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    Clinical Trial Results:
    Open-Label Study to Evaluate Long Term Safety and Treatment Effect of DiaPep277® in Subjects who Have Completed Study 1001 (EudraCT No.: 2009-015929-37)

    Summary
    EudraCT number
    		 2013-002775-17
    Trial protocol
    		 IT   CZ   HU   AT   LT   ES   PL  
    Global end of trial date
    02 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2016
    First version publication date
    16 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01898286
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Andromeda Biotech Ltd.
    Sponsor organisation address
    42 Hayarkon St., Yavne, Israel, 81227
    Public contact
    42 Hayarkon St. Industrial Area, Yavne 81227, Israel, Andromeda Biotech Ltd., 42 Hayarkon St. Industrial Area, Yavne 81227, Israel, Andromeda Biotech Ltd., +972 8 9387777,
    Scientific contact
    42 Hayarkon St. Industrial Area, Yavne 81227, Israel, Andromeda Biotech Ltd., 42 Hayarkon St. Industrial Area, Yavne 81227, Israel, Andromeda Biotech Ltd., +972 8 9387777,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This is an extension study to evaluate the safety and tolerability of long-term treatment with DiaPep277® and to determine the long-term treatment effect of DiaPep277® on parameters of metabolic control and on preservation of beta-cell function in subjects who have long exposure to DiaPep277®.
    Protection of trial subjects
    The Guidelines of the World Medical Association Declaration of Helsinki in its revised edition (64th World Medical Association General Assembly, Fortaleza, Brazil, October 2013), the Guidelines of International Conference of Harmonization (ICH) Good Clinical Practice (GCP) (CPMP/ICH/135/95), and the demands of national drug and data protection laws and other applicable regulatory requirements were followed during this study. This study also conformed to the laws and regulations of the countries in which it was conducted, as well as any applicable guidelines. All personnel involved in the study worked within the confines of the European Data Protection Directive as interpreted by each country’s laws.
    Background therapy
    		 -
    Evidence for comparator
    		 Not applicable (Intervention Model: Single Group Assignment)
    Actual start date of recruitment
    08 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    United States: 13
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Germany: 4
    Worldwide total number of subjects
    38
    EEA total number of subjects
    15
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    38
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects diagnosed with Type 1 diabetes mellitus up to six months before randomization to Study 1001 (EudraCT No.: 2009-015929-37), from medical sites in the EU, US, Russia, and Israel.

    Pre-assignment
    Screening details
    		 Ninety-nine subjects were screened for the study, 61 subjects failed screening and 38 subjects were enrolled: all 38 enrolled subjects completed the Baseline-Ext Visit (Month 0). The total duration of this study was planned to be up to 26 months: due to the early termination of the study, no subject reached the 9 month visit.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-Label

    Arms
    Arm title
    		 All 1010 Study Subjects treated with DiaPep277®
    Arm description
    		 All subjects enrolled in the 1010 study, whether previously treated with DiaPep277 or placebo in the 1001 study (EudraCT No.: 2009-015929-37). Subjects who completed the 1001 study and maintained clinically significant beta-cell function were offered a 2-year continuation of active treatment, since they were likely to benefit from use of the medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DiaPep277®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administration of DiaPep277® to subjects previously enrolled in the Phase 3 Study 1001 (EudraCT No.: 2009-015929-37): 1 mg of DiaPep277® subcutaneously in the upper arm at 0, 3, 6, 9, 12, 15, 18, and 21 months, for a total of 8 administrations.

    Number of subjects in period 1
    		All 1010 Study Subjects treated with DiaPep277®
    Started
    38
    Completed
    0
    Not completed
    38
         Consent withdrawn by subject
    1
         Premature Termination by the Sponsor
    36
         Dermal hypersensitivity
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 Treatment with DiaPep277® is expected to be long-term; stopping treatment may result in the eventual loss of the preserved beta-cell function. Indeed, extension of phase 2 studies has shown that subjects who were initially treated with DiaPep277® and maintained their initial beta-cell function, required continuation of treatment, losing beta-cell function if switched to Placebo. These extension studies were too small for the outcome to be statistically significant, but they suggested that continuation of treatment is needed for long-term maintenance of efficacy. Therefore, in this extension study, subjects who completed the 1001 study and maintained clinically significant beta-cell function were offered a 2-year continuation of active treatment, since they were likely to benefit from use of the medication. Sponsor prematurely ended the study hence this report presents the data of subjects assessed until the study end.

