DATA FILE
All the correspondence related to this clinical study should be conserved
in the adequate files.
The registries of the patients, the source documents, the Data Collection
Notebooks, the medication inventary and the correspondence between the Ethical
Committee and the Promoter should be filed. The investigator should conserve the
patient identification codes for a minimum of 15 years after finalization or
suspension of the trial. The clinical histories of the patients and other data should
be conserved during a maximum period of time allowed by the hospital, institution
or private practice.
If an investigator is transferred to another center, withdraws from the
investigation or retires, the responsibility of the conservation of the registries can


be transferred to another person (i.e. another investigator) who agrees to accept
this responsibility. The Promoter-Principal Investigator will be notified and agree to
the transfer of information.
C) DATA MANAGEMENT AND CONTROL
In addition to the Data Collection Notebooks, the investigator should maintain the 
remaining registries of the subjects including the dates of the revisions and the data 
referring to: vital signs, medical history or examinations performed, eventual adverse 
events and findings and all other opportune notes. All this information constitutes the 
“original data”. All the data registered in the Data Collection Notebooks should be 
supported by the original data.
The Data Collection Notebooks should be adequately maintained and
updated so that they always reflect the last observations of the patients included in
the study.
The history of each patient should be together with the signed Informed
Consent. When the study treatment has finalized, the Informed Consent should be
filed with a copy of the Data Collection Notebook, which will include a note
indicating where this can be found.
All the original laboratory reports should be available for review in the file of
each subject. It is important for the original reports to be available for review due to
the possibility of inaccuracies or confusions being produced in the transcription of
the data from the original documents to the Data Collection Notebooks.
For each subject included in the study, the Data Collection Notebook should
be completed in a legible form signed by the investigator. This will be done as soon
as possible after finalization of the treatment. The study monitor will review the
Data Collection Notebooks.
After finalization or suspension of the trial, the investigator should conserve
the patient identification codes for at least 15 years. The histories of the patients
and the remaining data sources should be conserved during the maximum period
allowed by the hospital.
D) VERIFICATION OF THE STUDY DATA
Both the study Monitor and the health care authorities can compare the data
of the Data Collection Notebooks with the source documents.


Estudio MIMO
SAMPLES
A) SAMPLE MANAGEMENT AND CONSERVATION
The Pharmacy Department will supply the study samples according to
normalized working procedures.
The Pharmacy Department will maintain a control sheet of the samples that
will be filled in as the samples are supplied to the patients.
XI.
  STATISTICAL
 
  ANALYSIS
 
 
Information in the final plan for statistical analysis.
XII.
 
  PUBLICATIONS
 
 
The data obtained in the clinical trial are the property of the Promoter. They
will be used in conjunction by the members of the investigative team of the project
and not in an individual manner. Authorization from the Promoter will be necessary
for general diffusion or publication of data, information or results related to the trial.
The Promoter and the Principal Investigators are obliged to publish the results,
whether positive or negative, of the trial in scientific journals and include mention of
the Ethical Committee of Investigation with the drugs approved for the study.
XIII.
 
  REFERENCES.
 
 
1. Heart Failure Society of America. HFSA 2010 Comprehensive Heart
Failure Practice Guideline. J Card Fail. 2010; 16:e1-e194.
2. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M,
Dickstein K, et al. ESC guidelines of the diagnosis and treatment of
acute and chronic heart failure 2012: the task Force for the diagnosis
and Treatment of Acute and Chronic Heart Failure 2012 of the
European Society of Cardiology. Developed in collaboration with the
Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;
14:803-69.


