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    Summary
    EudraCT Number:2015-005276-14
    Sponsor's Protocol Code Number:RGCH004
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-10-19
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2015-005276-14
    A.3Full title of the trial
    Prolonging the response by low-dose Rituximab maintenance therapy in immune thrombocytopenia: a randomized placebo-controlled trial- the PROLONG trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Maintenance treatment With rituximab in ITP
    A.3.2Name or abbreviated title of the trial where available
    PROLONG-trial
    A.4.1Sponsor's protocol code numberRGCH004
    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 SponsorSykehuset Østfold HF
    B.1.3.4CountryNorway
    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 supportHelse Sør Øst (South-Eastern Norway Regional Health Authority
    B.4.2CountryNorway
    B.4.1Name of organisation providing supportSykehuset Østfold HF
    B.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSykehuset Østfold HF
    B.5.2Functional name of contact pointWaleed Ghanima
    B.5.3 Address:
    B.5.3.1Street AddressKalnesveien 300
    B.5.3.2Town/ cityPB 300, Grålum
    B.5.3.3Post code1714
    B.5.3.4CountryNorway
    B.5.4Telephone number+4741303440
    B.5.6E-mailWaleed.Ghanima@so-hf.no
    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 Mabthera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namerituximab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 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 Dexamethasone Abcur
    D.2.1.1.2Name of the Marketing Authorisation holderAbcur AB
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 nameDexamethasone
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Immune thrombocytopenia
    E.1.1.1Medical condition in easily understood language
    An autoimmune disease charcaterized by low platelet count and increased risk of bleeding
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10021245
    E.1.2Term Idiopathic thrombocytopenic purpura
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine if maintenance therapy with low-dose rituximab is superior to placebo in prolonging responses among ITP patients who achieved an initial response with rituximab.
    E.2.2Secondary objectives of the trial
    1. To explore if the initial overall response rate, at week 24, can be improved by at least 10% by adding dexamethasone to rituximab (induction phase).
    2. To assess the safety of study treatment, especially infectious episodes (induction & maintenance phases).
    3. To assess bleeding complications during the study (induction & maintenance phases).
    4. To assess the use of rescue medications and other platelet-elevating therapies during the study (induction & maintenance phases).
    5. To determine rate of sustained Complete Response (CR) (induction & maintenance phases).
    6. To determine the duration of overall response and CR (induction & maintenance phases).
    7. To assess health-related quality of life and fatigue (induction & maintenance phases).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. To determine levels of CD19+ cells following induction and during maintenance phases, in order to investigate an eventual association between CD19+ cells and response or relapse.
    2. Ancillary (spin-off) studies to the proposed trial (Ancillary studies will be only performed in certain centers in Norway), with the following objectives (more details are provided in Appendix III; procedures are provided in a separate protocol):
    a. To study the effect of rituximab on antiplatelet antibodies and to investigate an eventual association between antiplatelet antibodies and response.
    b. To study the effect of rituximab on gene expression profiling and miRNA expression in ITP.
    c. To study the effect of rituximab on megakaryocyte differentiation and apoptosis.
    d. To study the effect of rituximab on B, memory B and T-cells in the peripheral blood and in bone marrow in responding, non-responding and relapsing patients.
    e. To study the association between response to rituximab and human microbiota.
    E.3Principal inclusion criteria
    First randomization (Induction phase)
    1. Male or female aged ≥18 years.
    2. Diagnosis of primary ITP of less than one-year duration and having a platelet count of ≤ 30 x109/L measured within 4 weeks prior to inclusion with failure to achieve response or relapse after one or more cycles of dexamethasone (40 mg daily for 4 days) or after at least 3 weeks under any other steroid (prednisone or prednisolone). Platelet count between 31 to 50 x109/L is accepted if higher platelet count is required due to concomitant antiplatelet therapy or bleeding.
    3. Scheduled intravenous treatment of rituximab.
    4. Rituximab infusion will be more than 2 weeks after the first injection of an anti-COVID-19 vaccine.
    5. Signed and dated written informed consent.
    6. Females of child-bearing potential accepting to follow effective contraceptive methods for at least 12 months following the last administration of rituximab or placebo.
    Second randomization (maintenance phase)
    7. Completion of the induction phase (phase 1) of the study.
    8. Sustained response at the end of phase 1.
    9. Randomization within:
    a. 4 weeks after the completion of phase 1, i.e. between week 24 and 28 for a patient who can’t be vaccinated or is already vaccinated against COVID-19 or,
    b. 16 weeks after the completion of phase 1 if needed to allow the patient to receive anti-COVID-19 vaccine (see Section 10.4.5.2. for vaccination recommendations).
