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    Summary
    EudraCT Number:2016-002128-10
    Sponsor's Protocol Code Number:BP39144
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2016-10-24
    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 - PEI
    A.2EudraCT number2016-002128-10
    A.3Full title of the trial
    An adaptive Phase I/II study to assess safety, efficacy, pharmacokinetics and pharmacodynamics of RO7112689 in healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Assess Safety, Effectiveness, Pharmacokinetics, and Pharmacodynamics of RO7112689 in Healthy Volunteers and Patients With Paroxysmal Nocturnal Hemoglobinuria
    A.4.1Sponsor's protocol code numberBP39144
    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 SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    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.3.2Product code RO7112689/F01
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 1917321-26-6
    D.3.9.2Current sponsor codeRO7112689
    D.3.9.3Other descriptive nameC5 inh MAb, SKY59, RO/CH7092230
    D.3.9.4EV Substance CodeSUB183839
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number170
    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 Yes
    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 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.3.2Product code RO7112689/F03-01
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 1917321-26-6
    D.3.9.2Current sponsor codeRO7112689
    D.3.9.3Other descriptive nameC5 inh MAb, SKY59, RO/CH7092230
    D.3.9.4EV Substance CodeSUB183839
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number170
    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 Yes
    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 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.3.2Product code RO7112689/F03-03
    D.3.4Pharmaceutical form Solution for injection/infusion in pre-filled syringe
    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 INNNot available
    D.3.9.1CAS number 1917321-26-6
    D.3.9.2Current sponsor codeRO7112689
    D.3.9.3Other descriptive nameC5 inh MAb, SKY59, RO/CH7092230
    D.3.9.4EV Substance CodeSUB183839
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number170
    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 Yes
    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 injection/infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Paroxysmal nocturnal hemoglobinuria (PNH)
    E.1.1.1Medical condition in easily understood language
    Paroxysmal nocturnal hemoglobinuria is a rare, acquired, life-threatening disease of the blood that leads to the premature death and impaired production of red blood cells
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10055629
    E.1.2Term Paroxysmal nocturnal hemoglobinuria
    E.1.2System Organ Class 100000004857
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1
    •Evaluate the safety and tolerability of single doses of RO7112689 in
    healthy volunteers (HVs)
    Part 2, 3 and 4
    •Evaluate the safety and tolerability of RO7112689 for a total duration of
    5 months in treatment naïve patients with PNH and PNH patients
    switching treatment to RO7112689
    •Evaluate the pharmacodynamic (PD) effect of multiple doses of
    RO7112689 on complement activity in patients with PNH
    Open Label Extension (OLE)
    •Assess the long term safety of RO7112689
    E.2.2Secondary objectives of the trial
    Part 1
    •Characterize the PD effects of a single-dose of RO7112689 on complement activity (CA) & other related biomarkers
    •Describe the single-dose pharmacokinetic (PK) profile of RO7112689
    •Assess the bioavailability of subcutaneous (SC) administration of RO7112689

    Part 2, 3 and 4
    •Describe the multiple-dose PK properties of RO7112689 in treatment naïve patients (Pts) with PNH and PNH Pts switching treatment to RO7112689
    •Characterize other PD effects of RO7112689
    •Characterize the exposure-response relationship of RO7112689 following different SC dosing regimens
    •Assess the efficacy, Pt-related outcomes & treatment satisfaction of RO7112689 in treatment naïve Pts with PNH, and/or PNH Pts switching treatment to RO7112689
    Parts 1, 2 & 3
    •Explore the PK/PD relationship of single-ascending & multiple doses of RO7112689 on CA & other related biomarkers
    •Evaluate the immunogenicity of RO7112689 in HVs and in Pts with PNH
    OLE
    •Assess the long term safety of RO7112689
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part 1 (HVs only)
    - Healthy male volunteers between the age of 21 and 55 years
    - Neisseria meningitidis vaccination against serogroups B and A, C, W,
    and Y
    - Subjects with a negative hepatitis B surface antigen (HBsAg),
    hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test
    result are eligible for the study
    - Subjects who have been vaccinated against hepatitis B
    Parts 2, 3 and 4 (PNH patients only)
    - Male or female patients between the age of 18 and 75 years
    - Neisseria meningitidis vaccination in accordance with most current
    local guidelines or Standard of Care (SOC) for patients at increased risk
    for meningococcal disease (Part 2 and Part 4 Arm A)
    - Patient has been vaccinated with Neisseria meningitidis vaccine(s) in
    accordance with most current local guidelines or SOC for patients at
    increased risk for meningococcal disease or is being revaccinated if
    applicable (Part 3 and Part 4 Arm B)
    - Stable dose for >= 28 days prior to screening of other therapies
    (immunosuppressant therapy, corticosteroids, iron supplements)
    - Negative pregnancy test for women of childbearing potential
    Part 2 and Part 4 Arm A only (currently untreated PNH patients who are candidates for
    treatment with complement inhibitors only):
    - Hepatitis B patients can be enrolled if their LFT values are less than 2
    × ULN and there is no liver function impairment
    - PNH patients who have not been treated with any complement
    inhibitor or if previously treated stopped treatment due to lack of
    efficacy based on a single missense C5 heterozygous mutation
    Part 3 and Part 4 Arm B only (PNH patients currently treated with eculizumab only):
    - Subjects with a negative hepatitis B surface antigen (HBsAg),
    hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test
    result are eligible for the study.
    o Subjects sero positive for HCV but adequately treated without
    detectable HCV RNA are eligible
    o Subjects who have been vaccinated against hepatitis B are eligible
    o Subjects sero positive for HBV but adequately treated without
    detectable HBV DNA are eligible
    - Patients are adequately controlled based on investigator opinion
    - Patients receive regular infusions of eculizumab
    OLE only - PNH patients:
    - PNH patients who have completed Parts 2, 3 and 4 respectively
    - PNH patients who derived, in the Investigator's opinion, benefit from
    treatment with RO7112689
    E.4Principal exclusion criteria
    Parts 1, 2, 3 and 4:
    - Known or suspected hereditary complement deficiency
    - History of meningococcal meningitis
    - Any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 28 days prior to screening or oral antibiotics within 2 weeks prior to screening and up to first study drug administration
    - History of or currently active primary or secondary immunodeficiency, including known history of HIV infection
    - Evidence of malignant disease including myelodysplastic syndrome, or malignancies diagnosed within the previous 5 years

