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    Summary
    EudraCT Number:2021-004789-36
    Sponsor's Protocol Code Number:173-01
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-03-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2021-004789-36
    A.3Full title of the trial
    Randomized, controlled trial of the use of intranasal midazolam for the treatment of terminal agitation in palliative care patients
    Randomisierte, kontrollierte Studie zur Anwendung von intranasalem Midazolam zur Behandlung von Terminaler Unruhe bei Palliativpatienten
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study on the use of midazolam nasal spray for restlessness in the dying phase
    Studie zur Anwendung von Midazolam Nasenspray bei Unruhe in der Sterbephase
    A.3.2Name or abbreviated title of the trial where available
    MinTU
    MinTU
    A.4.1Sponsor's protocol code number173-01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversität Heidelberg
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedizinische Fakultät Mannheim der Universität Heidelberg, III. Medizinische Klinik
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedizinische Fakultät Mannheim der Universität Heidelberg
    B.5.2Functional name of contact pointIII. Medizinische Klinik
    B.5.3 Address:
    B.5.3.1Street AddressTheodor-Kutzer-Ufer 1-3
    B.5.3.2Town/ cityMannheim
    B.5.3.3Post code68167
    B.5.3.4CountryGermany
    B.5.4Telephone number004906213833978
    B.5.5Fax number004906213833831
    B.5.6E-mailmintu-studie@medma.uni-heidelberg.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMidazolam Nasenspray 25 mg/ml
    D.3.4Pharmaceutical form Nasal spray, solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntranasal use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMIDAZOLAM HYDROCHLORIDE
    D.3.9.1CAS number 59467-96-8
    D.3.9.4EV Substance CodeSUB03289MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMIDAZOLAM HYDROCHLORIDE
    D.3.9.1CAS number 59467-96-8
    D.3.9.4EV Substance CodeSUB03289MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Terminal agitation in the final phase
    Terminale Unruhe in der Finalphase
    E.1.1.1Medical condition in easily understood language
    Restlessness in the dying phase
    Unruhe in der Sterbephase
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of midazolam after intranasal application in palliative patients with terminal agitation. To determine whether intranasal application of midazolam reduces the symptomatology of terminal agitation.
    Nachweis der Wirksamkeit von Midazolam nach intranasaler Anwendung bei Palliativpatienten mit terminaler Unruhe. Es soll festgestellt werden, ob durch die intranasale Applikation von Midazolam die Symptomatik der terminalen Unruhe reduziert wird.
    E.2.2Secondary objectives of the trial
    -To demonstrate the efficacy of midazolam after subcutaneous application in palliative patients with terminal agitation. To determine whether standard therapy as recommended by the S3 guideline Palliative Care for Patients with Noncurable Cancer, by subcutaneous application of midazolam reduces the symptomatology of terminal agitation.
    -Therapeutic effect levels in a concentration range c ≥ 30 ng/ml after intranasal and after subcutaneous application of midazolam. To determine that twenty minutes after the first midazolam application, therapeutic drug levels in a concentration range c ≥ 30 ng/ml are achieved, independent of the mode of administration (i. n. or s. c.).
    -Five minutes after intranasal application, higher or at least the same effect levels as after subcutaneous application. To determine whether midazolam flushes faster or at least as fast after intranasal application as after subcutaneous injection.
    -Nachweis der Wirksamkeit von Midazolam nach subkutaner Anwendung bei Palliativpatienten mit terminaler Unruhe. Zur Feststellung, ob durch die Standardtherapie nach Empfehlung der S3 Leitlinie Palliativmedizin für Patienten mit einer nicht heilbaren Krebserkrankung, durch subkutane Applikation von Midazolam, die Symptomatik der terminalen Unruhe reduziert wird.
    -Therapeutische Wirkspiegel in einem Konzentrationsbereich c ≥ 30 ng/ml nach intranasaler und nach subkutaner Applikation von Midazolam. Zur Feststellung, dass zwanzig Minuten nach der ersten Midazolam-Applikation, unabhängig von der Applikationsart (i. n. oder s. c.) therapeutische Wirkspiegel in einem Konzentrationsbereich c ≥ 30 ng/ml erreicht werden.
