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    Clinical Trial Results:
    A Phase 3, Open-label Trial of TMC435 in Combination With Peginterferon α-2a and Ribavirin for HCV Genotype 1 Infected Subjects who Participated in the Placebo Group of a Phase 2/3 TMC435 Study (C201, C205, C206, C208, C216 or HPC3007), or who Received Short-term (up to 14 Days) Direct-acting Antiviral Treatment for Hepatitis C Infection in a Selected Tibotec*-sponsored Phase 1 Study

    Summary
    EudraCT number
    2011-000416-25
    Trial protocol
    BE   GB   ES   AT   PT   NL   DE   PL   BG  
    Global end of trial date
    31 Mar 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Mar 2016
    First version publication date
    19 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TMC435-TiDP16-C213
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01323244
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen R&D Ireland
    Sponsor organisation address
    Eastgate Village, Little island, Co. Cork, Ireland,
    Public contact
    Janssen R&D Ireland, Janssen R&D Ireland, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen R&D Ireland, Janssen R&D Ireland, ClinicalTrialsEU@its.jnj.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
    31 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of SMV (Simeprevir) in combination with PegIFNα-2a and RBV (Ribavirin), with respect to the proportion of subjects with SVR12 (Sustained virologic response 12).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. The study protocol was reviewed by an Independent Ethics Committee. Safety evaluations were based upon the type, incidence, and severity of AEs (adverse events) reported throughout the study, changes in clinical laboratory tests (hematology, biochemistry and urinalysis), vital sign measurements, 12-lead ECGs (electrocardiogram), physical examination (including weight, height, and temperature), and monitoring of hypoglycemia.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Dec 2011
    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
    Israel: 3
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    141
    EEA total number of subjects
    79
    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)
    131
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Total 141 participants were enrolled in this study; who had participated in the placebo group of a Phase 2/3 SMV study, or who had received short-term (up to 14 days) DAA treatment for HCV infection in the selected JRD‑sponsored Phase 1 studies.

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

    Arms
    Arm title
    Simeprevir 150mg 12Wks PR24/48
    Arm description
    In the first 24 weeks, subjects received SMV (simeprevir) 150 milligram (mg) daily in combination with PegIFNá 2a [peginterferon alfa-2a (Pegasys) 180 microgram] and RBV [ribavirin (Copegus)] for 12 weeks, followed by 12 weeks of PegIFNá 2a and RBV or 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In the first 24 weeks, subjects received SMV (simeprevir) 150 milligram (mg) daily in combination with PegIFNα 2a [peginterferon alfa-2a (Pegasys)] and RBV [ribavirin (Copegus)] for 12 weeks, followed by 12 weeks of PegIFNα 2a and RBV or 48 weeks.

    Investigational medicinal product name
    Peginterferon alfa-2a (PegIFNα-2a)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PegIFNα-2a was given as Pegasys 180 mc (microgram) once a week, administered as subcutaneous (SC) injection of 0.5 mL (millilitre) for 24 weeks or 48 weeks.

    Investigational medicinal product name
    Ribavirin (RBV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    If the baseline body weight was more than <75 kg (kilogram), the total daily dose of Ribavarin (RBV) was 1,000 (mg) milligram, administered as 400 mg (2 tablets of 200 mg) in the morning and 600 mg (3 tablets of 200 mg) in the evening. If the baseline body weight was less than or equal to ≥75 kg, the total daily dose was 1,200 mg, administered as 2 x 600 mg (3 tablets of 200 mg per intake, morning and evening).

    Number of subjects in period 1
    Simeprevir 150mg 12Wks PR24/48
    Started
    141
    Completed
    127
    Not completed
    14
         Consent withdrawn by subject
    8
         Lost to follow-up
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Simeprevir 150mg 12Wks PR24/48
    Reporting group description
    In the first 24 weeks, subjects received SMV (simeprevir) 150 milligram (mg) daily in combination with PegIFNá 2a [peginterferon alfa-2a (Pegasys) 180 microgram] and RBV [ribavirin (Copegus)] for 12 weeks, followed by 12 weeks of PegIFNá 2a and RBV or 48 weeks.

