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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy, Safety and Tolerability Study of TV-1106 in Growth Hormone Deficient Adults Who Are Not Current Users of rhGH Treatment

    Summary
    EudraCT number
    2014-003796-32
    Trial protocol
    DE   HU   CZ   IT   AT   ES   SI   LT   GR   PL   BG   RO   SK   HR  
    Global end of trial date
    18 Dec 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Dec 2016
    First version publication date
    26 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV1106-IMM-30021
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02410343
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Pharmaceutical Industries Ltd.
    Sponsor organisation address
    5 Bazel St., Petach Tikva, Israel, 49131
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info-era-clinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, info-era-clinical@teva.de
    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
    01 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to determine the efficacy of 6 months of treatment with TV-1106 compared with placebo on body fat composition. Based on evolving data from the two ongoing global Phase III studies in adults (TV1106-IMM-30021 and -30022) and the ongoing pediatric Phase II study (TV1106-IMM-20001) and as well as the recently completed adult Phase II study (TV1106-GHD-201), the Sponsor Teva Pharmaceuticals Ltd. reassessed the benefit/risk balance of TV-1106 and the likelihood of regulatory success for TV-1106. As a consequence of this reassessment, the Sponsor took the decision to terminate the development of TV-1106 and stop all ongoing clinical trials. Notably, no new safety issues were identified with the administration of TV-1106.
    Protection of trial subjects
    This study was conducted in full accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; EU Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use). Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Apr 2015
    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
    Austria: 1
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    14
    EEA total number of subjects
    5
    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)
    11
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Of the 46 patients screened, 14 patients at 10 centers located in the US and Europe (Austria, Greece, Hungary) met entry criteria and were considered eligible for randomization. Of the 32 patients not randomly assigned to study treatment, 26 were excluded on the basis of inclusion/exclusion criteria and 6 were excluded for "other" reasons

    Pre-assignment
    Screening details
    Participants were randomly allocated to 1 of 2 treatment groups (TV-1106 or placebo) in a 2:1 allocation to prevent selection bias.

    Period 1
    Period 1 title
    Core Period (24 Weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    The 24-week core phase of the study was double-blind, and therefore, the sponsor, investigators, patients, and site staff did not have knowledge of treatment assignment. Blinded persons remained blinded until last patient randomized completed the core phase, at which time analysis of the accrued data from the core phase was to be performed.The central reader was unblinded, as were the bioanalytical scientists. The 48-week extension phase of the study was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. To maintain the blind, placebo could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 to match the effect of dose titration. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Matching placebo
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo treatment was administered in a blinded fashion and titrated on weeks 4, 8, 12 and 16 to mimic the active treatment.

    Arm title
    TV-1106
    Arm description
    TV-1106 was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. A common starting dose was 5.0 mg. Doses could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 until the participant's insulin-like growth factor 1 (IGF-1) standard deviation score (SDS) was within the range of -0.5 to +1.5. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106.
    Arm type
    Experimental

    Investigational medicinal product name
    TV-1106
    Investigational medicinal product code
    Other name
    long-acting growth hormone, albutropin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A starting dose of 5.0 mg was expected to be appropriate for most patients because the daily recommended starting dose of recombinant human growth hormone (rhGH) treatments (e.g. somatropin) is 0.2 mg/day, and the conversion factor was 28. Dosage could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 until the participant's insulin-like growth factor 1 (IGF-1) standard deviation score (SDS) was within the range of -0.5 to +1.5.

    Number of subjects in period 1
    Placebo TV-1106
    Started
    6
    8
    Completed
    1
    1
    Not completed
    5
    7
         Adverse event, non-fatal
             1
             -
         Early termination of study by sponsor
             4
             7
    Period 2
    Period 2 title
    Extension Period (12 Months)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    TV-1106 - Extension Period
    Arm description
    Participants from both the Placebo and TV-1106 groups who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. Due to early termination of the study, two participants spent a maximum of two weeks in the extension period.
    Arm type
    Experimental

    Investigational medicinal product name
    TV-1106
    Investigational medicinal product code
    Other name
    long-acting growth hormone, albutropin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    After completion of the core phase and at initiation of the extension phase (visit 7), all patients were to revert to the starting dose of TV-1106, as determined by the unblinded central reader, to ensure the core phase of the study remained blinded during the transition to the open-label period.

