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    Summary
    EudraCT Number:2017-004259-22
    Sponsor's Protocol Code Number:ISIS766720-CS2
    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:2018-04-25
    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 number2017-004259-22
    A.3Full title of the trial
    A Double Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of ISIS 766720 (IONIS GHR-LRX, an Antisense Inhibitor of the Growth Hormone Receptor) Administered Once Every 28 Days for 16 Weeks in Patients with Acromegaly Being Treated with Long-acting Somatostatin Receptor Ligands (SRL)
    Eine doppelblinde, placebokontrollierte Studie der Phase II zur Beurteilung der Sicherheit, Verträglichkeit und Wirksamkeit von ISIS 766720 (IONIS GHR-LRX, ein Antisense-Inhibitor des Wachstumshormon-Rezeptors), verabreicht einmal alle 28 Tage über 16 Wochen an Patienten mit Akromegalie, die mit lang wirkenden Somatostatin-Rezeptor-Liganden (SRL) behandelt werden

    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 efficacy of the study drug, ISIS 766720, in patients with acromegaly (a hormonal disorder that results from too much growth hormone in the body)
    A.4.1Sponsor's protocol code numberISIS766720-CS2
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03548415
    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 pointSeung Chun Assistant Director, RA
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post codeCA 92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1760603-3804
    B.5.5Fax number+1760603-3891
    B.5.6E-mailSChun@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.3.1Product nameISIS 766720
    D.3.2Product code ISIS 766720
    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 INNnot yet available
    D.3.9.1CAS number 2131025-83-5
    D.3.9.2Current sponsor codeISIS 766720
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    Acromegaly is a chronic disorder caused by GH hypersecretion, most commonly as a result of a GH-secreting pituitary adenoma.
    E.1.1.1Medical condition in easily understood language
    Acromegaly is a hormonal disorder that results from too much growth hormone (GH) in the body. Most cases the overproduction of GH is due to a benign tumor of the pituitary gland called an adenoma.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10000599
    E.1.2Term Acromegaly
    E.1.2System Organ Class 10014698 - Endocrine disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To evaluate the efficacy of ISIS 766720 subcutaneous injection on serum insulin-like growth factor 1 (IGF-1) vs. placebo as an add-on therapy to long acting somatostatin receptor ligands (SRL) octreotide or lanreotide.
    - To evaluate the safety and tolerability of ISIS 766720 subcutaneous injection vs. placebo on add-on therapy of SRL.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of ISIS 766720 to normalize serum IGF-1 levels.
    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 with documented diagnosis of Acromegaly*. Aged 18 to 75 years old (inclusive) at the time of informed consent
    * Defined as a previous diagnosis of GH-secreting adenoma by surgical pathology; or the presence of a pituitary adenoma on magnetic resonance imaging (MRI) and serum IGF-1 levels above the upper limit of normal for age and sex at time of diagnosis (serum IGF-1 level and MRI at diagnosis will be collected in the CRF)
    3. Patients must be on stable maximum or maximally tolerated dose of SRL (lanreotide Autogel or octreotide LAR, per treating physician judgment) every 28 days for a minimum of 3 months prior to screening and will be required to continue their stable dose of SRL throughout the study. In accordance with US approved prescribing information, the maximal dose recommended per the package insert for lanreotide Autogel is 120 mg every 28 days and for octreotide LAR is 40 mg every 28 days (the reason for the maximally tolerated dose of SRL will be collected in the CRF). SRL dose should not exceed the maximum dose as approved in the local region (as indicated in the SRL label). Prior use of other medications for treating acromegaly (pasireotide, dopamine agonist or pegvisomant) is allowed but not within 6 weeks of screening
    4. At Screening, serum IGF-1 (performed at central lab) between 1.3 to 5 x ULN, inclusive, adjusted for age and sex
    5. Females must be non-pregnant and non-lactating, and either
    a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy)
    b. 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)
    c. abstinent or
    d. Women of childbearing potential (WOCBP) should agree to taking all precaution to avoid pregnancy during the trial period (including Post-Treatment), including agreeing to receive pregnancy testing before each monthly dose, using 1 highly effective method of birth control (Section 6.3.1) from the time of signing the informed consent form until 14 weeks after the last dose of Study Drug administration
    Males must be surgically sterile, abstinent or, if engaged in sexual relations with a female of child-bearing potential, the patient or the patient’s non-pregnant female partner must be using 1 highly effective contraceptive method (refer to Section 6.3.1) from the time of signing the informed consent form until 14 weeks after the last dose of Study Drug.