3. McMurray JJ, et al. Guía de práctica clínica de la Sociedad Europea
de Cardiología (ESC) para el diagnóstico y tratamiento de la
insuficiencia cardiaca aguda y crónica (2012) . Rev Esp Cardiol.
2012;65(10):938.e1-e59.
4. Collins S, Storrow AB, Kirk JD, Pang PS, Diercks DB, Gheorghiade
M. Beyond pulmonary edema: diagnostic, risk stratification, and
treatment challenges of acute heart failure management in the
Emergency department. Ann Emerg Med. 2008; 51:45-57.
5. Collins S, Levy PD, Lindsell CJ, Pang PS, Storrow AB, Miller CD, et
al. The rationale for an acute heart failure syndromes clinical trials
network. J Card Fail. 2009; 15:467-74.
6. Di Somma S, Magrini L. Drug Therapy for Acute Heart Failure. Rev
Esp Cardiol (Engl Ed). 2015;68:706-13.
7. Peacock WF, Allegra J, Ander D, Collins S, Diercks D, Emerman C,
et al. Management of acute decompensated heart failure in the
emergency department. Cong Heart Fail. 2003; 9(Suppl 1):3-18.
8. Peacock WF, Fonarow GC, Emerman CL, Mills RM, Wynne J,
ADHERE Scientific Advisory Committee and Investigators; Adhere
Study Group. Impact of early initiation of intravenous therapy for
acute decompensated  heart  failure  on  outcomes  in  ADHERE.
Cardiology. 2007; 107:44-51.
9. Joseph SM, Cedars AM, Ewald GA, Geltman EM, Mann DL. Acute
decompensated heart failure. Contemporary medical management.
Tex Hearst Inst J. 2009; 36:510-20.
10. Lee G, DeMaria AN, Amsterdam EA et al. Comparative effects of
morphine, meperidine and pentazocine on cardiocirculatory dynamics
in patients with acute myocardial infarction. Am J Med 1976;60:949–
955.
11. Coons JC, McGraw M, Murali S. Pharmacotherapy for acute heart
failure syndrome. Am J Health Syst Pharm. 2011; 658:21-35.
12. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS,


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Ganiats TG, et al.ACCF/AHA guidelines for the diagnosis and
management of heart failure in adults: a report of the American
College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines. J Am Coll Cardiol. 2009; 54:1343-82.
13.Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J
Pharmacol. 2014;722:67-78.
14. Radke JB, Owen KP, Sutter ME, Ford JB, Albertson TE. The effects
of opioids on the lung. Clin Rev Allergy Immunol. 2014;46:54-64.
15.Pattinson KT. Opioids and the control of respiration. Br J Anaesth.
2008; 100:747-58.
16. Peacock WF, Hollander JE, Diercks DB, Lopatin M, Fonarow G,
Emerman CL. Morphine and outcomes in acute decompensated
heart failure: an ADHERE analysis. Emerg Med J. 2008; 25:205-9.


Estudio MIMO
ANNEX
 
  I:   STUDY
 
  DESIGN
 
  AND
 
  PLANNING
 
  
Procedure
Selecti
on 
Day
0
Da
y
1
D
a
y
2
D
a
y
 
3
D
a
y
 
4
D
a
y
 
5
D
a
y
 
6
Remaining
admissi
on 
period
Stay in 
ICU
Hospi
tal stay
Clinic
al 
histor
y
X
Physical
examinati
o n
X
Check
inclusio
n 
criteria
X
Check 
exclusio
n
criteria
X
Informe
d 
consen
t
X
Administrati
on 
MORPHIN
E
or 
MIDAZOL
A
M
X
Collection
of
demograp
hi c
characteri
sti cs
X
X
X
X
X
X
X
X


Collectcio
n of 
analytical
characterist
ic s and 
ECG
X
X
X
X
X
X
X
X
Collection 
of in-
hospital 
treatment
X
X
X
X
X
X
X
X
X
33


Estudio MOME
Collection 
of
clini
cal 
eve
nts
X
X
X
X
X
X
X
X
X
X
* Clinical events: in-hospital mortality, need for invasive mechanical ventilation, need for cardiopulmonary resuscitation.