    Number of subjects in period 2
    TV-1106 - Extension Period
    Started
    2
    Completed
    0
    Not completed
    2
         Early termination of study by sponsor
             2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. To maintain the blind, placebo could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 to match the effect of dose titration. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106.

    Reporting group title
    TV-1106
    Reporting group description
    TV-1106 was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. A common starting dose was 5.0 mg. Doses could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 until the participant's insulin-like growth factor 1 (IGF-1) standard deviation score (SDS) was within the range of -0.5 to +1.5. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106.

    Reporting group values
    Placebo TV-1106 Total
    Number of subjects
    6 8 14
    Age categorical
    Units: Subjects
        <40 years
    1 1 2
        >=40 years
    5 7 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.3 ± 12.86 56.4 ± 17.7 -
    Gender categorical
    Units: Subjects
        Female
    3 4 7
        Male
    3 4 7
    Race
    Units: Subjects
        White
    5 7 12
        Missing
    1 1 2
    Growth-Hormone Deficiency Onset
    Units: Subjects
        Adult (>+18 years)
    5 7 12
        Childhood (<18 years)
    1 1 2
    Cause of Growth-Hormone Deficiency
    Units: Subjects
        Secreting pituitary adenoma
    0 1 1
        Non-secreting pituitary adenoma
    3 2 5
        Idiopathic
    0 1 1
        Other
    3 4 7
    Prior Treatment for Growth-Hormone Deficiency
    Units: Subjects
        Yes
    2 1 3
        No
    0 0 0
        Missing
    4 7 11
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    80.963 ± 24.1867 80.448 ± 13.3406 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    175.093 ± 9.1702 170.13 ± 8.5363 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    26.04 ± 6.1675 27.716 ± 3.3512 -
    Insulin-like Growth Factor 1 Standard Deviation Score
    IGF-1 SDS represents the standard deviation from a 'normal' population
    Units: standard deviations
        arithmetic mean (standard deviation)
    -2 ± 0.978 -1.4 ± 0.545 -
    Duration of Growth-Hormone Deficiency Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    9.27 ± 9.312 11.104 ± 13.1631 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. To maintain the blind, placebo could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 to match the effect of dose titration. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106.

    Reporting group title
    TV-1106
    Reporting group description
    TV-1106 was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. A common starting dose was 5.0 mg. Doses could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 until the participant's insulin-like growth factor 1 (IGF-1) standard deviation score (SDS) was within the range of -0.5 to +1.5. Participants who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106.
    Reporting group title
    TV-1106 - Extension Period
    Reporting group description
    Participants from both the Placebo and TV-1106 groups who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. Due to early termination of the study, two participants spent a maximum of two weeks in the extension period.

    Primary: Body Fat Mass at Baseline, Week 24 and Endpoint in Core Period

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    End point title
    Body Fat Mass at Baseline, Week 24 and Endpoint in Core Period [1]
    End point description
    The primary efficacy measure for the study was body fat mass (kg) measured by DXA imaging. The primary outcome as defined in the protocol was the change from baseline to week 24 in body fat mass. Due to the early termination of the study, observed values including endpoint values are reported. Endpoint is the last observed value. Values of 999 indicate not estimable due to single patient being reported.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1, pre-dose), Week 24, Endpoint in Core period
    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: As the study was terminated early, limited efficacy analyses are included. Because the study was terminated while enrollment was ongoing, the sample size was smaller than planned; 14 patients enrolled, 6 of whom received placebo and 8 of whom received TV-1106 during the core phase of the study. Thus, limited efficacy analyses were completed and, as only 2 patients (1 in each treatment group) completed the core phase of the study, no efficacy conclusions were reached.
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [2]
    8 [3]
    Units: kg
    arithmetic mean (standard deviation)
        Baseline (n=6, 8)
    24.38 ± 7.495
    29.5 ± 10.922
        Week 24 (n=1, 1)
    28.9 ± 999
    34.8 ± 999
        Endpoint (n=3, 6)
    23.37 ± 7.389
    31.05 ± 13.256
    Notes
    [2] - Intent to treat population (ITT)
    [3] - Intent to treat population (ITT)
    No statistical analyses for this end point

