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    Clinical Trial Results:
    An Open-Label Multiple-Dose Study of RZ358 in Patients with Congenital Hyperinsulinism

    Summary
    EudraCT number
    		 2016-004186-83
    Trial protocol
    		 GB   DE   DK   BG   ES  
    Global end of trial date
    14 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Dec 2023
    First version publication date
    01 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RZ358-606
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04538989
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND Number: 119319
    Sponsors
    Sponsor organisation name
    Rezolute, Inc
    Sponsor organisation address
    275 Shoreline Drive, Suite 500, Redwood City, United States, CA 94065
    Public contact
    Clinical Trials Info, Rezolute, Inc, +1 650206-4507, info@rezolutebio.com
    Scientific contact
    Clinical Trials Info, Rezolute, Inc, +1 650206-4507, info@rezolutebio.com
    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
    19 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and glycemic efficacy of multiple ascending doses of RZ358 administered for 8 weeks in patients with hyperinsulinemic hypoglycemia due to congenital hyperinsulinism (CHI).
    Protection of trial subjects
    Children represented the primary target population for RZ358 and younger patients with CHI tend to have the most severe disease and most significant unmet need, so it was desirable and necessary to conduct the clinical trial in younger-age children to fully understand the efficacy and safety in this population. The combined non-clinical and clinical PK, PD, and safety data available supported a good benefit-to-risk rationale for conducting the study in adults and children aged 2 and above. Protection and safety of children was ensured (including minimisation of risks and burden) through use of appropriately trained staff and paediatric experts available at the trial sites. Furthermore, during the development of the RZ358-606 protocol, patients and families from the patient advocacy group Congenital Hyperinsulinism International were involved in the design of the study to ensure that the patient and parent perspectives were taken into consideration. The main aims of their involvement were to minimise risk and burden for participants and their families. At any sign of distress the trial procedure could be stopped; and time allowed for the child to feel in control and to allow further age appropriate explanation. Assessments were made on an ongoing basis to continue or abandon the procedure if the child remained distressed, or even withdraw the child from the trial.
    Background therapy
    		 The trial design was an add-on to existing therapies (diazoxide, lanreotide, sirolimus, pasireotide, or octreotide and/or nutritional supplementation) when those therapies had substantially failed the patient and they had significant residual hypoglycemia, whether or not they adequately tolerated those same therapies.
    Evidence for comparator
    		 Not applicable, no comparators used in this study.
    Actual start date of recruitment
    24 Feb 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Georgia: 1
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    23
    EEA total number of subjects
    6
    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)
    19
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment began on 24 February 2020 and finished on 13 Jan 2022. Participants were recruited from Bulgaria, Canada, Denmark, Germany, Spain, UK, Georgia, Israel, Turkey, Russia and the USA.

    Pre-assignment
    Screening details
    		 There was a 10 day CGM and gylcemic eligibility evaluation as part of the screening. Those who experienced glucose values <70 mg/dL (3.9 mmol/L) for ≥4% of the overall monitored CGM time with at least 3 severe hypoglycemia events by CGM threshold of <50 mg/dL (2.8 mmol/L) during the last 7 days of evaluation period were eligible per this criteria

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RZ358-606 Cohort 1_Overall
    Arm description
    		 Includes baseline, treatment, and follow-up periods. Baseline is defined as the last non-missing value. For aggregate/integrated glycemic endpoints by SMBG or CGM, Baseline was defined as the cumulative ≥ 10-day period of SMBG or CGM measurement preceding the first dose, and the on-treatment efficacy evaluable period (8 weeks) was defined as the cumulative 2-week period of SMBG and CGM measurement following the last dose of RZ358.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RZ358
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the 8 week treatment period patients in this cohort received RZ358 3mg/kg as an IV infusion over 30 minutes every two weeks. No treatment was received during the baseline or follow-up periods.

