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    Summary
    EudraCT Number:2013-002172-40
    Sponsor's Protocol Code Number:ISIS426115-CS2
    National Competent Authority:Romania - National Agency for Medicines and Medical Devices
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-07-18
    Trial results View 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 ConcernedRomania - National Agency for Medicines and Medical Devices
    A.2EudraCT number2013-002172-40
    A.3Full title of the trial
    A Randomized, Double Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability and Efficacy of ISIS 426115 (an Antisense Glucocorticoid Receptor Antagonist) Administered Subcutaneously Once Weekly for 6 Weeks to Patients with Type 2 Diabetes Mellitus Being Treated with Metformin
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A controlled study to assess the safety, tolerability, and effectiveness of the study drug, ISIS 426115, in patients with Type 2 Diabetes who are being treated with Metformin
    A.3.2Name or abbreviated title of the trial where available
    ISIS 426115-CS2
    A.4.1Sponsor's protocol code numberISIS426115-CS2
    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 SponsorIsis Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportIsis Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIsis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointTiffany Baumann
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Ct.
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number011760603-2302
    B.5.5Fax number011760603-3891
    B.5.6E-mailtbaumann@isisph.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 ISIS 426115
    D.3.4Pharmaceutical form Solution for injection
    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 INNISIS 426115
    D.3.9.1CAS number 1431900-72-9
    D.3.9.2Current sponsor codeISIS 426115
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Yes
    D.3.11.13.1Other medicinal product typeAntisense Oligonucleotide
    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
    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
    Type 2 Diabetes Mellitus
    E.1.1.1Medical condition in easily understood language
    Type 2 Diabetes Mellitus
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10067585
    E.1.2Term Type 2 diabetes mellitus
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of ISIS 426115 subcutaneous injection (dosage: 210 mg/week) on the endpoint of serum fructosamine in combination with metformin versus metformin + placebo.

    To evaluate the safety and tolerability of ISIS 426115 subcutaneous injection (dosage: 210 mg/week) in combination with metformin versus metformin + placebo.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of ISIS 426115 subcutaneous injection on endpoints including fasting plasma glucose, insulin, C-peptide, serum glycated albumin, weekly average SMPG and serum lipids.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements
    2. Males or females. Aged 18 to 75 years at the time of informed consent
    3. Females must be non-pregnant and non-lactating and either surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-menopausal (12 months of natural [spontaneous] amenorrhea together with FSH confirmation of postmenopausal state). Males must be surgically sterile, abstinent or if engaged in sexual relations with women of child-bearing potential, the patient must be using an acceptable contraceptive method during dosing and for 12 weeks after the last dose of Study Drug
    4. BMI ≥25 kg/m2
    5. Clinically confirmed diagnosis of T2DM
    6. Patients must have been on a stable dose of oral metformin (at least 1000 mg/day) for a minimum of 3 months prior to Screening and will be required to continue the stable dose of metformin throughout the study
    7. HbA1c ≥7.5% and ≤10.5% at Screening
    8. Agree to maintain current diet and exercise regimen throughout the study
    9. Agree to conduct daily morning (fasted) blood glucose testing using the study glucometer throughout the study
    10. Agree to abstain from alcoholic beverages 48 hours prior to Study Center visits
    E.4Principal exclusion criteria
    1. Clinically significant abnormalities in medical history
    2. Screening laboratory results as follows
    • Urine protein/creatinine (P/C) ratio >0.2 mg/mg. In the event of P/C ratio above this threshold eligibility may be confirmed by a quantitative total urine protein measurement of <300 mg/24 hour
    • Positive test (including trace) for blood on urinalysis. In the event of a positive test, eligibility may be confirmed with urine microscopy showing <5 red blood cells per high power field
    • Serum creatinine >ULN
    • Estimated GFR <60 mL/min (as determined by the Cockcroft-Gault Equation for Creatinine Clearance)
    • History of or clinical signs or symptoms of liver disease, acute or chronic hepatitis, or ALT or AST >1.5 x ULN; or total bilirubin >ULN at Screening
    • Have a current or previous diagnosis of Gilbert’s disease
    • Platelet count <140,000/mm3 at Screening