    Secondary: Total Trunk Fat at Baseline, Week 24 and Endpoint in Core Period

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    End point title
    Total Trunk Fat at Baseline, Week 24 and Endpoint in Core Period
    End point description
    Trunk fat (kg) was assessed based on DXA results. Trunk fat was defined as fat mass - (total arm fat + total leg fat + total head fat). The outcome as defined in the protocol was the within-patient change from baseline to week 24 in trunk fat. Due to the early termination of the study, observed values including endpoint values are reported. Endpoint is the last observed value. Values of 999 indicate not estimable due to reporting a single patient.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [4]
    8 [5]
    Units: kg
    arithmetic mean (standard deviation)
        Baseline (n=6, 8)
    12.02 ± 4.716
    15.05 ± 5.041
        Week 24 (n=1, 1)
    15.6 ± 999
    12.6 ± 999
        Endpoint (n=3, 6)
    11.2 ± 4.173
    15.05 ± 6.369
    Notes
    [4] - ITT
    [5] - ITT
    No statistical analyses for this end point

    Secondary: Insulin-Like Growth Factor 1 Standard Deviation Score (IGF-I SDS) at Baseline, Week 24 and Endpoint in Core Period

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    End point title
    Insulin-Like Growth Factor 1 Standard Deviation Score (IGF-I SDS) at Baseline, Week 24 and Endpoint in Core Period
    End point description
    IGF-I SDS, as reported by the central laboratory, was a key secondary variable. The week 24 value is a trough value as it was taken 7 days after the last TV-1106 or placebo injection. The outcome as defined in the protocol was the within-patient change from baseline to week 24. Due to the early termination of the study, observed values including endpoint values are reported. Endpoint is the last observed value and is of variable length of time since last TV-1106 or placebo injection. Values of 999 = not estimable due to reporting a single patient.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [6]
    8 [7]
    Units: standard deviation score
    arithmetic mean (standard deviation)
        Baseline (n=6, 8)
    -2 ± 0.978
    -1.4 ± 0.545
        Week 24 (n=1, 1)
    -2 ± 999
    -1.3 ± 999
        Endpoint (n=5, 6)
    -1.66 ± 0.493
    -0.67 ± 0.896
    Notes
    [6] - ITT
    [7] - ITT
    No statistical analyses for this end point

    Secondary: Scored Analysis of Quality of Life Assessment of GH Deficiency in Adults (QoL-AGHDA) at Baseline, Week 24 and Endpoint in Core Period

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    End point title
    Scored Analysis of Quality of Life Assessment of GH Deficiency in Adults (QoL-AGHDA) at Baseline, Week 24 and Endpoint in Core Period
    End point description
    The AGHDA instrument is comprised of 25 questions, with yes or no answers. To each of the 25 questions comprising QOL AGHDA, a score of 1 was assigned if the answer was affirmative and 0 if the answer was negative. Data reported is the total score across the 25 questions for a total range of 0-25 with higher scores representing a poorer quality of life. The outcome as defined in the protocol was the within-patient change from baseline to week 24. Due to the early termination of the study, observed values including endpoint values are reported. Endpoint is the last observed value. Values of 999 = not estimable since reporting on a single patient.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Week 24, Endpoint in Core Period
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [8]
    8 [9]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=6, 8)
    3.8 ± 5.46
    9.6 ± 8.14
        Week 24 (n=1, 1)
    1 ± 999
    0 ± 999
        Endpoint (n=6, 8)
    2.8 ± 4.62
    6.5 ± 6.12
    Notes
    [8] - ITT
    [9] - ITT
    No statistical analyses for this end point

    Secondary: Participants With Adverse Events During the Core Period

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    End point title
    Participants With Adverse Events During the Core Period
    End point description
    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 24 Weeks
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [10]
    8 [11]
    Units: participants
        >=1 adverse event
    3
    4
        Severe adverse event
    1
    0
        Treatment-related adverse event
    0
    2
        Deaths
    0
    0
        Other serious adverse events
    1
    0
        Discontinued from study drug due to adverse events
    1
    0
    Notes
    [10] - Safety population
    [11] - Safety population
    No statistical analyses for this end point

    Secondary: Participants With Potentially Clinically Significant Abnormal Blood and Urine Test Results