34


Estudio MIMO
ANNEX II
COMMITMENT OF THE INVESTIGATOR
………………………………………………………………………………
States that:
They recognize and accept to participate as Principal Investigator in the
clinical trial with the protocol code MIMO/2016, EudraCT number: 2016-000884-17,
entiled:  Multicenter, Open-Labeled, Randomized Controlled Trial Comparing
Midazolam versus Morphine in Acute Cardiogenic Pulmonary Edema (MIMO
trial).
They commit to managing and controlling each subject according to what
has been  established  in  the  protocol  authorized  by  the  Ethical  Committee  of
Clinical Investigation and by the General Pharmacy and Health Care Products
Administration.
They will respect the ethical norms applicable to this type of study.
This trial will be carried out in the Emergency Department.


Estudio MIMO
ANNEX III. 
INVESTIGATOR MANUAL
1. Importance of acute pulmonary edema
Acute pulmonary edema is an acute and potentially severe heart disease.
According to international guidelines, when patients with acute pulmonary edema
arrive at the emergency department, the usual therapeutic focus is aimed at
improving the signs and symptoms, correct the volume overload and improve
cardiac hemodynamics increasing perfusion of the vital organs. The treatment
recommended for immediately treating acute pulmonary edema is characterized by
the use of intravenous diuretics, oxygen therapy and vasodilators. Although these
measure alleviate the symptoms, they do not have a favorable influence on short-
and long-term mortality.
Another drug that is used is morphine due to its expected anxiolytic and
vasodilator effects. However, during the last decade there has been debate about
the benefits and risks that accompany the use of this drug in the case of acute
pulmonary edema. The retrospective ADHERE study performed in 2008 reported
that the use of morphine constitutes an independent predictive variable of hospital
mortality with an odds ratio of 4.8 (95%CI: 4.52-5.18, p < 0.001)14.
2. Reasons that justify a clinical trial with morphine
The guidelines of the European Society of Cardiology2 support the use of
morphine for the treatment of acute pulmonary edema. However, the Heart Failure
Society of America1, does not make a formal recommendation with respect to
morphine but sustains that it should be used with caution. Therefore, a prospective
randomized clinical trial should be performed to evaluate the utility or not of
morphine in acute pulmonary edema


Estudio MIMO
4. What is morphine?
It is a pentacyclic alkaloid derived from 4-phenylpiperidine. It is a powerful
agonist of opioid µ receptors. From a clinical point of view, stimulation of µ
receptors produces  analgesia,  euphoria, circulatory  depression,  reduction of
peristaltism, myosis  and  dependence.  Other  clinical  effects  which  may  be
produced  by  opioids 
include  suppression  of  cough,  hypotension  and
nausea/vomiting. Hypotension is due to a increase in the release of histamine and
depression of the vasomotor center of the medulla. The induction of nausea is the
result of direct stimulation of the vestibular system.
The cardiovascular effects of morphine are complex because of the involvement of
neurogenic, cardiac and vascular factors as well as the physiological status of the 
person. If pulmonary ventilation is ensured, cardiovascular function resists the action of 
morphine. It can produce bradycardia of vagal origin, which is more notable if the 
administration is intravenous. It also induces hypotension due to action on the vasomotor 
center as well as arterial and venous vasodilatation which has repercussion on the 
reduction of after- and preload, respectively. Morphine induces vasodilatation of brain 
circulation due to the increase of pCO2, with elevation of intracranial pressure.
In addition, morphine has a supposed anxiolytic effect which, together with 
the sedative effect, reduces the activity of the sympathetic nervous system.


Estudio MIMO
ANNEX IV 
NORMALIZED WORK PROCEDURES
I. GOOD CLINICAL PRACTICE NORMS OF THE COMMITTEE OF
PHARMACEUTICAL SPECIALTIES OF THE EUROPEAN COMMUNITY (2004)
OBLIGATIONS
 