    Reporting group values
    Simeprevir 150mg 12Wks PR24/48 Total
    Number of subjects
    141 141
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    131 131
        From 65 to 84 years
    10 10
        85 years and over
    0 0
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    52 (22 to 72) -
    Title for Gender
    Units: subjects
        Female
    48 48
        Male
    93 93

    End points

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    End points reporting groups
    Reporting group title
    Simeprevir 150mg 12Wks PR24/48
    Reporting group description
    In the first 24 weeks, subjects received SMV (simeprevir) 150 milligram (mg) daily in combination with PegIFNá 2a [peginterferon alfa-2a (Pegasys) 180 microgram] and RBV [ribavirin (Copegus)] for 12 weeks, followed by 12 weeks of PegIFNá 2a and RBV or 48 weeks.

    Subject analysis set title
    Phase 2/3 Group
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects who had participated in the Placebo group of Phase 2/3 SMV (sustained virologic response) study and subjects with HCV genotype 1 infection who had received short-term (up to 14 days) DAA (direct-acting antiviral agent) treatment for HCV (hepatitis C virus) infection in Phase 1 study.

    Subject analysis set title
    Phase 1 Group
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects who had participated in the Placebo group of Phase 2/3 SMV (Sustained virologic response) study and subjects with HCV genotype 1 infection who had received short-term (up to 14 days) DAA (direct-acting antiviral agent) treatment for HCV (hepatitis C virus) infection in Phase 1 study.

    Primary: The percentage of participants with sustained viral response at 12 weeks after the planned End of Treatment (SVR12)

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    End point title
    The percentage of participants with sustained viral response at 12 weeks after the planned End of Treatment (SVR12) [1]
    End point description
    Subjects were considered to have achieved SVR 12 if 2 conditions were met: 1) at the actual end of treatment - HCV RNA <25 IU/mL undetectable, and 2) 12 weeks after the planned EOT - HCV RNA <25 IU/mL undetectable or detectable.Intend to treat population included all randomized participants who received at least 1 dose of the study drug.
    End point type
    Primary
    End point timeframe
    12 Weeks After the Planned End of Treatment
    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: No statistical analysis has been performed for this endpoint.
    End point values
    Phase 2/3 Group Phase 1 Group
    Number of subjects analysed
    125
    16
    Units: Percentage
        number (confidence interval 95%)
    69.6 (61.5 to 77.7)
    37.5 (13.8 to 61.2)
    No statistical analyses for this end point

    Secondary: The percentage of participants with sustained viral response at 4 and 24 weeks after planned end of treatment (SVR4 and SVR24)

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    End point title
    The percentage of participants with sustained viral response at 4 and 24 weeks after planned end of treatment (SVR4 and SVR24)
    End point description
    Subjects were considered to have achieved SVR X if 2 conditions were met: 1) at the actual end of treatment - HCV RNA <25 IU/mL undetectable, and 2) X weeks after the planned EOT - HCV RNA <25 IU/mL undetectable or detectable. Intend to treat population included all randomized participants who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    24 weeks after planned end of treatment
    End point values
    Phase 2/3 Group Phase 1 Group
    Number of subjects analysed
    125
    16
    Units: Percentage
    number (confidence interval 95%)
        Sustained virologic response 4 weeks (SVR4)
    73.6 (65.9 to 81.3)
    37.5 (13.8 to 61.2)
        Sustained virologic response 24 weeks (SVR24)
    69.6 (61.5 to 77.7)
    37.5 (13.8 to 61.2)
    No statistical analyses for this end point

    Secondary: Change from baseline of 'on-treatment' HCV RNA level

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    End point title
    Change from baseline of 'on-treatment' HCV RNA level
    End point description
    Intend to treat population included all randomized participants who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    On treatment
    End point values
    Phase 2/3 Group Phase 1 Group
    Number of subjects analysed
    125 [2]
    16 [3]
    Units: Log10 International Unit per milliliter
    arithmetic mean (standard error)
        Week 1 (n=122, 15)
    -4.47 ± 0.06
    -4.36 ± 0.14
        Week 4 (n=125, 15)
    -5.17 ± 0.09
    -5.47 ± 0.09
        Week 8 (n=118, 15)
    -5.36 ± 0.09
    -5.63 ± 0.11
    Notes
    [2] - N signifies number of subjects for this endpoints
    [3] - N signifies number of subjects for this endpoints
    No statistical analyses for this end point

