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    Summary
    EudraCT Number:2018-003229-27
    Sponsor's Protocol Code Number:ImPRESS
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-02-26
    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 ConcernedNorway - NOMA
    A.2EudraCT number2018-003229-27
    A.3Full title of the trial
    ImPRESS - Imaging Perfusion Restrictions from Extracellular Solid Stress - An open-label losartan study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Open-label study on losartan to minimize elevated tissue stiffness and physics pressure in patients with brain tumors
    A.3.2Name or abbreviated title of the trial where available
    ImPRESS
    A.4.1Sponsor's protocol code numberImPRESS
    A.5.4Other Identifiers
    Name:ERC Starting Grant 2017Number:ImPRESS - 758657
    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 SponsorOslo University Hospital
    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 supportEuropean Research Council
    B.4.2CountryEuropean Union
    B.4.1Name of organisation providing supportThe Research Council of Norway
    B.4.2CountryNorway
    B.4.1Name of organisation providing supportSouth-Eastern Norway Regional Health Authority
    B.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOslo University Hospital
    B.5.2Functional name of contact pointPaulina B Due-Tønnessen
    B.5.3 Address:
    B.5.3.1Street AddressSognsvannsveien 20
    B.5.3.2Town/ cityOslo
    B.5.3.3Post code0372
    B.5.3.4CountryNorway
    B.5.4Telephone number+4793088126
    B.5.6E-mailpdue@ous-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 Cozaar
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme
    D.2.1.2Country which granted the Marketing AuthorisationNorway
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with newly diagnosed or recurrent glioblastomas
    Patients with brain metastases from non-small-cell lung cancer
    E.1.1.1Medical condition in easily understood language
    The study includes patients with primary or metastatic cancers to the brain
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    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 assess the dose-response relationship of the angiotensin II receptor inhibitor losartan on perfusion and mechanical solid stress in brain tumors.
    E.2.2Secondary objectives of the trial
    1. To assess the dose-response relationship of losartan on conventional and experimental radiographic characteristics in patients with glioblastoma and metastases to the brain
    2. To assess the dose-response relationship of losartan as add-on to standard treatment on clinical or patient reported endpoints in patients with glioblastoma and metastases to the brain
    3. To assess the safety of losartan treatment in patients with glioblastoma and metastases to the brain
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. A histologically confirmed intracranial glioblastoma, WHO grade 4 (Study A), or a minimum of one radiographically confirmed metastasis to the brain from a primary non-small-cell lung cancer (Study B)

    2. Ability to undergo an MRI exam, including administration of a standard clinical dose of an MRI-specific contrast agent of gadolinium or similar

    3. Measurable intracranial disease (Study A – recurrent glioblastoma, and Study B only), defined as at least one lesion that can be accurately measured in at least one dimension as ≥10 mm with MRI – or – compromise more than 30 image voxels on perfusion MRI to ensure adequate parametric statistical assessments. For a perfusion MRI resolution of 1.2x1.2x5mm, this equals a tumor volume of 0.2 cubic centimeters (cc).

    4. Age ≥18 years

    5. Eligible for administration of the active substance (losartan) in concordance with study protocol, the criteria of the product label (Cozaar) and deemed fit for trial by the treating physician.

    6. An ECOG performance status of ≤2 or equivalent KPS of ≥60%

    7. Life expectancy from start of treatment of more than 3 months

    8. Previous history of a neurosurgical procedure at time of study inclusion (Study A only)

    9. Scheduled for chemotherapy and/or radiotherapy and/or stereotactic radiosurgery (Study A – recurrent glioblastoma), neurosurgery, radiotherapy and chemotherapy (Study A – newly diagnosed glioblastoma), immunotherapy and/or chemotherapy and/or stereotactic radiosurgery (Study B)

    10. Pre-study documentation on O6-methylguanin-DNA-methyltransferase (MGMT) promoter methylation status and on the isocitrate dehydrogenase (IDH) gene mutation status of their disease (study A only)

    11. Organ functions of sufficient quality and robustness to undergo study treatment as determined by the study principal investigator (PI) or designee

    12. Female patients of childbearing potential (postmenarcheal, not postmenopausal (>12 continuous months of amenorrhea with no identified cause other than menopause), and no surgical sterilization) should use highly effective contraception and take active measures to avoid pregnancy while undergoing IMP treatment and for at least 14 days after the last dose. Birth control methods considered to be highly effective include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence when it is the preferred and usual lifestyle of the subject.

    13. Ability to understand and the willingness to sign a written informed consent document
    E.4Principal exclusion criteria
    1. Hypersensitivity to the active substance (losartan) or to any of the excipients

    2. Patients on other antihypertensive agents of any type. This includes substances inducing hypotension like tricyclic antidepressants, antipsychotics, baclofene, amifostine. Moreover, lithium, NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs), fluconazole (inhibitor of CYP2C9), rifampicine (inducer of matabolism enzymes) and drugs that retain potassium (e.g. potassium-sparing diuretics: amiloride, triamterene, spironolactone) or may increase potassium levels (e.g. heparin), potassium supplements or salt substitutes containing potassium are all prohibited during the study