    Arm title
    		 RZ358-606 Cohort 2_Overall
    Arm description
    		 Includes baseline, treatment, and follow-up periods. Baseline is defined as the last non-missing value. For aggregate/integrated glycemic endpoints by SMBG or CGM, Baseline was defined as the cumulative ≥ 10-day period of SMBG or CGM measurement preceding the first dose, and the on-treatment efficacy evaluable period (8 weeks) was defined as the cumulative 2-week period of SMBG and CGM measurement following the last dose of RZ358.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RZ358
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the 8 week treatment period patients in this cohort received RZ358 6mg/kg as an IV infusion over 30 minutes every two weeks. No treatment was received during the baseline or follow-up periods.

    Arm title
    		 RZ358-606 Cohort 3_Overall
    Arm description
    		 Includes baseline, treatment, and follow-up periods. Baseline is defined as the last non-missing value. For aggregate/integrated glycemic endpoints by SMBG or CGM, Baseline was defined as the cumulative ≥ 10-day period of SMBG or CGM measurement preceding the first dose, and the on-treatment efficacy evaluable period (8 weeks) was defined as the cumulative 2-week period of SMBG and CGM measurement following the last dose of RZ358.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RZ358
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the 8 week treatment period patients in this cohort received RZ358 9mg/kg as an IV infusion over 30 minutes every two weeks. No treatment was received during the baseline or follow-up periods.

    Arm title
    		 RZ358-606 Cohort 4_Overall
    Arm description
    		 Includes baseline, treatment, and follow-up periods. Baseline is defined as the last non-missing value. For aggregate/integrated glycemic endpoints by SMBG or CGM, Baseline was defined as the cumulative ≥ 10-day period of SMBG or CGM measurement preceding the first dose, and the on-treatment efficacy evaluable period (8 weeks) was defined as the cumulative 2-week period of SMBG and CGM measurement following the last dose of RZ358.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RZ358
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the 8 week treatment period, patients in this cohort received RZ358as an IV infusion over 30 minutes every two weeks (bi-weekly fixed dose-titration from 3 to 9 mg/kg for the first 4 weeks, followed by a fixed 9 mg/kg dose amount thereafter for the remaining 4 weeks). No treatment was received during the baseline or follow-up periods.

    Number of subjects in period 1
    		RZ358-606 Cohort 1_Overall RZ358-606 Cohort 2_Overall RZ358-606 Cohort 3_Overall RZ358-606 Cohort 4_Overall
    Started
    4
    8
    8
    3
    Completed
    4
    8
    8
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Reporting group values
    		 Overall Total
    Number of subjects
    		 23 23
    Age categorical
    All subjects were age 2-64 years
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 19 19
        Adolescents (12-17 years)
    		 3 3
        Adults (18-64 years)
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.7 ( 5.50 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 13 13
    Standard of Care Treatment at Study Entry
    Units: Subjects
        Diazoxide
    		 6 6
        Somatostatin Analogs
    		 8 8
        Somatostatin Analogs and Continuous Enteral Nutrit
    		 3 3
        Somatostatin Analogs and Sirolimus
    		 1 1
        Diazoxide and Continuous Enteral Nutrition
    		 1 1
        Pancreatectomy
    		 3 3
        Diazoxide and Pancreatectomy
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    RZ358-606 Cohort 1_Overall
    Reporting group description
    		 Includes baseline, treatment, and follow-up periods. Baseline is defined as the last non-missing value. For aggregate/integrated glycemic endpoints by SMBG or CGM, Baseline was defined as the cumulative ≥ 10-day period of SMBG or CGM measurement preceding the first dose, and the on-treatment efficacy evaluable period (8 weeks) was defined as the cumulative 2-week period of SMBG and CGM measurement following the last dose of RZ358.

    Reporting group title
    RZ358-606 Cohort 2_Overall
    Reporting group description
    		 Includes baseline, treatment, and follow-up periods. Baseline is defined as the last non-missing value. For aggregate/integrated glycemic endpoints by SMBG or CGM, Baseline was defined as the cumulative ≥ 10-day period of SMBG or CGM measurement preceding the first dose, and the on-treatment efficacy evaluable period (8 weeks) was defined as the cumulative 2-week period of SMBG and CGM measurement following the last dose of RZ358.

