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    Summary
    EudraCT Number:2020-003604-14
    Sponsor's Protocol Code Number:RBHP-2020-MOISSET
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-12-04
    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 ConcernedFrance - ANSM
    A.2EudraCT number2020-003604-14
    A.3Full title of the trial
    Evaluation of the efficacy of a single infusion of ketamine combined with magnesium sulfate to treat refractory chronic cluster headache
    Evaluation de l’efficacité d’une perfusion de kétamine combinée au sulfate de magnésium dans le traitement de l’algie vasculaire de la face chronique réfractaire
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Re-purposing of 2 well-known molecules (ketamine and magnesium sulfate) to treat a specific and excruciating type of pain (chronic cluster headache) in patients who are not relieved by currently recommended treatments
    A.3.2Name or abbreviated title of the trial where available
    KETALGIA
    A.4.1Sponsor's protocol code numberRBHP-2020-MOISSET
    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 SponsorCHU de Clermont-Ferrand
    B.1.3.4CountryFrance
    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 supportCHU de Clermont-Ferrand
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU de Clermont-Ferrand
    B.5.2Functional name of contact pointLACLAUTRE Lise
    B.5.3 Address:
    B.5.3.1Street Address58 rue Montalembert
    B.5.3.2Town/ cityClermont-Ferrand
    B.5.3.3Post code63000
    B.5.3.4CountryFrance
    B.5.4Telephone number+33473754963
    B.5.5Fax number+33473754730
    B.5.6E-mailpromo_interne_drci@chu-clermontferrand.fr
    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 Yes
    D.2.1.1.1Trade name ketamine
    D.2.1.1.2Name of the Marketing Authorisation holderLaboratoire RENAUDIN
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameketamine
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNKETAMINE
    D.3.9.1CAS number 6740-88-1
    D.3.9.4EV Substance CodeSUB08365MIG
    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.2.1.1.1Trade name hydroxyzine
    D.2.1.1.2Name of the Marketing Authorisation holderLaboratoire renaudin
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 namehydroxyzine
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHYDROXYZINE
    D.3.9.1CAS number 68-88-2
    D.3.9.4EV Substance CodeSUB08088MIG
    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: 3
    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 Yes
    D.2.1.1.1Trade name Sulfate de magnesium
    D.2.1.1.2Name of the Marketing Authorisation holderLaboratoires Chaix et du Marais
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 namesulfate de magnesium
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMAGNESIUM SULFATE
    D.3.9.1CAS number 7487-88-9
    D.3.9.4EV Substance CodeSUB14448MIG
    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
    Refractory chronic cluster headache
    E.1.1.1Medical condition in easily understood language
    A specific type of headache (cluster headache) without remission for at least one year and not properly controlled with the 3 main validated treatments
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]
    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
    Evaluate the efficacy of a single infusion of ketamine combined with magnesium sulfate compared to a control group receiving hydroxyzine (active placebo) in terms of the proportion of patients with at least 50% daily attacks decrease between the 7 days before infusion and days 7 and 8 after infusion.
    Evaluer l’efficacité de la combinaison Kétamine + magnésium en comparaison à un groupe contrôle de patients qui recevront un placebo actif (Hydroxyzine) en termes de proportion de patients répondeurs à 50% entre les 7 jours avant la perfusion et les jours 7 et 8 (J7-J8) après la perfusion
    E.2.2Secondary objectives of the trial
    - Evaluate patient's global impression of change (PGIC) at D8, D15, D29 and D90
    - Evaluate the delay between infusion and daily attacks frequency reduction
    - Evaluate pain intensity during attacks
    - Evaluate psychological impact
    - Evaluate safety of use of this treatment (side effects during the infusion)
    - Evaluate the cost effectiveness of such treatment
    - Evaluer l’impression clinique globale du patient à J8, J15, J29 et J90
    - Evaluer le délai d’apparition avant la réduction de la fréquence des crises
    - Evaluer l’intensité des crises
    - Evaluer l’impact psychologique
    - Evaluer la sécurité d’emploi (fréquence des effets indésirables durant la perfusion)
    - Evaluer l’aspect médico-économique (coût-efficacité d’un point de vue assurantiel) de cette prise en charge.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age >= 18
    - Chronic cluster headache diagnosis made according to ICHD-3 criteria