  OF
 
  THE
 
  PROMOTER,
 
  MONITOR,
 
  AND
 
  INVESTIGATOR
 
 
PROMOTER
The responsibilities of the CHIEF INVESTIGATOR are:
1. Choose the investigators after considering their adequacy and availability
of the study centers and the means of these centers. Verify the qualifications of the
investigators and ensure their availability along the duration of the study and verify
the conformity of the investigators to carry out the study as it is established in the
protocol, according to the norms of Good Clinical Practice and acceptance of the
procedures of verification, audits and inspections.
2.
Provide the investigator with chemical/pharmaceutical, toxicology,
pharmacologic and clinical information (including previous and ongoing trials) that
justify the nature, scale and duration of the study as a previous requisite for
planning the trial. Inform the investigator regarding all new relevant information that
emerges during the development of the study. All relevant  information will be
included in the investigator manual which will be complemented and/or updated by
the Promoter provided that new pertinent information is available.
3. Present the notification/request to the opportune authorities (when
indicated) and ensure the presentation of all the documents necessary to the
Ethical Committee of Clinical Investigation and ensure the communication of all
modifications or violations of the protocol as the change might affect the safety of


Estudio MIMO
5. For references purposes, conserve sufficient samples of each lot together
with a registry of the analyses and characteristics.
6. A registry of the quantities of the investigation products should be kept,
including the lot and series numbers. The Promoter should check that the
investigator establishes an adequate manipulation and conservation system in
their institution and ensure safe use of the study products delivered.
7. Arrange  the  availability and ensure  permanent training of  adequately
trained monitors and assisting clinical investigation personnel.
8. Designate the appropriate individuals and/or committees for the
management, supervision, data management, statistical processing and writing of
the trial report.
9. Together with the investigator, rapidly consider all severe adverse events
and take the necessary adequate means to safeguard the interests of the study
subjects and inform the pertinent authorities according to the requirements.
10. Rapidly inform the investigator of all relevant information that becomes
available during the development of the trial and verify that, when necessary, the
investigator(s) notify the Ethical Committee.
11. Ensure the preparation of a final global trial report that is adequate for
health care registry purposes when necessary, regardless of whether the trial is
completed or not. From the safety point of view, data uptakes may be necessary.
12. Provide adequate compensation and adequate treatment of the subjects
in the case of lesion or death related to the study and adequate coverage (legal
and economical) to the investigator, except in the case of malpractice or
negligence.
13.
Agree with the investigator(s) as to the assignment of responsibilities in
relation to data processing, statistical analyses, result reporting and publication
policy.


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1. Work according to predetermined Normalized Work Procedures, visit the
investigator before, during and after the study to control the fulfillment of the
protocol and ensure that all the data have been correctly collected and reported
and that the informed  consent  of  the  study  subjects  has  been  obtained  and
registered prior to their participation in the study.
2. Verify that the study center has adequate space, means (including
laboratories), equipment and personnel and that during the study the appropriate
number of subjects has been recruited.
3. Verify that all the personnel that will assist the investigator in the study
have been adequately informed about the study and fulfill the study requisites.
4. Rapidly enable and ensure communication between the investigator and
the Chief Investigator at all times.
5. Compare the data of the Data Collection Notebooks with the source
documents and report any error/omission to the investigator.
6.
Verify that the storage, distribution, return and documentation of the
product(s) delivered during the study are adequate and correct and are in
accordance with local norms.
7. Help the investigator in the case of requiring notification/request before
the pertinent organisms.
8. Help the investigator report the study data and results to the Promoter.
9. Elaborate a written report after each visit (monitor report) and after all
telephone calls, letters and other relevant contacts with the investigator (audit of
document verification).
INVESTIGATOR
The responsibilities of the investigator are:
1. Know in detail the properties of the product(s) under investigation


Estudio MIMO
3. Provide retrospective data on the values of patients who previously
satisfied the inclusion criteria proposed by the study with the aim of ensuring that
the study will have an adequate subject recruitment time.
4. Present an updated curriculum vitae and other credentials to the
Promoter and, when necessary, to the pertinent authorities.
5. Agree with the protocol, sign it together with the Promoter and confirm in
writing that the protocol has been read, understood and will be carried out as
established and according to the norms of Good Clinical Practice, accepting
inspections by the monitor and control procedures and being in agreement with the
publication policy of the Promoter.
6. Name (if appropriate) a local study coordinator who can help in managing
the study.
7. Present the notification / request to pertinent organisms, including the
administration  of  the  hospital  and  the  Ethical  Committee  together  with  the
Promoter when indicated.
8. Provide the pertinent information to all the members of the team
participating in the study or in other aspects of patient treatment.
9. Obtain the informed consent from the study subjects prior to their
inclusion in the study.
10. Establish a system in relation to the medical study products that ensures
that these products from the Promoter are correctly received by a specific person
(for example; a pharmacist) and that the delivery is registered, the study products
are manipulated and stored safely and adequately, the study products are only
delivered to the study subjects according to the protocol, and all the products that
concordance between the registries of medication delivery and those used and
returned. All possible discrepancies should be explained. The documents of