    Reporting group title
    RZ358-606 Cohort 3_Overall
    Reporting group description
    		 Includes baseline, treatment, and follow-up periods. Baseline is defined as the last non-missing value. For aggregate/integrated glycemic endpoints by SMBG or CGM, Baseline was defined as the cumulative ≥ 10-day period of SMBG or CGM measurement preceding the first dose, and the on-treatment efficacy evaluable period (8 weeks) was defined as the cumulative 2-week period of SMBG and CGM measurement following the last dose of RZ358.

    Reporting group title
    RZ358-606 Cohort 4_Overall
    Reporting group description
    		 Includes baseline, treatment, and follow-up periods. Baseline is defined as the last non-missing value. For aggregate/integrated glycemic endpoints by SMBG or CGM, Baseline was defined as the cumulative ≥ 10-day period of SMBG or CGM measurement preceding the first dose, and the on-treatment efficacy evaluable period (8 weeks) was defined as the cumulative 2-week period of SMBG and CGM measurement following the last dose of RZ358.

    Subject analysis set title
    Per Protocol_Baseline_Cohort 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Baseline_Cohort 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Baseline_Cohort 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Baseline_Cohort 4
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Baseline_Total
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Treatment_Cohort 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Treatment_Cohort 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Treatment_Cohort 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Treatment_Cohort 4
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Treatment_Total
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Change from Baseline_Cohort 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Change from Baseline_Cohort 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Change from Baseline_Cohort 3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Change from Baseline_Cohort 4
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    Per Protocol_Change from Baseline_Total
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least 4 Wks of study drug (2 bi-weekly doses), with no major protocol violations. A patient in the Per protocol population was excluded from one or more specific efficacy analyses (i.e., SMBG-related endpoints or CGM-related endpoints), if they had a major protocol deviation affecting only that endpoint (e.g., non-compliance with SMBG only, or non-compliance with CGM only).

    Subject analysis set title
    PK population_Cohort 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received study drug and have a sufficient number and quality (biologically plausible) of results.

    Subject analysis set title
    PK population_Cohort 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received study drug and have a sufficient number and quality (biologically plausible) of results.

    Subject analysis set title
    PK population_Cohort 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received study drug and have a sufficient number and quality (biologically plausible) of results.

    Subject analysis set title
    PK population_Cohort 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received study drug and have a sufficient number and quality (biologically plausible) of results.

    Primary: The glycemic efficacy of RZ358 as evaluated by the average daily percent time within a glucose target range of 70-180 mg/dL (3.9-10 mmol/L) by CGM.