    3. Patients with hepatic or renal impairment of any reason

    4. Patients with symptomatic hypotension of any reason

    5. Patients with primary hyperaldosteronism

    6. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine

    7. Inadequate recovery from toxicity and/or complications of previous therapy as determined by the treating physician

    8. Patients with evidence of recurrence less than 3 months since last radiotherapy fraction (Study A – recurrent glioblastoma only)

    9. Patients with evidence of recurrence inside the radiotherapy target volume less than 3 months since last radiotherapy fraction (Study A – recurrent glioblastoma only)

    10. For Study B subjects only: A diagnosis of immunodeficiency or hypersensitivity to PD-1 inhibitors or any excipients.

    11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, coronary heart disease and cerebrovascular disease, unstable angina pectoris, cardiac arrhythmia, angioedema, intravascular volume depletion, or psychiatric illness/social situations that would limit compliance with study requirements, as determined by the treating physician

    12. Patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy

    13. Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study as determined by the treating physician

    14. Pregnant or breastfeeding patient

    15. Known additional active non-study related malignancy

    16.Applies to Study B patients qualifying for immunotherapy only: Active autoimmune disease that has required systemic treatment in the last 2 years (including use of non-study related disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed
    17. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

    18. Unable to undergo brain MRI according to study protocol

    19. Removed in Protocol version 6
    E.5 End points
    E.5.1Primary end point(s)
    1. Change from baseline in the radiographic biomarker relative cerebral blood flow (rCBF)

    2. Change from baseline in the radiographic biomarker relative solid stress
    E.5.1.1Timepoint(s) of evaluation of this end point
    For primary endpoint 1:
    Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44
    Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44
    Study B (lung patients with metastases to the brain) Baseline, Day 90-7d, Day 180-7d, Day 270-7d

    For primary endpoint 2:
    Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44
    Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44
    Study B (lung patients with metastases to the brain) Baseline, Day 90-14d, Day 180-14d, Day 270-14d
    E.5.2Secondary end point(s)
    • Change from baseline in experimental radiographic biomarkers from MRI, including perfusion MRI, diffusion MRI, or MR Elastography. [Time Frame:
    Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78-8/+1, Day 162-8/+1.
    Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44, Day 148-8/+1, Day 232-8/+1.
    Study B (lung cancer patients with metastases to the brain) Baseline, Day 90-14d, Day 180-14d, Day 270-14d

    • Drug tolerance of IMP (NCI-CTCAE v4.0) according to follow-up period, including number and frequency of losartan treatment emerging adverse events (TEAE), vital signs (weight, blood pressure, pulse) and conventional laboratory blood parameters [Time Frame:
    Study A (patients with recurrent glioblastoma) 168 days + 14 days
    Study A (patients with newly diagnosed glioblastoma) 238 days + 14 days
    Study B (lung cancer patients with metastases to the brain) 270 days + 14 days]

    • Change from baseline in neurologic performance scores by Karnofsky Performance Score (KPS), Eastern Cooperative Oncology Group (ECOG) and/or Neurologic Assessment in Neuro-Oncology (NANO) scores. [Time Frame:
    Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 42-44, Day 85±4, Day 169±4.
    Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 42-44, Day 71±4, Day 155±4, Day 239±4.
    Study B (lung cancer patients with metastases to the brain) Baseline, Day 90-7, Day 180-7, Day 270-7, Day 360±7

    • Change from baseline in radiographic status on MRIs of intracranial disease or corresponding treatment response (size of edema, occurrence of radionecrosis, pseudoprogression or tumor progression) by the Response Assessment in Neuro-Oncology (RANO) criteria. [Time Frame:
    Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78±4, Day 162±4, Day 360±7.
    Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44, Day 148±4, Day 232±4, Day 360±7.
    Study B (lung cancer patients with metastases to the brain) Baseline, Day 90-14, Day 180-14, Day 270-14, Day 360±7.

    • Total dose and change in steroids dosage during study treatment duration. [Time Frame:
    Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 57±4, Day 85±4, Day 113±4, Day 127+4 for Lomustine and Day 141±4 for Temodal, Day 169±4.
    Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44, Day 71±4, Day 99±4, Day 127±4, Day 155±4, Day 183±4, Day 211±4, Day 239±4
    Study B (lung cancer patients with metastases to the brain) Baseline, Day 90-7, Day 180-7, Day 270-7, Day 360±7]

    • Change from baseline in the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ BN20) core 30 version 3.0. [Time Frame:
    Study A (patients with recurrent glioblastoma) Baseline, Day 42-44, 169±4.
    Study A (patients with newly diagnosed glioblastoma) Baseline, Day 42-44, Day 155±4, Day 239±4.
    Study B (lung cancer patients with metastases to the brain) Baseline, Day 90-7, Day 180-7, Day 270-7, Day 360±7

    • Six-months progression free survival (6M-PFS) [Time Frame: Day +180]

    • Progression free survival (PFS) [Time Frame: up to 24 months]

    • Overall survival (OS) at 12 and 24 months [Time Frame: at 12 months, 24 months]

    • Overall survival [Time Frame: up to 24 months]
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please see timepoints of evaluation for all secondary endpoints in section E.5.2. because of space.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 Yes
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    The patients are their own controls (baseline), and other patients not on the IMP at readout
    E.8.2.4Number of treatment arms in the trial9
    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 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 years4
    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: 84
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 69
    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 state153
    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 Decision2019-04-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-04
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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