    Part 1 (HVs only):
    - Any clinically relevant history or the presence of moderate to severe respiratory, renal, hepatic, gastrointestinal, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, or connective tissue disease
    - Any major illness within one month before the screening examination or any febrile illness within 2 weeks prior to screening and up to first study drug Administration
    - Prior splenectomy
    - History or presence of clinically significant electrocardiogram (ECG) abnormalities or cardiovascular disease
    - Congenital or acquired complement deficiency
    - Carriers of Neisseria meningitides based on cultures from naso-pharyngeal swabs

    Parts 2, 3 and 4 (PNH patients only):
    - Evidence of moderate to severe concurrent renal, liver, cardiac, pulmonary or gastrointestinal disease not related to PNH as determined by the Investigator
    - History of bone marrow transplantation
    - Treatment with azathioprine or erythrocyte-stimulating agents within 14 days prior to first study drug Administration
    - Splenectomy < 1 year before start of RO7112689.
    Part 3 and 4 Arm B ( PNH patients only):
    - Any evidence of sero-positive auto-immune connective tissue
    diseases
    - Any evidence of active inflammatory conditions
    E.5 End points
    E.5.1Primary end point(s)
    Safety (Parts 1, 2, 3 and 4):
    1. Incidence of dose-limiting events
    2. Incidence and severity of adverse events (AEs), serious adverse events and AEs leading to withdrawal
    PD (Parts 1, 2, 3 and 4):
    3. Ex vivo liposome lysis in serum and ex-vivo lysis of antibody-coated erythrocytes
    4. Total and target engaged C5 concentration
    5. Serum LDH
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety and PD (Parts 1, 2, 3 and 4):
    1-5. Approximately 6 months for Part 1; approximately 8 months for Parts 2 and 3; up to a maximum of three years from entry into OLE
    E.5.2Secondary end point(s)
    Efficacy (Parts 2, 3 and 4):
    1. Change in LDH
    2. Change in free-haemoglobin
    3. Proportion of patients with stabilized haemoglobin levels
    4. Change in fatigue as measured by the functional assessment of chronic illness therapy fatigue
    5. Change in health-related quality of life as measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire-core 30
    6. Number of packed RBC units transfused per patient
    7. Time to (1) first transfusion or (2) persistent elevation of LDH
    8. Proportion of patients with LDH below ULN
    9. Proportion of patients with complement suppression throughout the
    dosing interval
    PK (Parts 1, 2, 3 and 4):
    10. Pharmacokinetic profile of RO7112689; Cmax, Tmax, AUC, T1/2,
    bioavailability following SC administration
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy and PK (Parts 1, 2, 3 and 4):
    1-10. Approximately 6 months for Part 1; approximately 8 months for Parts 2 and 3; up to a maximum of three years from entry into OLE
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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 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) 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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    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
    France
    Germany
    Hungary
    Italy
    Japan
    Korea, Republic of
    Netherlands
    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
    LPLV
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 37
    F.4.2.2In the whole clinical trial 49
    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 Sponsor will offer post-trial access to the study drug (RO7112689) free of charge to eligible patients, i.e., patients who derive clinical benefit from RO7112689, in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product. Please see section 4.4.4 of the protocol for further information.
    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 Decision2017-03-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-14
    P. End of Trial
    P.End of Trial StatusRestarted
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