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    End point title
    Participants With Potentially Clinically Significant Abnormal Blood and Urine Test Results
    End point description
    Parameters with potentially clinically significant abnormal test results include Serum chemistry: blood urea nitrogen, creatinine and bilirubin Hematology: leukocytes, hemoglobin, hematocrit, platelets and neutrophils Urinalysis: none Significance criteria are listed below with the test.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 24 Weeks
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [12]
    8 [13]
    Units: participants
        Blood urea nitrogen: >=10.71 mmol/L
    0
    1
        Creatinine: >=177 mmol/L
    0
    1
        Bilirubin: >=34.2 mmol/L
    2
    0
        Leukocytes: <=3.0 10^9/L
    1
    0
        Hemoglobin: (male) <=115 g/L
    1
    0
        Hematocrit: (male) <0.37 L/L
    1
    0
        Platelets: <=75 10^9/L
    1
    0
        Neutrophils: <=1.0 10^9/L
    1
    0
    Notes
    [12] - Safety
    [13] - Safety
    No statistical analyses for this end point

    Secondary: Shift From Baseline To Endpoint in Core Period in Electrocardiogram Findings

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    End point title
    Shift From Baseline To Endpoint in Core Period in Electrocardiogram Findings
    End point description
    Shifts represented as baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicates an abnormal but not clinically significant finding. Abnormal CS indicates an abnormal and clinically significant finding.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), up to Week 24
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [14]
    8 [15]
    Units: participants
        Normal - Normal
    4
    6
        Normal - Abnormal NCS
    1
    0
        Normal - Abnormal CS
    0
    0
        Abnormal NCS - Normal
    1
    1
        Abnormal NCS - Abnormal NCS
    0
    1
        Abnormal NCS - Abnormal CS
    0
    0
    Notes
    [14] - Safety
    [15] - Safety
    No statistical analyses for this end point

    Secondary: Thyroid Stimulating Hormone (TSH) at Baseline and Endpoint

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    End point title
    Thyroid Stimulating Hormone (TSH) at Baseline and Endpoint
    End point description
    Observed values of TSH which is the first of three thyroid hormones measured.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [16]
    8 [17]
    Units: MIU/L
    arithmetic mean (standard deviation)
        Baseline (n=6, 6)
    0.365 ± 0.3791
    1.028 ± 2.0259
        Endpoint (n=6, 7)
    0.545 ± 0.5439
    0.796 ± 1.6971
    Notes
    [16] - Safety
    [17] - Safety
    No statistical analyses for this end point

    Secondary: Free Thyroxin (Free T4) at Baseline and Endpoint

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    End point title
    Free Thyroxin (Free T4) at Baseline and Endpoint
    End point description
    Observed values of Free T4 which is the second of three thyroid hormones measured.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [18]
    8 [19]
    Units: PMOL/L
    arithmetic mean (standard deviation)
        Baseline (n=6, 7)
    17.22 ± 5.375
    15.26 ± 1.696
        Endpoint (n=6, 8)
    15.65 ± 2.18
    14.54 ± 3.259
    Notes
    [18] - Safety
    [19] - Safety
    No statistical analyses for this end point

    Secondary: Triiodothyronine (Total T3) at Baseline and Endpoint

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    End point title
    Triiodothyronine (Total T3) at Baseline and Endpoint
    End point description
    Observed values of Total T3 which is the third of three thyroid hormones measured.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [20]
    8 [21]
    Units: NMOL/L
    arithmetic mean (standard deviation)
        Baseline (n=6, 7)
    1.8 ± 1.228
    1.71 ± 0.302
        Endpoint (n=6, 7)
    1.32 ± 0.133
    1.64 ± 0.351
    Notes
    [20] - Safety
    [21] - Safety
    No statistical analyses for this end point

    Secondary: Glycated Hemoglobin (HbA1c) at Baseline and Endpoint

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    End point title
    Glycated Hemoglobin (HbA1c) at Baseline and Endpoint
    End point description
    Glycated Hemoglobin (HbA1c) is a measure of glucose homeostasis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [22]
    8 [23]
    Units: percentage of total hemoglobin
    arithmetic mean (standard deviation)
        Baseline (n=6, 7)
    5.53 ± 0.647
    5.49 ± 0.422
        Endpoint (n=6, 7)
    5.45 ± 0.797
    5.51 ± 0.358
    Notes
    [22] - Safety population
    [23] - Safety population
    No statistical analyses for this end point

    Secondary: Fasting Blood Glucose at Baseline and Endpoint

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    End point title
    Fasting Blood Glucose at Baseline and Endpoint
    End point description
    Fasting blood glucose is another measure of glucose homeostasis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [24]
    8 [25]
    Units: MMOL/L
    arithmetic mean (standard deviation)
        Baseline (n=6, 8)
    5.37 ± 2.38
    4.83 ± 0.32
        Endpoint (n=6, 8)
    4.82 ± 0.818
    5.01 ± 0.344
    Notes
    [24] - Safety
    [25] - Safety
    No statistical analyses for this end point