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    End point title
    		 The glycemic efficacy of RZ358 as evaluated by the average daily percent time within a glucose target range of 70-180 mg/dL (3.9-10 mmol/L) by CGM. [1]
    End point description
    This was not a powered study; thus, the primary and key, clinically-relevant secondary efficacy endpoints are interchangeable from a statistical perspective and should be interpreted accordingly, for this proof-of-concept study. Time in range, 70-180 mg/dL, was also assessed by CGM. Across all doses, there was an improvement in time spent in range by 8%. A response of 16% was observed at the highest dose and a more pronounced response of >25% was observed in patients without baseline hyperglycemia on SOC. RZ358’s ability to increase time and range spent in normoglycemia by >25% in patients who were not on background therapies without hyperglycemia further establishes its potential as a monotherapy for congenital HI
    End point type
    Primary
    End point timeframe
    Baseline and end of treatment. EOT is defined as the period of the final dose plus 14 days
    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: The statistics for this endpoint cannot be correctly reported due to the limitations of this system.
    End point values
    		 Per Protocol_Baseline_Cohort 1 Per Protocol_Baseline_Cohort 2 Per Protocol_Baseline_Cohort 3 Per Protocol_Baseline_Cohort 4 Per Protocol_Baseline_Total Per Protocol_Treatment_Cohort 1 Per Protocol_Treatment_Cohort 2 Per Protocol_Treatment_Cohort 3 Per Protocol_Treatment_Cohort 4 Per Protocol_Treatment_Total Per Protocol_Change from Baseline_Cohort 1 Per Protocol_Change from Baseline_Cohort 2 Per Protocol_Change from Baseline_Cohort 3 Per Protocol_Change from Baseline_Cohort 4 Per Protocol_Change from Baseline_Total
    Number of subjects analysed
    4
    8
    7
    3
    22
    4
    8
    7
    3
    22
    4
    8
    7
    3
    22
    Units: percent
        arithmetic mean (standard deviation)
    81.528 ( 6.916 )
    74.221 ( 8.028 )
    68.997 ( 27.894 )
    67.643 ( 16.898 )
    72.990 ( 17.369 )
    85.958 ( 8.994 )
    74.839 ( 16.420 )
    79.367 ( 13.247 )
    72.433 ( 8.661 )
    77.973 ( 13.402 )
    4.430 ( 4.222 )
    0.618 ( 19.491 )
    10.370 ( 21.777 )
    4.790 ( 9.818 )
    4.983 ( 17.054 )
    No statistical analyses for this end point

    Primary: Repeat-dose PK of RZ358

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    End point title
    		 Repeat-dose PK of RZ358 [2]
    End point description
    All patients who received RZ358 and for whom the primary PK data was considered to be sufficient and interpretable were to be included in the PK analyses. Individual and mean plasma concentration data is summarized descriptively at the specified timepoints. The results of this study may be combined with those of other studies for analysis and modeling (e.g., population PK and PK-PD), and therefore the PK parameters are reported separately, as part of an iterative population PK approach.
    End point type
    Primary
    End point timeframe
    From pre-dose and 1 h after the start of infusion on each dosing day, 24 h post-dose on Day 2 of each dosing Wk, 48 h post-dose on Day 3 (Wk 1 only), and at outpatient follow-up visits.
    Notes
    [2] - 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: The results of this study may be combined with those of other studies for analysis and modeling (e.g.,population PK and PK-PD), and therefore the PK parameters are reported separately, as part of an iterative population PK approach
    End point values
    		 PK population_Cohort 1 PK population_Cohort 2 PK population_Cohort 3 PK population_Cohort 4
    Number of subjects analysed
    4 [3]
    8 [4]
    8 [5]
    3 [6]
    Units: Concentration µg/mL
    geometric mean (standard deviation)
        pre Wk1 dose
    0 ( 0 )
    0 ( 0 )
    55648 ( 0 )
    0 ( 0 )
        1 hr post Wk1/D1 dose
    29093 ( 43188 )
    120368 ( 36668 )
    164047 ( 54035 )
    43593 ( 8835 )
        pre Wk3 dose
    38951 ( 28296 )
    28397 ( 5936 )
    41512 ( 13015 )
    8961 ( 1703 )
        pre Wk5 dose
    20692 ( 0 )
    82646 ( 120416 )
    74457 ( 15208 )
    34243 ( 8130 )
        pre Wk7 dose
    31902 ( 0 )
    56919 ( 18798 )
    95721 ( 22293 )
    55532 ( 10717 )
        1hr post Wk7 dose
    94593 ( 0 )
    178090 ( 47312 )
    280843 ( 131841 )
    245905 ( 144257 )
        FU Day 14/EOT
    59542 ( 17383 )
    70990 ( 16506 )
    105005 ( 19779 )
    110134 ( 17019 )
        FU Day 28
    46751 ( 45750 )
    39385 ( 10560 )
    63201 ( 19423 )
    52039 ( 5015 )
        FU Day 42
    23166 ( 6686 )
    24226 ( 24226 )
    43034 ( 11961 )
    37394 ( 10540 )
        FU Day 105
    2307 ( 953 )
    4231 ( 5508 )
    9269 ( 3944 )
    4194 ( 1786 )
    Notes
    [3] - At pre Wk1, Wk5 and Wk7 dose, only data for 1 patient is available, hence SD is entered as 0
    [4] - No patients analysed at preWk1 dose and on FU Day 28 7pts analysed.
    [5] - 1 patient analysed at preWk1 dose and 7 patients at 1hr post dose Wk1, preWk3, FU Day 14 &105
    [6] - No patients analysed at preWk1 dose, hence mean & SD is entered as 0
    No statistical analyses for this end point

