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    Summary
    EudraCT Number:2012-003939-27
    Sponsor's Protocol Code Number:1-10-72-356-12
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-02-12
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2012-003939-27
    A.3Full title of the trial
    Objective evaluation of the effects of pasireotide on gastrointestinal and colorectal transit times, rectal wall properties, and postprandial response in patients with carcinoid diarrhea
    Undersøgelse af pasireotids effekt på transittiden gennem tarmen, endetarmens egenskaber samt respons efter fødeindtag hos patienter med diare grundet en neuroendokrin tumor
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Objective evaluation of the effects of pasireotide on gastrointestinal and colorectal transit times, rectal wall properties, and postprandial response in patients with carcinoid diarrhea
    Undersøgelse af pasireotids effekt på transittiden gennem tarmen, endetarmens egenskaber samt respons efter fødeindtag hos patienter med diare grundet en neuroendokrin tumor
    A.4.1Sponsor's protocol code number1-10-72-356-12
    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 SponsorKlaus Krogh
    B.1.3.4CountryDenmark
    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 supportNovartis
    B.4.2CountryDenmark
    B.4.1Name of organisation providing supportAarhus University
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTine Gregersen
    B.5.2Functional name of contact pointTine Gregersen
    B.5.3 Address:
    B.5.3.1Street AddressNørrebrogade 44, bulid. 7, 3
    B.5.3.2Town/ cityAarhus
    B.5.3.3Post code8000
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4522334161
    B.5.6E-mailtg@ki.au.dk
    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 Signifor 0.6 mg s.c.
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/671
    D.3 Description of the IMP
    D.3.4Pharmaceutical form 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 INNPasireotide
    D.3.9.1CAS number 396091-73-9
    D.3.9.3Other descriptive namePASIREOTIDE
    D.3.9.4EV Substance CodeSUB31564
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.6
    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
    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
    Patients with neuroendocrine tumors and carcinoid diarrhea
    E.1.1.1Medical condition in easily understood language
    Patients with neuroendocrine tumors and diarrhea caused by the hormones released by the tumor
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level LLT
    E.1.2Classification code 10062476
    E.1.2Term Neuroendocrine tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare gastrointestinal transit times and motility patterns in NET patients, with diarrhea (3 or more bowel movements/day) when treated with either a) pasireotide 600 µg s.c. * 2/day or b) placebo.
    And
    To compare rectal wall properties and the postprandial response in NET patients, with diarrhea (3 or more bowel movements/day) when treated with either a) pasireotide 600 µg s.c. * 2/day or b) placebo.
    And
    To describe gastrointestinal transit times and motility patterns in NET patients, with diarrhea (3 or more bowel movements/day) and compare that to healthy subjects.
    And
    To describe rectal wall properties and the postprandial response in NET patients, with diarrhea (3 or more bowel movements/day) and compare that to healthy subjects.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The study consists of 4 sub-studies.
    Only one title but with 4 objectives, pointed out above.
    E.3Principal inclusion criteria
    In substudy 1 and 2 all inclusion criteria listed below have to be fulfilled. In substudy 3 and 4 inclusion criteria 1-7 have to be fulfilled.
    1. Male or female patients  18 years of age
    2. NET confirmed by histology
    3. Diarrhea, (at least 3 bowel movements per day) as part of carcinoid syndrome
    4. Treatment naïve or without treatment with long-acting SA for at least eight weeks or short acting SA for at least 14 days
    5. WHO/ ECOG Performance Status of 0-2.
    6. Life expectancy 12 weeks
    7. Written informed consent obtained prior to any screening procedures
    8. Patients with a known history of impaired fasting blood glucose (glucose >100 and <126 (>5.5mmol/l and <7 mmol/l)) may be included at the discretion of the PI. These patients will be monitored closely throughout the trial and anti-hyperglycemic treatment adjusted as necessary. Patients that are deemed non eligible due to elevated glucose can be re-screened after adequate medical treatment if not started in other SA treatment
    9. Adequate end organ function as defined by:
    • Adequate bone marrow function:
    • WBC ≥ 2.5 x 109/L
    • Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
    • Platelets ≥ 100 x 109/L
    • Hb ≥ 9 g/dL (≥5.6 mmol/l)
    • No evidence of significant liver disease:
    • Serum bilirubin ≤1.5 x ULN
    • INR < 1.3
    • ALT and AST ≤ 3 x ULN
    • Serum creatinine ≤ 2.0 mg/dl and estimated glomerular filtration rate (eGFR) > 30 ml/min/m2
    • Serum amylase ≤ 1.5 x ULN
    • Alkaline phosphatase ≤ 2.5 x ULN
    10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
    E.4Principal exclusion criteria
    In substudy 1 and 2 all exclusion criteria listed below have to be fulfilled. In substudy 3 and 4 exclusion criteria 1-5 have to be fulfilled.
    1. Patients with known malabsorption syndrome, short bowel or chologenic diarrhea not controlled by specific therapeutic means.
    2. Patients who have undergone major surgery/surgical therapy for any cause within 1 month. Patients should have recovered from the treatment and have good clinical condition before entering the study.
    3. Patients who have any current or prior medical condition that may interfere with the conduct of the study or the study or the evaluation of its results.
    4. Use of an investigational drug within 1 month prior to dosing
    5. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
    6. Female patients who are pregnant or lactating, or are of childbearing potential (defined as all women physiologically capable of becoming pregnant) and not practicing an effective method of contraception/birth control. Sexually active males must use a condom during intercourse while taking the drug and for 2 months after the last dose of study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Effective contraception methods include:
    • Use of oral, injected or implanted hormonal methods of contraception or
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
    • Total abstinence or patient sterilization (male or female)
    7. Patients with a known hypersensitivity to SA or any component of the pasireotide s.c. formulation.
    8. Patients with abnormal coagulation (PT or aPTT elevated by 30% above normal limits).
    9. Patients on continuous anticoagulation therapy. Patients who were on anticoagulant therapy must complete a washout period of at least 10 days and have confirmed normal coagulation parameters before study inclusion.
    10. Patients with symptomatic cholelithiasis.
    11. Patients who are not biochemically euthyroid. Patients with known history of hypothyroidism are eligible if they are on adequate and stable replacement thyroid hormone therapy for at least 3 months.
    12. QT-related exclusion criteria:
    • QTcF at screening > 450 msec
    • History of syncope or family history of idiopathic sudden death
    • Sustained or clinically significant cardiac arrhythmias
    • Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or high-grade AV block
    • Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure
    • Family history of long QT syndrome
    • Concomitant medications known to prolong the QT interval.
    • Potassium < or = 3.5 mmol/L