Estudio MIMO
when necessary,  the  Ethical  Committee  (and  the  pertinent  authorities  when
indicated) in the case of severe adverse events and take the appropriate measures
to safeguard the interests of the study subjects.
14. Facilitate all the data to the Promoter / monitor and the pertinent
authorities (when required) for purposes of verification /audit / inspection.
15. Sign and send the data (Data Collection Notebook), results and
interpretations (analyses and reports) of the study performed in the center to the
Promoter (and the pertinent authorities when indicated). These documents should
also be signed by the collaborators of the investigator and those responsible for the
analyses (including statistical analyses) and interpretation of the results.
16. Coordinate and sign the Final Study Report. In multicenter type studies,
the signature of the Coordinator Investigator may be sufficient if established in the
protocol.
17. Ensure that the confidentiality of all the information of the study subjects
is respected by all the persons participating in the study as well as the information
provided by the Promoter.
18. Follow the points below especially related to patient care:
1* The investigator is medically responsible for the subjects under their care
during the study, and it should be assured that after the study these patients
continue to receive the appropriate medical care.
2* Significant clinical alterations of laboratory values or clinical observations
should be followed until the recovery of the subjects after finalizatin of the study.
3* The medical records of the patients should clearly indicate that the
subject is participating in a clinical trial.
DOCUMENTATION FILING PROCEDURE
All the information corresponding to this study will remain in a safe file that


Estudio MIMO
Promotor and the Investigators are committed to saving the documentation during
the time established in Article 43 of Royal Decree 1090/2015 regarding Clinical
Trials with Medications.
III. MONITORING PROCEDURE
In the present trial the monitoring actions are designed to:
1*
Ensure ethical and technical correction in the performance of the study
2*
Obtain data coinciding with the real findings.
3*
Have documents which in all cases allow following information 
from its origin so that it can be verified.
Monitoring will be carried out by Dr. Ana Aldea Perona, study monitor
according to the established monitoring plan.
Additionally, the investigators will hold bimonthly meetings along the study 
period. The data collected in the Data Collection Notebooks will be transferred to a 
database elaborated in SPSS for Windows software for posterior statistical analysis. 
The specific study database will be operative from the introduction of the first patient 
in the study and will be completed the same day that information from the Data 
Collection Notebooks is added under the responsibility of the Principal Investigator. 
This will allow a new validation of the information collected in the Data Collection 
Notebooks in order to detect uncorrected noted values or values outside a 
reasonable range. The database used will include the necessary statistics to explore 
the data weekly and detect outliers. This wills complete the validation and 
verification
of the data.
IV.
OTHER INFORMATION.
The regulation of the procedures of supply, registry and the dispensing
destination as well as the procedure for the notification of adverse event is