    Secondary: Average weekly incidence of hypoglycemia (< 70 mg/dL) by self-monitored blood glucose (SMBG)

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    End point title
    		 Average weekly incidence of hypoglycemia (< 70 mg/dL) by self-monitored blood glucose (SMBG)
    End point description
    This was not a powered study; thus, the primary and key, clinically-relevant secondary efficacy endpoints are interchangeable from a statistical perspective and should be interpreted accordingly, for this proof-of-concept study. Significant and generally dose-dependent improvements from baseline in total (<70 mg/dL) hypoglycemia events were observed by BGM, with a mean improvement of approximately 50-70% (p ≤0.01) for the pooled RZ358 treated subjects across all doses.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment. EOT is defined as the period of the final dose plus 14 days.
    End point values
    		 Per Protocol_Baseline_Cohort 1 Per Protocol_Baseline_Cohort 2 Per Protocol_Baseline_Cohort 3 Per Protocol_Baseline_Cohort 4 Per Protocol_Baseline_Total Per Protocol_Treatment_Cohort 1 Per Protocol_Treatment_Cohort 2 Per Protocol_Treatment_Cohort 3 Per Protocol_Treatment_Cohort 4 Per Protocol_Treatment_Total Per Protocol_Change from Baseline_Cohort 1 Per Protocol_Change from Baseline_Cohort 2 Per Protocol_Change from Baseline_Cohort 3 Per Protocol_Change from Baseline_Cohort 4 Per Protocol_Change from Baseline_Total
    Number of subjects analysed
    3
    8
    7
    2
    20
    3
    8
    7
    2
    20
    3
    8
    7
    2
    20
    Units: average events per week
        arithmetic mean (standard deviation)
    10.070 ( 3.065 )
    15.939 ( 15.554 )
    16.181 ( 7.609 )
    9.295 ( 1.704 )
    14.479 ( 10.790 )
    8.640 ( 2.735 )
    8.999 ( 7.891 )
    5.057 ( 8.388 )
    7.595 ( 2.963 )
    7.425 ( 7.053 )
    -1.430 ( 5.673 )
    -6.940 ( 10.126 )
    -11.124 ( 5.500 )
    -1.700 ( 1.259 )
    -7.054 ( 8.057 )
    No statistical analyses for this end point

    Secondary: Average daily percent time with hypoglycemia at threshold of <70mg/dL (3.9 mmol/L) by continuous glucose monitoring