    13. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
    • Uncontrolled diabetes as defined by HbA1c > 8% despite adequate therapy,
    • Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunodeficiency, including a positive HIV test result (ELISA and Western blot). An HIV test will not be required; however, previous medical history will be reviewed.
    • Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with this study treatment.
    • Life-threatening autoimmune and ischemic disorders.
    14. Patients who have a history of another primary malignancy within the last year, with the exception of locally excised non-melanoma skin cancer and carcinoma in situ of uterine cervix. Patients who have had no evidence of disease from another primary cancer for 1 or more years are allowed to participate in the study.
    15. History of pancreatitis
    16. Hepatic related exclusion criteria
    • History of liver disease, such as cirrhosis or chronic active hepatitis B and C.
    • Presence of Hepatitis B surface antigen (HbsAg)
    • Presence of Hepatitis C antibody test (anti-HCV)
    • History of, or current alcohol misuse/abuse within the past 12 months
    • Known gallbladder or bile duct disease, acute or chronic pancreatitis
    • Baseline ALT or AST > 3 x ULN
    • Baseline total bilirubin > 1.5x ULN
    E.5 End points
    E.5.1Primary end point(s)
    The difference in effect of pasireotide and placebo on gastrointestinal transit time and rectal wall stiffness in sub-study 1 and 2. The difference in gastrointestinal transit time and rectal wall stiffness between NET patients with carcinoid diarrhea and healthy subjects.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 15 patients have gone through sub-study 1 and 2 or 3 and 4, however there will be a interim analysis after 10 patients have been through sub-study 1 and 2.
    E.5.2Secondary end point(s)
    Sub-study 1:
    The difference in effect of pasireotide and placebo on:
    Small intestinal transit time
    Velocity through the small intestine
    Gastric emptying
    Orocecal transit time
    Colorectal transit time
    Number of bowel movements/day
    Number of flushing episodes/day
    Chromogranin A and serotonin levels
    Urinary 5HIAA excretion

    Sub-study 2:
    The difference in effect of pasireotide and placebo on:
    Postprandial changes in rectal cross sectional area
    Rectal compliance
    Ractal fasting tone
    Rectal sensibility to distension
    Rectal sensibility to temperature

    Sub-study 3:
    The difference between NET patients with diarrhea and healhty subjects on:
    Small intestinal transit time
    Velocity through the small intestine
    Gastric emptying
    Orocecal transit time
    Colorectal transit time

    Sub-study 4:
    The difference between NET patients with diarrhea and healhty subjects on
    Postprandial changes in rectal cross sectional area
    Rectal compliance
    Ractal fasting tone
    Rectal sensibility to distension
    Rectal sensibility to temperature
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 15 patients have gone through the studies, however there will be a interim analysis after 10 patients have been through sub-study 1 and 2.
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 No
    E.8.1.6Cross over Yes
    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.8.5The 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 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, or if there is a difference in the primary endpoint at the interim analysis after patient number 10's last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 8
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state15
    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 afterwards be treated in accordance with the department policy and usual guidelines for patients with a neuroendocrine tumor
    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 Decision2013-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-08-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-08-19
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