Estudio MIMO

SAP_001.pdf: 
StaƟsƟcal Analysis Plan
SAP Version Number 
1.0


This document is the StaƟsƟcal Analysis Plan (SAP) for the MIMO trial, and
should be read in conjuncƟon with the current trial protocol. This SAP details the
proposed analyses and presentaƟon of the data for the main paper(s) reporƟng
the results for the MIMO trial. The results reported in these papers will follow
the strategy set out here. The analysis will be carried out by an appropriately
qualiﬁed staƟsƟcian, who should ensure integrity of the data during their data
cleaning processes.
The complete MIMO protocol has been published previously1. In brief, MIdazolan
versus Morphine in acute cardiogenic pulmonary edema (MIMO) Trial compared the
eﬃcacy and safety of midazolam versus morphine head-to-head using a randomized,
single-blinded, mulƟcenter design.
The primary end point for comparing midazolam and morphine was in-hospital all-cause
mortality.  The  secondary  end  points  were  30-day  all-cause  mortality,  use  of  invasive
mechanical venƟlaƟon and length of hospital stay (from ED arrival to ﬁnal discharge, either
home or due to death). The ﬁnal adjudicaƟon of outcomes was performed at a local level by
the principal invesƟgator of the center because of the objecƟvity of the endpoints.
The  reporƟng  of  adverse  event  was  considered  the  main  safety  endpoint.  A
composite endpoint formed by 30-day mortality and serious adverse event.
1.- INTRODUCCION
2.- BACKGROUND AND RATIONALE
3.-  TRIAL OBJECTIVES
3.1. Eﬃcacy assessment
3.-  TRIAL OBJECTIVES
3.2. Safety assessment


MIMO  is  a  prospecƟve,  randomized  open-label  blinded  endpoint  clinical  trial
comparing the use of Midazolam and Morphine in paƟents with acute pulmonary
edema1.
Midazolam (administered intravenously at a dosage of 1 mg, up to a maximum dose
of 3 mg).
Morphine (administered intravenously at a dosage of 2-4 mg, up to a maximum dose
of 8 mg).
At emergency department arrival eligible paƟents were randomized in a 1:1 raƟo to
either midazolam  or  morphine via a password-protected encrypted website that
uses a computer-generated minimizaƟon algorithm to ensure balance between the
treatment groups.
Power  calculaƟon  was  determined  by  retrospecƟve  analysis  of  the  Acute
Decompensated Heart Failure NaƟonal Registry (ADHERE), in which among 147,362
hospitalizaƟons, 20,782 (14.1%) received morphine and 126,580 (85.9%) did not.
PaƟents who received morphine  showed a greater mortality (13.0% vs. 2.4%)2.
Therefore, we esƟmated that 136 paƟents (68 paƟents per group) were needed to
have an 80% power with a two-sided type I error of 5% to detect a staƟsƟcally
signiﬁcant diﬀerence between the two groups.
4.-  TRIAL METHODS
4.1. Trial design
4.-  TRIAL METHODS
4.2. Trial intervenƟons
4.-  TRIAL METHODS
4.3. RandomisaƟon
4.-  TRIAL METHODS
4.4. Sample size.


The objecƟve of the trial is to test the superiority of one intervenƟon to 
another as well as to assess the safety.
Null
 
  Hypothesis
 
  for
   primary
 
  outcome and safety 
 
 :
No diﬀerence in the in-hospital all-cause mortality neither in the adverse events 
when comparing a strategy of midazolam versus morphine in paƟents with acute 
cardiogenic pulmonary edema.
AlternaƟve
 
  Hypothesis
 
 :
Use of midazolam versus morphine in paƟents with acute cardiogenic pulmonary
edema is superior based in the in-hospital all-cause mortality and adverse events.
A joint oversight commiƩee comprising a Steering CommiƩee (SC) and Data and
Safety Monitoring Board (DSMB) will be responsible of the security of this clinical
trial. The role of the SC is to provide the overall supervision of the trial. The SC will
monitor trial progress and conduct and advice on scienƟﬁc credibility. The SC will
consider and act, as appropriate, upon the recommendaƟons of the DSMB. 
DSMB will be established to oversee the safety of parƟcipants in the trial. The DSMB
will meet prior to the trial opening to enrolment, and then meet at least annually, or
as per a Ɵmetable agreed by the DMC prior to trial commencement. Data analyses
will be supplied in conﬁdence to the DMC, which will be asked to give advice on
whether the accumulated data from the trial, together with the results from other
relevant research, jusƟﬁes the conƟnuing recruitment of further parƟcipants. The
DMC will operate in accordance with the trial speciﬁc charter. The interim analysis
will be conducted for the primary measure of eﬃcacy as well as safety to determine
if there was strong evidence of eﬃcacy (according to the Peto-HaybiƩle guidelines,
with a criterion of P<0.001) or harm (P<0.05) for any arm of treatment. 
DSMB will perform a planned interim analysis when data from the ﬁrst 50% of
4.-  TRIAL METHODS
4.5. Framework
4.-  TRIAL METHODS
4.6. Interim analyses and stopping guidance