    3. Show evidence of uncorrected hypothyroidism or hyperthyroidism at Screening. Patients receiving dose-stable thyroid replacement therapy for at least 3 months prior to Screening will be allowed to participate as long as thyroid tests (TSH/T3/T4) show that patient is euthyroid
    4. History of renal transplantation or renal dialysis
    5. Clinically significant complications of diabetes (e.g., history of painful neuropathy, nephropathy, proliferative retinopathy and/or foot ulcers)
    6. Within 6 months prior to Screening have any of the following:
    • More than 3 episodes of severe hypoglycemia requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions;
    • One (1) event of hypoglycemia in which the patient required hospitalization;
    • A current diagnosis of hypoglycemia unawareness
    7. Treatment with antidiabetic drugs other than metformin including insulin, thiazolidinedione, α-glucosidase inhibitor, GLP-1 agonist or DPP-IV inhibitor and other drugs that may affect plasma glucose levels (including systemic glucocorticoids), systemic steroids, corticosteroids, antiglucocorticoid therapies including mifepristone and ketoconazole (topical cream and systemic), immunosuppressive medications, somatostatin analogues or ACTH therapy within 3 months prior to Screening
    8. Confirmed reduction in fasting plasma glucose (FPG) of >40 mg/dL (>2.2 mmol/L) at the Pre-treatment Visit (Week-1, Day-7) compared to a FPG value taken during the Screening Period; or fasted self-monitored plasma glucose (SMPG) values <140 mg/dL for >75% of measurements collected during Week -3 through Week -2
    9. History of diabetic ketoacidosis
    10. Treatment with lipid lowering therapy with the exception of statins. Statins are allowed at stable doses (≥3 months) prior to Screening and within the dose levels listed below. Other statin regimens should be discussed with the Sponsor Medical Monitor or designee
    • Simvastatin at ≤40 mg/day
    • Atorvastatin, fluvastatin, or lovastatin at ≤20 mg/day
    • Rosuvastatin or pravastatin at ≤10 mg/day
    • Pitavastatin at ≤2 mg/day
    11. Treatment with non-selective beta-blockers such as propranolol within 3 months of Screening and throughout the study
    12. Clinically significant active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to the start of the Pre-Treatment Period
    13. Treatment with another investigational drug, biological agent, or device within one-month of Screening, or 5 half-lives of investigational agent, whichever is longer
    14. Concomitant use of anticoagulants/antiplatelet agents (e.g., warfarin, heparin, dabigatran, rivaroxaban, clopidogrel), the NSAID nimesulide or any other drug influencing coagulation (except low dose aspirin <160 mg/day and other short-acting NSAIDs with a half-life <20 hours)
    15. Treatment with any non-ISIS oligonucleotide (including siRNA) at any time or prior treatment with an ISIS oligonucleotide within 9 months of Screening. Patients who have previously received only a single dose of an ISIS-oligonucleotide as part of a clinical study may be included as long as a duration of ≥4 months has elapsed since dosing
    16. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
    17. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
    18. Recent history of or current drug or alcohol abuse. Regular use of alcohol within 6 months prior to Screening, or use of soft drugs (such as marijuana) within 3 months prior to Screening, or hard drugs within 1 year prior to Screening, or positive urine drug screen at Screening
    19. History of clinically significant abnormalities in coagulation parameters or clinically significant abnormalities in coagulation parameters at Screening
    20. Unwillingness to comply with study procedures
    21. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the change from Baseline to Week 7 in serum fructosamine concentration.
    E.5.1.1Timepoint(s) of evaluation of this end point
    continuously
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints include:
    •Percent change from Baseline to Week 7 in serum fructosamine
    •Change and percent change from Baseline in HbA1c (if analyzed), fasting plasma glucose, weekly average SMPG, and glycated albumin
    •Change and percent change from Baseline in fasting plasma glucose, fasting insulin and fasting C-peptide
    •Change and percent change from Baseline in fasting total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, VLDL cholesterol, ApoA1, ApoB, ApoCIII, and Lp(a)
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 7
    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 Yes
    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 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 No
    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
    Canada
    Romania
    South Africa
    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
    LVLS
    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 months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 40
    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)
    standard care
    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 Decision2014-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-04-09
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