    E.4Principal exclusion criteria
    First randomization (Induction phase)
    1. Previous treatment for ITP with: rituximab, other immune suppressants (including mycophenolate mofetil, azathioprin, cyclosporine), dapsone, danazol, thrombopoietin receptor agonist, chemotherapy or splenectomy.
    2. Anti-COVID-19 unvaccinated patient with at least one of the following characteristics:
    a. ≥65 years old
    b. Obesity
    c. Diagnosed Arterial hypertension
    d. Diagnosed Diabetes mellitus
    e. Known Kidney disease
    f. Known Lung disease
    3. Pregnancy or lactation.
    4. Known active gastro-duodenal ulcer.
    5. Secondary ITP: ITP associated with lymphoma, chronic lymphocytic leukemia, drug induced or ITP secondary to autoimmune disorders such as Systemic Lupus Erythematosis, Rheumatoid arthritis or Antiphospholipid syndrome, common variable immune deficiency, human immunodeficiency virus, hepatitis C or thrombocytopenia associated with myeloid dysplasia.
    6. Concomitant autoimmune hemolytic anemia.
    7. History of any major cardiovascular event within the 6 months prior to randomization, including but not limited to: myocardial infarction, unstable angina, cerebrovascular accident, or New York Heart Association Class III or IV heart failure.
    8. Active hepatitis B virus or patients with positive HBsAG or HBcAB.
    9. Patients with active severe infection, including systemic mycotic infections or a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection.
    10. Known allergy and/or sensitivity or contraindication to rituximab or dexamethasone or any of the ingredients.
    11. Patients in a severely immune compromised state.
    12. Known contraindication to a treatment with any proton-pump inhibitor.
    13. Active malignancy or history of malignant disease during the last 2 years
    14. Patients with history of poor compliance or history of alcohol/drug abuse or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
    Second randomization (maintenance phase)
    1. Severe allergic reaction or serum sickness due to rituximab in phase 1 of the study.
    2. Pregnancy.
    3. Treatment with rescue medication after week 18.
    4. Patients refusing to continue in the study (withdrawal of consent).
    5. Splenectomy performed for any cause.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint:
    sustained overall response during maintenance phase [loss of overall response is defined as: (1) two consecutive measurements with platelet counts < 50 x 109/L taken at 1-8-week interval, and/or, (2) use of any ITP-directed therapies, other than study medication, because of bleeding or thrombocytopenia, except for preoperative elevation of platelet count] (this endpoint applies to maintenance phase only).
    E.5.1.1Timepoint(s) of evaluation of this end point
    First randomization: 24 weeks and 52 weeks for 2. randomization
    E.5.2Secondary end point(s)
    Secondary endpoints:
    1. Overall response during induction phase defined as mean platelet count, determined in week 24 (± 2 weeks) after induction therapy, > 50 x 109/L, without use of any other ITP-directed therapies after week 18 following the first randomization (this endpoint applies to induction phase only).
    2. Safety assessed by the frequency of > grade II adverse events (this endpoint applies to both phases).
    3. Grade of bleeding (this endpoint applies to both phases).
    4. Sustained Complete Response (CR) during maintenance phase defined as platelet count > 100 x 109/L maintained during maintenance phase, without the use of any ITP-directed therapies
    5.Complete Response (CR) during induction phase, defined as platelet count, determined in week 24 (± 2 weeks), > 100 x 109/L without use of any other ITP-directed therapies after week 18 following the first randomization (induction phase)
    6.Administration of rescue medication or any other elevating platelet therapy
    1. After week 18 (induction phase)
    2. During maintenance phase (maintenance phase).
    7. Percentage of patients with more than 80% of platelet counts level > 50 x 109/L during the maintenance phase (this endpoint applies to maintenance phase only).
    8. Health-related quality of life (this endpoint applies to both phases).
    9. Fatigue using an analogical scale of 0-10 and General Fatigue Questionnaire (this endpoint applies to both phases).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.Sustained overall response:24weeks and 52 weeks for 1. and 2.randomization
    2.Sustained complete response: 24 weeks and 52 weeks .Rescue medication and remaining endpoints: 18 weeks and 52 weeks
    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 Yes
    E.6.13.1Other scope of the trial description
    mechanisms and biomarkers
    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 No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    First Phase : open-label, 2 parallel arms.Second phase doubleblind with 2 paralell arms
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Egypt
    Tunisia
    Denmark
    France
    Norway
    E.8.7Trial has a data monitoring committee Yes
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial 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: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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 No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 130
    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 as yet
    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 Decision2016-12-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-08
    P. End of Trial
    P.End of Trial StatusOngoing
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