    Secondary: Insulin at Baseline and Endpoint

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    End point title
    Insulin at Baseline and Endpoint
    End point description
    Insulin is another measure of glucose homeostasis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Endpoint (up to Week 24)
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [26]
    8 [27]
    Units: PMOL/L
    arithmetic mean (standard deviation)
        Baseline (n=6, 8)
    68 ± 68.9
    57 ± 22.68
        Endpoint (n=6, 7)
    65 ± 49.68
    94.3 ± 89.04
    Notes
    [26] - Safety
    [27] - Safety
    No statistical analyses for this end point

    Secondary: Local Tolerability Assessed by Injection Site Reactions

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    End point title
    Local Tolerability Assessed by Injection Site Reactions
    End point description
    Participants reporting at least one injection site reaction.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 24
    End point values
    Placebo TV-1106
    Number of subjects analysed
    6 [28]
    8 [29]
    Units: participants
        Pain (n=6, 7)
    0
    2
        Tenderness (n=6, 8)
    0
    1
        Erythema (n=6, 7)
    0
    0
        Warmth (n=6, 7)
    0
    0
        Swelling (n=6, 7)
    0
    0
    Notes
    [28] - Safety
    [29] - Safety
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Serum Concentration of TV1106 by Nominal Sampling Timepoints

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    End point title
    Pharmacokinetic Serum Concentration of TV1106 by Nominal Sampling Timepoints
    End point description
    Weeks 4 and 8 serum samples obtained 2 days after TV1106 administration. Weeks 12 and 24 serum samples obtained 7 days after TV1106 administration. Week 16 serum samples obtained 1 day after TV1106 administration. In study documentation, only minimum and maximum values are presented at visits where more than 50% of results are below the limit of quantitation. The lower limit of quantification was 4 ng/mL. However EUdraCT requires a median value so 'zero' has been entered in Baseline, Week 4, Week 12 and Week 24 as a placeholder.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1, pre-dose), Weeks 4, 8, 12, 16, 24
    End point values
    Placebo TV-1106
    Number of subjects analysed
    0 [30]
    8 [31]
    Units: ng/mL
    median (full range (min-max))
        Baseline (n=0, 8)
    ( to )
    0 (0 to 0)
        Week 4 (n=0, 4)
    ( to )
    0 (0 to 5.8)
        Week 8 (n=0, 3)
    ( to )
    4.5 (0 to 4.7)
        Week 12 (n=0, 2)
    ( to )
    0 (0 to 0)
        Week 16 (n=0, 2)
    ( to )
    9.05 (6.6 to 11.5)
        Week 24 (n=0, 1)
    ( to )
    0 (0 to 0)
    Notes
    [30] - Not performed on placebo group
    [31] - Safety
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Core Period: Day 1 to Week 24 Extension Period: Week 25-26
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo - Core Period
    Reporting group description
    Placebo was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. To maintain the blind, placebo could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 to match the effect of dose titration.

    Reporting group title
    TV-1106 - Core Period
    Reporting group description
    TV-1106 was injected subcutaneously once weekly on the same day and time for 24 weeks during the Core Period. A common starting dose was 5.0 mg. Doses could be titrated by an unblinded central reader on weeks 4, 8, 12 and 16 until the participant's insulin-like growth factor 1 (IGF-1) standard deviation score (SDS) was within the range of -0.5 to +1.5.

    Reporting group title
    TV-1106 - Extension Period
    Reporting group description
    Participants from both the Placebo and TV-1106 groups who completed the Core Period were eligible to enter an open-label extension phase for 12 additional months where all participants received treatment with TV-1106. Due to early termination of the study, two participants spent a maximum of two weeks in the extension period.

    Serious adverse events
    Placebo - Core Period TV-1106 - Core Period TV-1106 - Extension Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Endocrine disorders
    Pituitary haemorrhage
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo - Core Period TV-1106 - Core Period TV-1106 - Extension Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    4 / 8 (50.00%)
    1 / 2 (50.00%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    Injection site swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    2
    Injection site rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    The sample size was smaller than the planned; 14 patients enrolled. Limited efficacy analyses were completed; as only 2 patients (1 in each treatment group) completed the core phase of the study, no efficacy conclusions were reached.
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