enrolled  paƟents  were  available.  Depending  of  this  analysis  the  DSMB  will
recommended a second analysis to review adverse events in any arm of treatment.
DSMB will recommended that enrollment into the trial be conƟnued or stopped.
AŌer this second interim analysis, the DSMB recommended that the trial be stopped
due to concerns about safety. The SC concurred with this plan and was informed of
the results of the interim analysis. 
All estimates of differences between groups will be presented with two-
sided 95% confidence intervals, unless otherwise stated. P-values will be
reported from two-sided tests.
No correction for multiple testing will be made.
All primary analyses (primary and secondary outcomes including safety
outcomes) will be by intention-to-treat (ITT). Participants will be analysed
in the intervention group to which they were randomised, and all
participants shall be included whether or not they received the allocated
intervention. 
A  protocol  deviation/violation  is  defined  as  a  failure  to  adhere  to  the
protocol such as errors in applying  the inclusion/exclusion criteria,  the
incorrect  intervention  being  given,  incorrect  data  being  collected  or
measured, follow-up visits outside the visit window or missed follow-up
visits. We will apply a strict definition of the ITT principle and will include all
participants as per the ITT population.
5.-  STATISTICAL PRINCIPLES
5.1. Conﬁdence intervals and p-values
5.-  STATISTICAL PRINCIPLES
5.2. Adjustments for mulƟplicity
5.-  STATISTICAL PRINCIPLES
5 3 Analysis populaƟons
5.-  STATISTICAL PRINCIPLES
5 4 Handing protocol deviaƟons and violaƟons


A flow diagram (as recommended by CONSORT3) will be produced to
describe  the participant flow  through each  stage  of the trial. This  will
include information on the number (with reasons) of losses to follow-up
(drop- outs and withdrawals) over the course of the trial. A template for
reporting this is given in Appendix A.
Categorical data were summarised by number of participants, counts and
percentages.  Continuous  data  were  summarised  by  the  number of
participants, median and interquartile range. Tests  of  statistical
significance will not be undertaken, nor confidence intervals presented4.
The Trial StaƟsƟcian will derive all responses from the raw data recorded in the database. We
compared group diﬀerences using a chi-squared test or Fisher’s exact test for categorical
variables and Mann-Whitney U test for conƟnuous variables. Risk raƟos (RR) with their 95% CI
were calculated for the outcome measures. The reference group was considered to be the
morphine arm. Survival analysis was esƟmated using Kaplan-Meier tables, and the survival rate
of each group was compared using the log-rank test. Although a mulƟvariate analysis had been
planned in the original staƟsƟcal analysis plan, the authors decided not to carry it out due to
the insuﬃcient number of events5. Instead, the authors decided to run a post-hoc subgroup
analysis for the primary outcome of eﬃcacy (in-hospital mortality) and for serious adverse
events in order to search for interacƟon in 6 key variables: sex, age (dichotomized as <80 or
≥80 years), coronary artery disease, previous episodes of heart failure, room air oximetry at
emergency department arrival (dichotomized as <85 or ≥85%), and NT-proBNP (dichotomized
as <5000 or ≥5000 pg/mL). InteracƟon was assessed using the Mantel-Haenszel test.
6.-  TRIAL POPULATION
6.1. Recruitment
6.-  TRIAL POPULATION
6.2. Baseline characterisƟcs
7.-  ANALYSIS METHODS
7.1. Data manipulaƟons
7.-  ANALYSIS METHODS
7.2. Handling missing data


