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    Summary
    EudraCT Number:2015-003337-10
    Sponsor's Protocol Code Number:ISIS449884-CS3
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-12-22
    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 ConcernedAustria - BASG
    A.2EudraCT number2015-003337-10
    A.3Full title of the trial
    A Double Blind, Placebo-Controlled, Phase 2A Mechanistic Study to Evaluate the Effect of ISIS 449884 (ISIS-GCGRRX an Antisense Inhibitor of the Glucagon Receptor) on Hepatic Lipid and Glycogen Content in Patients with Type 2 Diabetes 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 effect of the study drug, ISIS 449884, on hepatic lipids and glycogen content in patients with Type 2 diabetes treated with Metformin
    A.3.2Name or abbreviated title of the trial where available
    ISIS 449884-CS3
    A.4.1Sponsor's protocol code numberISIS449884-CS3
    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 SponsorIonis 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 supportIonis Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIonis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointTeresa Brandt
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad, CA
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1760603-2738
    B.5.5Fax number+1760603-3891
    B.5.6E-mailtbrandt@ionisph.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 449884
    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 449884
    D.3.9.1CAS number 1428588-67-3
    D.3.9.2Current sponsor codeISIS 449884
    D.3.9.3Other descriptive nameISIS 449884
    D.3.9.4EV Substance CodeSUB178283
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 type2'MOE Antisense 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
    Hyperglycemia in patients with type 2 diabetes
    E.1.1.1Medical condition in easily understood language
    High blood sugar in patients with type 2 diabetes
    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 19.0
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10020639
    E.1.2Term Hyperglycemia
    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 pharmacodynamics effects of GCGR Reduction by ISIS 449884 (100 mg) on Hepatic Lipid and Glycogen Content.
    E.2.2Secondary objectives of the trial
    To evaluate the safety, tolerability and pharmacokinetic profile of ISIS 449884.
    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, inclusive, at the time of informed consent
    3. Satisfy the following:
    • Females: Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved), or if engaged in sexual relations and of child-bearing potential, subject is using an acceptable contraceptive method from the time of signing the informed consent form until at least 18 weeks after the last dose of Study Drug.
    • Males: Surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, subject is utilizing an acceptable contraceptive method from the time of signing the informed consent form until at least 18 weeks after the last dose of Study Drug.
    4. Body Mass Index (BMI) ≥ 25.0 - < 36.0 kg/m2
    5. 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 evaluation and will be required to continue their stable dose of metformin throughout the study. If a patient has been on a stable dose of metformin plus a sulfonylurea (SU) or metformin plus a dipeptidyl peptidase-IV (DPPIV) inhibitor for a minimum of 3 months prior to Screening evaluation may be allowed with pre-approval documented from the Ionis Medical Monitor or Designee.
    7. HbA1c ≥ 7.5% and ≤ 10.5% at Screening
    8. Agree to maintain current diet and exercise regimen
    9. Agree to conduct daily morning (fasted plasma) glucose testing using the study glucometer
    10. Agree to abstain from alcoholic beverages for at least 48 hours prior to clinic visits and not increase alcohol consumption during the study
    E.4Principal exclusion criteria
    1.Clinically significant abnormalities in medical history or physical examination
    2.Screening laboratory results as follows or any other clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion
    a.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 hr
    b.Persistently 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 (RBC) per high power field (Persistently positive defined as 2 out of 3)
    c.Serum creatinine > ULN
    d.Estimated GFR < 60 mL/min (as determined by the Cockcroft-Gault Equation for creatinine clearance)
    e.History of or clinical signs or symptoms of liver disease, hepatitis B or C, or ALT or AST > ULN, bilirubin > ULN at Screening
    f.Have a current or previous diagnosis of Gilbert’s disease
    g.Platelet count < 140,000/mm3 (< 140 X 10 9 /L)at Screening
    3.Show evidence of uncorrected hypothyroidism or hyperthyroidism hormone results 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 liver transplantation, renal dialysis, diabetic ketoacidosis, clinically significant abnormalities in coagulation parameters
    5.Clinically significant complications of diabetes
    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
    •1 event of hypoglycemia in which the patient requires hospitalization
    •A current diagnosis of hypoglycemia unawareness
    7.Treatment with antidiabetic drugs (other than described in Inclusion #6) including drugs that may affect plasma glucose level (including systemic glucocorticoids) 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 -2, Day -14) compared to a FPG value taken during the Screening Period; or fasted self-monitored plasma glucose (SMPG) values < 140 mg/dL (< 7.8 mmol/L) for > 75% of measurements collected during Screening through Wk -3 (up to Day -14 visit)
    9.Patients receiving treatment with statins must have been on a stable dose and regimen for ≥ 3 months prior to Screening and should be within the dose levels listed below. Other statin regimens should be discussed and approved with the Sponsor Medical Monitor or designee.