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    End point title
    		 Average daily percent time with hypoglycemia at threshold of <70mg/dL (3.9 mmol/L) by continuous glucose monitoring
    End point description
    This was not a powered study; thus, the primary and key, clinically-relevant secondary efficacy endpoints are interchangeable from a statistical perspective and should be interpreted accordingly, for this proof-of-concept study. Improvements in duration of hypoglycemia by CGM were comparable to the observed reductions in hypoglycemia events by BGM. There was a ≥25% reduction in average daily percent time with hypoglycemia by CGM at the threshold of <70mg/dL by CGM across all dosing cohorts. Cohorts 2 and 3 experienced decreases from baseline in average daily percent time spent in hypoglycemia of 59% (p<0.01) and 65%, respectively. The difference in magnitude of improvement of hypoglycemia among cohorts elucidates a clear dose-response relationship.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment. EOT is defined as the period of the final dose plus 14 days
    End point values
    		 Per Protocol_Baseline_Cohort 1 Per Protocol_Baseline_Cohort 2 Per Protocol_Baseline_Cohort 3 Per Protocol_Baseline_Cohort 4 Per Protocol_Baseline_Total Per Protocol_Treatment_Cohort 1 Per Protocol_Treatment_Cohort 2 Per Protocol_Treatment_Cohort 3 Per Protocol_Treatment_Cohort 4 Per Protocol_Treatment_Total Per Protocol_Change from Baseline_Cohort 1 Per Protocol_Change from Baseline_Cohort 2 Per Protocol_Change from Baseline_Cohort 3 Per Protocol_Change from Baseline_Cohort 4 Per Protocol_Change from Baseline_Total
    Number of subjects analysed
    4
    8
    7
    3
    22
    4
    8
    7
    3
    22
    4
    8
    7
    3
    22
    Units: percent
        arithmetic mean (standard deviation)
    16.338 ( 5.345 )
    21.675 ( 8.821 )
    26.281 ( 29.684 )
    29.213 ( 16.351 )
    23.198 ( 18.039 )
    10.425 ( 5.745 )
    9.533 ( 7.760 )
    9.649 ( 11.838 )
    16.273 ( 9.127 )
    10.651 ( 8.837 )
    -5.913 ( 3.003 )
    -12.143 ( 10.136 )
    -16.633 ( 20.893 )
    -12.940 ( 7.380 )
    -12.547 ( 13.397 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported from the time of informed consent for participation in the study until the end of study visit.
    Adverse event reporting additional description
    A total of 41 TEAEs occurred in 16 subjects over the evaluation period, compared to a total of 17 non-TEAEs in 10 subjects that occurred over the ~1 month pre-treatment period. Therefore, on a time-adjusted basis, there was no significant difference in the number of AEs during RZ358 treatment compared to pre-treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cohort 1_Safety Population
    Reporting group description
    		 Cohort 1, 3mg/kg

    Reporting group title
    Cohort 2_Safety Population
    Reporting group description
    		 Cohort 2, 6mg/kg

    Reporting group title
    Cohort 3_Safety Population
    Reporting group description
    		 Cohort 3, 9mg/kg

    Reporting group title
    Cohort 4_Safety Population
    Reporting group description
    		 Bi-weekly fixed dose-titration from 3 to 9 mg/kg for the first 4 weeks, followed by a fixed 9 mg/kg dose amount thereafter for the remaining 4 weeks

    Reporting group title
    Non-TEAE_Safety Population
    Reporting group description
    		 AEs that occurred pre-treatment and after 42 days post treatment

    Serious adverse events
    		 Cohort 1_Safety Population Cohort 2_Safety Population Cohort 3_Safety Population Cohort 4_Safety Population Non-TEAE_Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 8 (25.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1_Safety Population Cohort 2_Safety Population Cohort 3_Safety Population Cohort 4_Safety Population Non-TEAE_Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    7 / 8 (87.50%)
    5 / 8 (62.50%)
    2 / 3 (66.67%)
    10 / 23 (43.48%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    General disorders and administration site conditions
    Extravasation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infusion site reaction
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Medical device pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Respiratory disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    0
    0
    1
    Eye disorders
    Chalazion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acanthosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    1
    1
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dermatitis atopic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypertrichosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    0
    0
    0
    2
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Sacral pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    0
    1
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    0
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 3 (33.33%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    1
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    1
    0
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    1
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2016
    Amendment 1 - protocol version not implemented and no patients were recruited under this version
    10 May 2017
    Amendment 2 - protocol version not implemented and no patients were recruited under this version
    12 Aug 2019
    Amendment 3 - Protocol version implemented for patient recruitment (1 patient enrolled)
    19 May 2020
    Amendment 4 - The Protocol inclusion criteria and endpoints were amended slightly
    17 Mar 2021
    Amendment 5 - The dosing frequency and visit schedule were reduced

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Not applicable
    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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