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 38 38
    Age categorical
    Units: Subjects
        ≤ 27 years
    		 11 11
        > 27 years
    		 27 27
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.16 ( 7.343 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 27 27
    Race
    Units: Subjects
        Caucasian
    		 33 33
        Hispanic
    		 1 1
        Black
    		 3 3
        Asian
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    All 1010 Study Subjects treated with DiaPep277®
    Reporting group description
    		 All subjects enrolled in the 1010 study, whether previously treated with DiaPep277 or placebo in the 1001 study (EudraCT No.: 2009-015929-37). Subjects who completed the 1001 study and maintained clinically significant beta-cell function were offered a 2-year continuation of active treatment, since they were likely to benefit from use of the medication.

    Subject analysis set title
    DiaPep277® - DiaPep277® group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who received DiaPep277® in both 1001 (EudraCT No.: 2009-015929-37) and the current study.

    Subject analysis set title
    Placebo - DiaPep277® group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who received Placebo in 1001 (EudraCT No.: 2009-015929-37) and DiaPep277® in the current study

    Primary: Hypoglycemic events

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    End point title
    		 Hypoglycemic events [1]
    End point description
    The number of hypoglycemic events recorded by each subject over the course of the study: due to this study's early termination and the submission of an abbreviated CSR, the number of hypoglycemic events of all 38 study subjects were not reported separately by the two subject analysis sets DiaPep277® - DiaPep277® and Placebo-DiaPep277®.
    End point type
    Primary
    End point timeframe
    At early termination visit, up to 25 months.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the early termination of the study, many of the endpoints described in the protocol could not be adequately assessed and a full SAP was not written. Hypoglycemic events from Continuous Glucose Monitoring System (CGMS) were listed as efficacy parameters: CGMS data were not evaluated
    End point values
    		 All 1010 Study Subjects treated with DiaPep277®
    Number of subjects analysed
    16
    Units: Hypoglycemic events
        arithmetic mean (standard deviation)
    3.3 ( 3.3 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Glucagon-stimulated C-peptide AUC at Early Termination Visit - Pancreatic Beta-cell Function

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    End point title
    		 Change From Baseline in Glucagon-stimulated C-peptide AUC at Early Termination Visit - Pancreatic Beta-cell Function
    End point description
    Beta-cell function, measured as change in stimulated C-peptide secretion measured 0, 2, 6, 10 and 20 minutes post administration [area under the curve (AUC), 0-20 minutes] at Baseline and the early termination visit (up to 25 months), during a glucagon stimulation test (GST). Change was calculated for each subject by substracting the baseline AUC value (defined as the last non-missing assessment prior to first dose in the 1010 study but after the end of study 1001 - EudraCT No.: 2009-015929-37) from the early termination visit AUC.
    End point type
    Secondary
    End point timeframe
    Baseline and Early Termination Visit, up to 25 months.
    End point values
    		 All 1010 Study Subjects treated with DiaPep277® DiaPep277® - DiaPep277® group Placebo - DiaPep277® group
    Number of subjects analysed
    9 [2]
    4 [3]
    5 [4]
    Units: nmol*minute/L
        arithmetic mean (standard deviation)
    0.2 ( 2.334 )
    1.1 ( 2.022 )
    -0.53 ( 2.518 )
    Notes
    [2] - Mean change from Baseline-Ext
    [3] - Mean change from Baseline-Ext
    [4] - Mean change from Baseline-Ext
    No statistical analyses for this end point

    Other pre-specified: Glycemic Control

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    End point title
    		 Glycemic Control
    End point description
    Change From Baseline in % HbA1c Due to this study's early termination and the submission of an abbreviated CSR, the number of hypoglycemic events of all 38 study subjects were not reported separately by the two subject analysis sets DiaPep277® - DiaPep277® and Placebo-DiaPep277®.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Early Termination Visit, Up to 25 Months
    End point values
    		 All 1010 Study Subjects treated with DiaPep277®
    Number of subjects analysed
    5
    Units: percent
        arithmetic mean (standard deviation)
    0.46 ( 0.907 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Daily Insulin Dose, Per kg Body Weight, at Early Termination Visit