    - A mean of at least 2 attacks/day during the 14 days before infusion
    - Insufficient efficacy or intolerance or contra-indication to the use of the 3 main validated treatments (verapamil, lithium and sub-occipital steroids injections)
    - Stable preventive treatment for at least 7 days before infusion
    - Homme ou femme ≥ 18 ans
    - Diagnostic d’algie vasculaire de la face chronique selon les critères ICHD-3 (AVF depuis plus d’un an, périodes de rémissions < 3mois)
    - Présence d’au moins 2 crises/ 24h en moyenne pendant les 14 jours précédant la perfusion de kétamine
    - Efficacité insuffisante, intolérance ou contre-indication à l’utilisation des 3 traitements majeurs pour la prise en charge de l’AVF (verapamil, lithium et injections sous-occipitales de corticoïdes)
    - Traitement préventif stable depuis au moins 7 jours au moment de la randomisation
    E.4Principal exclusion criteria
    - Pregnant or lactating woman
    - Contra-indication to ketamine use (uncontrolled high blood pressure, stoke history, severe cardiac failure)
    - Ketamine use during the previous year
    - Hypersensitivity to the product or their metabolites
    - Severe renal insufficiency (creatinine clearance < 30ml/min)
    - Femme enceinte ou allaitante
    - Contre-indication à l’utilisation de kétamine : hypertension artérielle non contrôlée, antécédent d’accident vasculaire cérébral, insuffisance cardiaque sévère (NYHA stade 3 ou 4, c’est-à-dire essoufflement pour monter moins de 2 étages)
    - Utilisation de kétamine dans l’année précédant l’étude
    - Hypersensibilité aux substances actives, à l’un des métabolites ou autres dérivés
    - Insuffisance rénale sévère (clairance de la créatinine < 30mL/min)
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of responders in each group, defined by a 50% decrease in the daily attack frequency between the 7 days before infusion (D0) and 7 and 8 days (D7-D8) after the infusion.
    Proportion de patients répondeurs dans chaque groupe, défini par une diminution ≥ 50% de la fréquence quotidienne des crises entre les 7 jours précédant la perfusion (J0) du traitement à l’étude et les jours 7 et 8 (J7-J8).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Days 7 and 8 after infusion (noted D0)
    E.5.2Secondary end point(s)
    - Proportion of 30%, 50% and 75% responders at D7-8, D9-15, D16-22, D23-29 and D83-90 according to the attack diary
    - Treatment response according to initial magnesemia
    - Daily attacks frequency and attacks intensity between the 7 days before infusion and D7-8 (attacks diary)
    - Area under the curve (AUC) for daily attacks evaluated each week between D0 and D90 (attacks diary)
    - Attacks treatment consumption (injectable sumatriptan and oxygene)
    - Anxiety and depression evolution (HAD scale)
    - patient global impression of change at D8, D15, D29 and D90
    - Proportion of patients necessitating rescue therapy (infusion of ketamine combined with magnesium) at D15
    - Direct medical cost (treatments, consultations, hospitalisations) in each group and cost effectiveness ratio taking 50% responder rate as efficacy criteria
    - La proportion de répondeurs à 30%, 50% et 75% : à J7-8, J9-15, J16-22, J23-29 et J83-90 selon le calendrier des crises
    - La réponse au traitement en fonction de la magnésémie initiale
    - La fréquence quotidienne et l’intensité des crises entre les 7 jours précédant la perfusion et J7-8, J9-15 et J16-22, J23-29 et J83-90 (calendrier des crises)
    - L’aire sous la courbe du nombre de crises quotidiennes évaluées par bloc d’une semaine entre J0 et J90 (données issues du calendrier de suivi des crises).
    - La prise de traitements de crise (sumatriptan injectable et oxygène).
    - Les scores d’anxiété et dépression via l’échelle HAD
    - Le score de l’échelle PGIC pour l’évaluation clinique globale à J8, J15 et J90
    - La proportion de patients nécessitant un traitement de secours (perfusion de kétamine + magnésium en ouvert) à J15.
    - Coûts directs médicaux (traitements, consultations, hospitalisations) dans chaque groupe et calcul du ratio cout-efficacité en prenant comme critère d’efficacité le critère de jugement principal.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Daily attacks diary completed every day from D0 to D90
    For HAD and PGIC: D8, D15, D29 and D90
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned9
    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 visit of the last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    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: 90
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state90
    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)
    None
    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 Decision2021-01-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-11
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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