All the invesƟgators went to great eﬀort to record all the data in the database. Therefore,
there was not missing data.
Any data that does not form a pre-speciﬁed outcome will be presented using simple
summary staƟsƟcs by intervenƟon group (i.e. numbers and percentages for binary data
and means (or medians) and standard deviaƟons (or inter-quarƟle ranges) for conƟnuous
normal (or non-normal) data.
The number and percentage of parƟcipants experiencing any adverse events were presented
by treatment arm. All safety analyses were based on the ITT principle and included all the
paƟents who underwent randomizaƟon. 
The signiﬁcance of an adverse event was used to describe the paƟent/event outcome or acƟon
criteria associated with events that pose a threat to a paƟent’s life or funcƟoning. The DSMB
adjudicated the severity of the adverse events using the Medical DicƟonary for Regulatory
AcƟviƟes (MedDRA) version 17.1 and graded using the Common Terminology Criteria for
Adverse Events version 4.03, as previously reported6. The MIMO trial deﬁned the severity in
the following grades: 

Grade 3 severe or medically signiﬁcant but not immediately life-threatening;
hospitalizaƟon or prolongaƟon of hospitalizaƟon indicated; disabling; limiƟng
self care acƟviƟes of daily living.

Grade 4 Life-threatening consequences; urgent intervenƟon indicated.  

Grade 5 Death related to adverse event. 
7.-  ANALYSIS METHODS
7.3. Exploratory outcomes and analyses
8.- SAFETY DATA


The serious adverse events were deﬁned with any of the degrees aforemenƟoned. A table
lisƟng all the serious adverse events was provided.
StaƟsƟcal analysis will be undertaken in the following staƟsƟcal soŌware packages:

SPSS 24.0 

EPIDAT 3.1 (Area of Health Analysis and Information Systems; World Health
Organization).

Stata version 16
1. Dominguez-Rodriguez A, Burillo-Putze G, Garcia-Saiz MDM, Aldea-Perona A,
Harmand MG, Mirò O, Abreu-Gonzalez P; MIMO invesƟgators.  Study Design
and RaƟonale of "A MulƟcenter, Open-Labeled, Randomized Controlled Trial
Comparing MIdazolam Versus MOrphine in Acute Pulmonary Edema": MIMO
Trial. Cardiovasc Drugs Ther. 2017;31:209-213. doi: 10.1007/s10557-017-6722-
5.
2. Peacock WF, Hollander JE, Diercks DB, LopaƟn M, Fonarow G, Emerman CL.
Morphine and outcomes in acute decompensated heart failure: an ADHERE
analysis. Emerg Med J. 2008;25(4):205-9. doi: 10.1136/emj.2007.050419.
3. Altman DG, Doré CJ. RandomisaƟon and baseline comparisons in clinical trials.
Lancet.  1990  Jan 20;335(8682):149-53. doi:  10.1016/0140-6736(90)90014-v.
PMID: 1967441.
4. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement:
updated guidelines for reporƟng parallel group randomised trials. BMC Med.
2010 Mar 24;8:18. doi: 10.1186/1741-7015-8-18. PMID: 20334633; PMCID:
PMC2860339.
5. Heinze  G,  Dunkler  D.  Five  myths  about  variable  selecƟon.  Transpl  Int.
2017;30(1):6-10. doi: 10.1111/tri.12895.
9.- STATISTICAL SOFTWARE
10.- REFERENCES


6. Saad F, Carles J, Gillessen S, Heidenreich A, Heinrich D, GraƩ J, Lévy J, Miller K,
Nilsson S, Petrenciuc O, Tucci M, Wirth M, Federhofer J, O'Sullivan JM; Radium-
223  InternaƟonal  Early  Access  Program  InvesƟgators.  Radium-223  and
concomitant therapies in paƟents with metastaƟc castraƟon-resistant prostate
cancer: an internaƟonal, early access, open-label, single-arm phase 3b trial.
Lancet Oncol. 2016 Sep;17(9):1306-16. doi: 10.1016/S1470-2045(16)30173-5.
Epub 2016 Jul 26. PMID: 27473888.