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    End point title
    		 Change From Baseline in Daily Insulin Dose, Per kg Body Weight, at Early Termination Visit
    End point description
    Due to this study's early termination and the submission of an abbreviated CSR, the number of hypoglycemic events of all 38 study subjects were not reported separately by the two subject analysis sets DiaPep277® - DiaPep277® and Placebo-DiaPep277®.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Early Termination Visit, up to 25 months.
    End point values
    		 All 1010 Study Subjects treated with DiaPep277®
    Number of subjects analysed
    11
    Units: IU/Kg
        arithmetic mean (standard deviation)
    0.025 ( 0.027 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AE) data were collected from the time of subject enrollment through each subject's early termination visit.
    Adverse event reporting additional description
    Due to this study's early termination and the submission of an abbreviated CSR, the AE of all 38 study subjects were not reported separately by the two study arms of DiaPep277®-DiaPep277® and Placebo-DiaPep277®.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    All 1010 Study Subjects treated with DiaPep277®
    Reporting group description
    		 Treatment with DiaPep277® is expected to be long-term; stopping treatment may result in the eventual loss of the preserved beta-cell function. Indeed, extension of phase 2 studies has shown that subjects who were initially treated with DiaPep277® and maintained their initial beta-cell function, required continuation of treatment, losing beta-cell function if switched to Placebo. These extension studies were too small for the outcome to be statistically significant, but they suggested that continuation of treatment is needed for long-term maintenance of efficacy. Therefore, in this extension study, subjects who completed the 1001 study and maintained clinically significant beta-cell function were offered a 2-year continuation of active treatment, since they were likely to benefit from use of the medication.

    Serious adverse events
    		 All 1010 Study Subjects treated with DiaPep277®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 38 (2.63%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 All 1010 Study Subjects treated with DiaPep277®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 38 (23.68%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Blood cholesterol increased
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Social phobia
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jan 2014
    The original protocol dated 18 June 2013, Version 1.0, was amended once during the study with the protocol version 2.0 (dated 20 January 2014). The major changes made in Protocol Version 2.0 are given below: - Modified the study title and study timelines. - Revised text on efficacy parameters and added a new efficacy parameter of CGMS in a subset of subjects. - Clarified text on solvent emulsion that would be supplied. - Added text for abnormal LFTs. - Added text in the study assessment schedule regarding Baseline-Ext visit and CGMS. - Added text on additional laboratory tests on serum antibodies. - Revised text in statistical methods. - Added text regarding informed consent process for optional CGMS.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Sep 2014
    The study was terminated by Hyperion Therapeutics Inc. on 08 September 2014: - All subject enrollment was stopped and no further sites were initiated. - The active sites with active subjects were instructed to follow the procedures for “Data Collection and Follow-up for Early Withdrawn Subjects” as outlined in the protocol. - The Investigators were instructed to bring all active subjects in for an Early Termination visit (Visit 21A) and complete all assessments for this visit according to the study schedule. However, many subjects refused to complete all of the assessments that were outlined for Visit 21A, and hence minimal data was collected at this Early Termination visit. - Due to the early termination of the study, many of the endpoints described in the protocol could not be adequately assessed and a full SAP was not written. The key changes between the planned analyses described in Protocol Version 2.0 and the Final SAP (Version 1.0. dated 23 December 2014) are as follows: 1. Efficacy parameters not evaluated: a. Percent of subjects who achieve HbA1c ≤ 7% . However, as per the Final SAP, only the change from baseline in HbA1c by visit was evaluated. b. “Percent of subjects whose daily dose of insulin is ≤ 0.5 IU/kg at endpoint weighted total insulin dose (units per kg body weight per day) average value”. However, as per the Final SAP, only the change from baseline in daily insulin dose per body weight by visit was evaluated. c. “Mean amplitude of glucose excursions by 4-point glucose profile, average value and change from baseline” d. AUC C-peptide level obtained by the MMTT e. Peak Cmax as an efficacy parameter f. Proportion of subjects in partial remission g. Hypoglycemic and hyperglycemic events (from CGMS) and post-prandial glucose excursions (from CGMS); CGMS data were not evaluated. 2. Safety parameters not evaluated: a. Incidence of treatment-emergent ECG findings b. DiaPep277® specific antibodies
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was prematurely terminated by Sponsor on 08Sep2014 and many of the endpoints described in the protocol could not be adequately assessed and a full SAP was not written (please refer to the above global Interruptions section).
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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