    •Simvastatin at ≤ 40 mg/day •Lovastatin at ≤ 20 mg/day •Atorvastatin and fluvastatin up to 40 mg/day •Rosuvastatin up to 20 mg/day or pravastatin up to 40 mg/day •Pitavastatin up to 4 mg/day
    10.Treatment with non-selective beta-blockers such as propranolol within 3 months of screening and throughout the study
    11.Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
    12.Malignancy within 5 years of signing informed consent, with some exceptions
    13.Treatment with another investigational drug, biological agent, or device within one (1) month of screening, or 5 half-lives of investigational drug, whichever is longer
    14.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
    15.Regular use of alcohol within 6 months prior to Screening (> 7 drinks/week for females, > 14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor), or use of soft drugs (such as marijuana) within 3 months prior to Screening, or hard drugs (such as cocaine and phencyclidine [PCP]) within 1 year prior to screening, or positive urine drug screen at Screening
    16.Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to the first dose of Study Drug and regular clinical monitoring is performed
    17.Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 60 days of screening
    18.Patients at possible risk for glucagonomas
    19.Patients with conditions contraindicated for MRS procedures e.g. claustrophobia, or who have any metal, who have worked as metal welders, who have tattoos on the left side of the abdominal region may not have an MRS scan
    20.Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study
    E.5 End points
    E.5.1Primary end point(s)
    PHARMACODYNAMIC
    • Differences in percent hepatic glycogen content between Baseline and post-treatment assessments for ISIS 449884 100 mg and placebo patients
    • Differences in percent hepatic lipid content between Baseline and post-treatment assessments for ISIS 449884 100 mg and placebo patients
    • Change from Baseline in percent fasting hepatic glycogen content and percent fasting hepatic lipid content for each patient who has MRS procedures conducted at Baseline, Week 6 and Week 14.
    • Change and percent change from Baseline to Week 14 in fasting plasma glucagon and fasting plasma total GLP-1 between ISIS 449884 100 mg and placebo group
    EFFICACY
    Comparisons of change and percent change from Baseline to Week 14 in HbA1c, FPG, plasma insulin, plasma C-peptide and weekly average SMPG between ISIS 449884 100 mg and placebo group in the Per-Protocol Set and Full Analysis Set.
    SAFETY
    The safety endpoints include:
    • Adverse events
    • Vital signs (including blood pressure) and body weight
    • Physical examination
    • Clinical laboratory tests (serum chemistry, hematology, urinalysis, coagulation, lipids, antibodies, pregnancy test for women with childbearing potential)
    • ECG
    • Use of concomitant medication
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluation will take place at the end of the study.
    PHARMACODYNAMIC
    • Between baseline and post-treatment assessments
    • Between baseline and post-treatment assessments
    • Between baseline and Week 14
    EFFICACY
    • Between baseline and Week 6 and Week 14
    SAFETY
    • Throughout the study
    E.5.2Secondary end point(s)
    No additional end points
    E.5.2.1Timepoint(s) of evaluation of this end point
    Not Applicable
    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 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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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
    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 months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months4
    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: 12
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 15
    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 return to standard of care. A 26-week Post-Treatment Period (weeks 14-38) is incorporated into the study. This includes scheduled visits to the study center and telephone contact. Adverse events and concomitant medications, safety and clinical laboratory evaluations will be performed regularly during the Post-Treatment period.
    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 Decision2016-01-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-04-19
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