    6. Willing to refrain from strenuous exercise/activity (for example heavy lifting, weight training, intense aerobics classes etc.) for at least 24 hours prior to study visits
    7. Willing to refrain from alcohol or tobacco use for 8 hours prior to study visits
    E.4Principal exclusion criteria
    1. Clinically-significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of screening, major non-pituitary surgery within 3 months of screening) or from screening physical examination
    2. Patients who received surgery for pituitary adenoma within the last 6 months before the trial, and/or planning to receive surgery during the trial
    3. Patients who received radiotherapy for pituitary adenoma within the last 3 years before the trial, and/or planning to receive radiotherapy during the trial
    4. Patients with a pituitary tumor that, per Investigator judgment, is worsening (e.g., either growing, or at risk of compressing or abutting the optic chiasm or other vital structures) as assessed by pituitary/sellar MRI protocol at Screening or within 6 months of screening
    5. Evidence of decompensated cardiac function per medical judgement and/or NYHA class 3 or 4
    6. Clinical evidence of symptomatic hyperprolactinemia that would necessitate treatment
    7. Symptomatic cholelithiasis, and/or choledocholithiasis
    8. Have a diagnosis of Gilbert’s disease
    9. Patients with history of hypoglycemia unawareness (who have had > 3 severe episodes in the past 6 months) or documented reactive hypoglycemia
    10. Screening laboratory results as follows, or any other clinically-significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion. (abnormalities may be retested for eligibility purposes)
    a. Urine protein/creatinine (P/C) ratio ≥ 500 mg/g. In the event of P/C ratio above this threshold eligibility may be confirmed by a quantitative total urine protein measurement of < 1000 mg/24 hr
    b. 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
    c. ALT or AST > 1.2 x ULN, bilirubin > ULN; alkaline phosphatase (ALP) > 3 x ULN
    d. eGFR < 45 mL/min/1.73m2 as determined by the Chronic Kidney Disease-Epidemiological Collaboration (CKD-EPI) equation for creatinine clearance OR serum creatinine > 1.8 mg/dL in males and > 1.5 mg/dL in females
    e. Platelet count < LLN
    f. Abnormal thyroid function tests must be approved by the Sponsor Medical Monitor
    g. HbA1c > 10%
    h. Morning (prior to 9 AM) blood cortisol < 10 mcg/dL (280 nmol/L)
    11. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
    12. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
    13. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
    14. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, follicular Stage 1 or papillary thyroid cancer that has been successfully treated; patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor
    15. Treatment with another investigational drug, biological agent, or device within 1 month of screening, or 5 half-lives of investigational agent, whichever is longer
    16. Treatment with any non- ION- or ISIS-oligonucleotide (including siRNA) at any time or prior treatment with an ION- or ISIS-oligonucleotide within 9 months of screening. Patients that have previously received only a single-dose of an ION- or ISIS oligonucleotide as part of a clinical study may be included as long as a duration ≥ 4 month has elapsed since dosing
    17. History of bleeding diathesis or coagulopathy
    18. Recent history of, or current drug or alcohol abuse that could affect study compliance per Investigator judgment
    19. Patients may not have insulin, chronic systemic use of glucocorticoids, weight loss medications or participate in weight loss programs within 2 months before randomization and during study participation
    20. Patients on anti-diabetes medications must be on a stable dose and regimen for ≥ 3 months prior to screen and throughout the trial. Patients taking GLP-1 agonists can be allowed with prior consultation with the Sponsor Medical Monitor
    21. Patients on estrogen containing medications must be on a stable dose and regimen for
    ≥ 3 months prior to screening and throughout the trial
    22. 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 during the trial
    23. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 60 days of screening and during the trial
    24. Have any other conditions, which, in the opinion of the Investigator and Sponsor 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)
    The primary efficacy endpoint is the percent change in IGF-1 from Baseline to 28 Days after last dose (PTWk5 Visit).
    The safety endpoints include:
    •Adverse events
    •Vital signs and weight and calculated BMI
    •Physical examination
    •Clinical laboratory tests
    •ECG
    •Use of concomitant medication
    E.5.1.1Timepoint(s) of evaluation of this end point
    Comparison of percent change from Baseline to PTWk5 (28 days after last dose) in serum IGF-1 between ISIS 766720 80 mg group and pooled placebo group in the Per Protocol Set.
    Safety Analyses:
    The treatment-emergent adverse events (TEAEs) and SAEs analysed the whole duration of the study.
    Laboratory tests including chemistry panel, CBC with differential, coagulation panel, complement etc., will be summarized by study visits for each treatment group.
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints include:
    • Proportion of patients achieve normalized IGF-1 levels to within 1.2 times of gender and aged limits at 28 days after last dose (PTWk5 Visit)
    • Proportion patients achieve normalized IGF-1 levels to within 1.0 times of gender and aged limits at 28 days after last dose (PTWk5 Visit)
    • Change from Baseline in serum IGF-1 over time
    • Percent change from Baseline in serum IGF-1 over time
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Measure of IGF-1 level at 28 days after last dose (PTWk5 Visit)
    • Serum IGF-1 level change measured throughout the study
    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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Austria
    Czech Republic
    Hungary
    Lithuania
    Poland
    Romania
    Russian Federation
    Serbia
    United States
    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 days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    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: 39
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 42
    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 Decision2018-08-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-04-02
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