    -Fünf Minuten nach intranasaler Applikation höhere oder mindestens gleiche Wirkspiegel wie nach subkutaner Applikation. Zur Feststellung, ob Midazolam nach intranasaler Anwendung schneller oder mindestens genauso schnell anflutet wie nach subkutaner Injektion.



    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Patient in a palliative stage of disease.
    -Age ≥ 18 years
    -Personal information of the patient or, in the case of patients not capable of giving consent, information of the legal representative by one of the investigators.
    -Ability of the participant or legal representative to understand the nature and scope of the clinical trial
    -Written informed consent of the patient
    -Diagnosis final phase
    -Diagnosis of terminal agitation
    -RASS-PAL Score > 0
    -Patient in einem palliativen Krankheitsstadium
    -Alter ≥ 18 Jahre
    -Persönliche Aufklärung des Patienten bzw. bei nicht einwilligungsfähigen Patienten die Aufklärung des gesetzlichen Vertreters durch einen der Prüfarzte
    -Fähigkeit des Teilnehmers bzw. des gesetzlichen Vertreters, Wesen und Tragweite der klinischen Prüfung zu verstehen
    -Schriftliche Einwilligungserklärung des Patienten
    -Diagnose Finalphase
    -Diagnose Terminale Unruhe
    -RASS-PAL Score > 0
    E.4Principal exclusion criteria
    -Conditions that interfere with nasal absorption
    -Hypersensitivity to midazolam or to any other component/excipient of the study medication
    -Parallel use of strong CYP 3A4 inducers or CYP 3A4 inhibitors
    -Other causes are responsible for the observed agitation symptomatology and can be treated causally
    -Non-drug therapy is effective and leads to improvement of the restlessness symptoms
    -Pregnant and breastfeeding women
    -Erkrankungen die eine nasale Resorption beeinträchtigen
    -Überempfindlichkeit gegen Midazolam oder gegen irgendeinen anderen Bestandteil/Hilfsstoff der Prüfmedikation
    -Parallele Einnahme von starken CYP 3A4 Induktoren oder CYP 3A4 Inhibitoren
    -Andere Ursachen sind für die beobachtete Unruhe Symptomatik verantwortlich und können kausal behandelt werden
    -Eine nicht-medikamentöse Therapie ist wirksam und führt zur Besserung der Unruhe Symptomatik
    -Schwangere und Stillende
    E.5 End points
    E.5.1Primary end point(s)
    Improvement in RASS-PAL score by at least one point between two observation time points after i. n. application.
    Verbesserung im RASS-PAL Score um mindestens einen Punkt zwischen zwei Beobachtungszeitpunkten nach i. n. Applikation.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit 3-5
    Visit 3-5
    E.5.2Secondary end point(s)
    -Improvement in RASS-PAL score by at least one point between two observation time points after s. c. application.
    -Detection of a midazolam drug concentration in blood of c ≥ 30 ng/ml after t3=20 min.
    -Quantitative analysis of blood samples at t2=5 min after drug application.
    -Verbesserung im RASS-PAL Score um mindestens einen Punkt zwischen zwei Beobachtungszeitpunkten nach s. c. Applikation.
    -Nachweis einer Midazolam Wirkstoffkonzentration im Blut von c ≥ 30 ng/ml nach t3=20 min.
    -Quantitative Analyse der Blutproben nach t2=5 min nach Wirkstoffapplikation.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -Visit 3-5
    -After laboratory chemical analysis of blood samples
    -After laboratory chemical analysis of blood samples
    -Visit 3-5
    -Nach laborchemischer Analyse der Blutproben
    -Nach laborchemischer Analyse der Blutproben
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last-Patient-Out
    Last-Patient-Out
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The treatment of patients after the end of the study is independent of the then current symptoms. Existing agitation requiring treatment will continue to be treated according to standard therapy.
    Die Behandlung der Patienten nach Studienende erfolgt unabhängig von der dann aktuellen Symptomatik. Bestehende behandlungsbedürftige Unruhe wird entsprechend Standardtherapie weiterbehandelt.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-06-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-06-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-07-31
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