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    Summary
    EudraCT Number:2017-001853-15
    Sponsor's Protocol Code Number:NL61830
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-04-30
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-001853-15
    A.3Full title of the trial
    An explorative study for halting inflammation in patients with emphysema by intravenous administration of autologous bone marrow derived mesenchymal stromal cells.
    Een exploratieve studie naar het effect van intraveneuze toediening van vermeerderde lichaamseigen mesenchymaal stromale cellen op longweefsel van patiënten met emfyseem.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Intravenous experimental treatment of pulmonary emphysema with patients own bone marrow-derived and cultured mesenchymal stromal cells.
    Experimentele behandeling van longemfyseem door intraveneuze behandeling met mesenchymale stromale cellen afkomstig uit het eigen beenmerg van de patient?
    A.3.2Name or abbreviated title of the trial where available
    HEP study
    HEP studie
    A.4.1Sponsor's protocol code numberNL61830
    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 SponsorLeiden University Medical Center
    B.1.3.4CountryNetherlands
    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 supportLeiden University Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointClinical Research Unit Longziekten
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 ZA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031715262950
    B.5.5Fax number0031715266927
    B.5.6E-mailj.stolk@lumc.nl
    D. IMP Identification
    D.IMP: 1
    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 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 nameautologous bone marrow derived mesenchymal stromal cells
    D.3.2Product code MSC
    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 INNHUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS
    D.3.9.3Other descriptive nameHUMAN AUTOLOGOUS MESENCHYMAL STEM CELLS
    D.3.9.4EV Substance CodeSUB180295
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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 placeboSolution 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
    Pulmonary emphysema
    patients between age 45 and 65 with moderate to severe emphysema; a gradient of emphysema severity towards the lung apex as assessed by CT-derived lung densitometry and equally distributed between left and right lung; FEV1 between 25% and 45% pred; Gas diffusion capacity between 30% and 45% pred.
    E.1.1.1Medical condition in easily understood language
    long emfyseem
    Patienten in de leeftijd tussen 45 en 65 jaar die matig tot ernstig longemfyseem hebben en die een gradient van emfyseem hebben zoals gemeten m.b.v. beelden van een long CT scan.
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    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
    Primary Objective is two fold: First, to detect the difference in the level of expression of PECAM-1 (CD31) on pulmonary microvascular endothelial cells (pMVECs) present in lung tissue harvested from patients at LVRS2 after 4 weeks of treatment with autologous BM-MSCs and patients treated with placebo. Second, to assess the safety and clinical efficacy (by CO diffusion capacity) of autologous MSC treatment up to 3 years following the last MSC dose
    E.2.2Secondary objectives of the trial
    1.to demonstrate safety of i.v. adm. of MSC to pts with mod. to sev emphysema
    2.the diff in the level of expr of CD31 on pMVECs present in lung tissue harvested from pts at LVRS2 after 12 wks of treatment with placebo and pts treated with MSC.
    3.the diff in the nr of CD3+ and CD4+ T-cells present in lung tissue harvested from LVRS2 from pts after 4 or 12 wks of treatment with placebo and pts treated with BMSC.
    4.As in 2 & 3, but then the diff between LVRS2 and 1.
    5.the diff in the nr of type II alveolar cells present in lung tissue harvested from LVRS2 from pts after 4 or 12 wks of treatment with placebo and pts treated with BMSC.
    6.The diff. in shear stress response of isolated pMVECs from LVRS1 and 2 of pts treated with either MSC or placebo
    7.The diff. in Cytosplore resp of isolated immune cells from LVRS1 and 2 of pts treated with either BMSCs or placebo.
    8.The corr with lung phys response prm and the outcome of the primary obj of the study for pts treated with BM-MSCs.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria:

    -Age lower than 65;
    -emphysema as reported by a radiologist present in CT images of the lung;
    -gradient of emphysema severity towards the lung apex as assessed by CT-derived lung densitometry by Pulmo CMS software (Medis, NL) and equally distributed between left and right lung;
    -FEV1 between 25% and 45% pred ;
    -TLCO between 30% and 45% pred.;
    -patients in a stable clinical condition.
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:

    -Significant cardiac failure; or active smoking, or
    -< 6 months smoking cessation;
    -or failure to complete pulmonary rehab program before randomization;
    -or women of child bearing potential;
    -or any other condition of the patient that the clinical investigator deemed harmful for study participation.
    E.5 End points
    E.5.1Primary end point(s)
    First: The difference in expression of PECAM-1 (CD31) on pulmonary microvascular endothelial cells per micrometer alveolar septum present in lung tissue harvested from patients at LVRS 2 after 4 weeks of treatment with autologous MSC or placebo.
    Second: . To assess the safety and clinical efficacy (by CO diffusion capacity) of autologous MSC treatment up to 3 years following the last MSC dose
    E.5.1.1Timepoint(s) of evaluation of this end point
    When all randomized patients have completed the study, all lung tissue samples will be investigated in one run for immunohistochemistry.
    E.5.2Secondary end point(s)
    1. The differences in expression of Surfactant Protein-C expression by alveolar type II cells in lung tissue obtained from study patients treated with placebo or MSC.
    2. The difference in immunostaining of various leukocytes in resected lung tissue, including T lymphocytes, B lymphocytes, macrophages and neutrophils obtained from study patients treated with placebo or MSC.
    3. The difference in the composition of the immune cells present in surgically resected lung tissue parts and paired peripheral blood mononuclear cell samples analysed by CyTOF obtained from patients treated with MSC or placebo.
    4. The difference in shear stress responses, expressed as % elongation of 100 cells, of isolated pMVECs ex vivo obtained from study patients treated with placebo or MSC.
    5. The difference in immune-modulatory and regenerative capacity, determined by flow cytometry value, of MSC from emphysema patients and healthy controls stored in our biobank.
    6. The difference in endothelial microparticles concentration and concentration of immunological markers in blood samples from study patients treated with placebo or MSC.
    7. The correlation between arterial pO2 or gas transfer value TLCO at 12 weeks after discharge of admission for LVRS 2 (measured as standard of care) and the outcome of the primary objective of the study for patients treated with MSC or placebo.
    In addition Safety parameters will be measured during and up to 2 hr after i.v. infusion of autologous bone marrow derived MSC or placebo and will be evaluated according to the WHO toxicity criteria by grade.
    E.5.2.1Timepoint(s) of evaluation of this end point
    When all randomized patients have completed the study, all lung tissue samples will be investigated in one run for immunohistochemistry or CytoF experiments, except for the MSC that will be studied for item number 5. This work will be performed will the bone marrow is harvested from all study particpants during the first lung volume reduction surgery session.
    Safety parameters will be measured during MSC treatment of each randomized study participant.
    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 No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    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 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
    The last study visit is at 3 years after the last patient had its second lung volume reduction surgery perfomed.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    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: 30
    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 state30
    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)
    Patients will be referred back to their physician for care in their referring hospital
    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 Decision2018-07-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-02-06
    P. End of Trial
    P.End of Trial StatusOngoing
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