    Secondary: Number of participants with viral breakthrough

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    End point title
    Number of participants with viral breakthrough
    End point description
    Viral breakthrough was defined as a confirmed increase of more than >1 log10 IU/mL (International Unit per millilitre) in HCV RNA level from the lowest level reached, or a confirmed HCV Hepatitis C Virus RNA level of more than >100 IU/mL in subjects whose HCV RNA levels had previously been below the limit of quantification (less than <25 IU/mL detectable) or undetectable (<25 IU/mL undetectable) while on study treatment. Intend to treat population included all randomized participants who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Up to End of treatment
    End point values
    Phase 2/3 Group Phase 1 Group
    Number of subjects analysed
    125
    15
    Units: Percentage
        number (not applicable)
    9.6
    6.7
    No statistical analyses for this end point

    Secondary: Number of participants with viral relapse

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    End point title
    Number of participants with viral relapse
    End point description
    Viral relapse was defined as undetectable HCV RNA at the actual end of treatment and HCV RNA measurement during follow-up more than or equal to ≥25 IU/mL (International unit per millilitre). The incidence of viral relapse was only calculated for subjects with undetectable HCV RNA at end of treatment and with at least 1 follow up HCV RNA measurement.Intend to treat population included all randomized participants who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Through Week 48
    End point values
    Phase 2/3 Group Phase 1 Group
    Number of subjects analysed
    104
    12
    Units: Percentage
        number (not applicable)
    14.4
    41.7
    No statistical analyses for this end point

    Secondary: Number of participants with 'on-treatment' normalized alanine aminotransferase levels

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    End point title
    Number of participants with 'on-treatment' normalized alanine aminotransferase levels
    End point description
    Intend to treat population included all randomized participants who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    Phase 2/3 Group Phase 1 Group
    Number of subjects analysed
    59
    6
    Units: Percentage
    number (not applicable)
        No Normalization
    28.8
    16.7
        Normalization
    71.2
    83.3
    No statistical analyses for this end point

    Secondary: Percentage of participants with on-treatment failure

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    End point title
    Percentage of participants with on-treatment failure
    End point description
    Subjects were considered as an on-treatment failure if: at actual EOT (End of treatment), detectable HCV RNA levels (ie, Less than 25 IU/mL (International unit per milliliter) detectable or =>25 IU/mL) were noted. Intend to treat population included all randomized participants who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    Phase 2/3 Group Phase 1 Group
    Number of subjects analysed
    125
    16
    Units: Percentage
        number (not applicable)
    16
    18.8
    No statistical analyses for this end point

    Secondary: Number of participants affected by an adverse event

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    End point title
    Number of participants affected by an adverse event
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should have been exercised in other situations. Refer to the general AE/SAE module for a list of AEs (occurring at a frequency threshold >=3%) and SAEs. Intend to treat population included all randomized participants who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    Simeprevir 150mg 12Wks PR24/48
    Number of subjects analysed
    141
    Units: Percentage
    number (not applicable)
        Simeprevir + PR Phase
    90.8
        Entire Treatment Phase
    92.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Treatment Phase
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Simeprevir 150mg 12Wks PR24/48
    Reporting group description
    Participants in this study will receive TMC435 in combination with peginterferon alfa-2a (Pegasys) and ribavirin (Copegus) followed by peginterferon alfa-2a and ribavirin alone. The total treatment duration will be 24 or 48 weeks, depending on how the patients respond to treatment and which was their previous response to peginterferon alfa-2a and ribavirin alone. After a patient stops taking study medication, subjects receiving a planned 24 weeks of treatment continue in the trial until Week 48, while subjects receiving a planned 48 weeks of treatment continue in the trial until Week 72.The total duration of the study is 78 weeks (including screening).The above arm description is for subjects from a Phase II/III group trial. Subjects from a Phase I group trial were also included, these subjects had a planned treatment duration of 48 weeks, followed by 24 weeks of Follow-up.

    Serious adverse events
    Simeprevir 150mg 12Wks PR24/48
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 141 (6.38%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cell carcinoma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Papilloedema
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Biloma
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Simeprevir 150mg 12Wks PR24/48
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 141 (90.07%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    13 / 141 (9.22%)
         occurrences all number
    13
    Cough
         subjects affected / exposed
    11 / 141 (7.80%)
         occurrences all number
    12
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    35 / 141 (24.82%)
         occurrences all number
    78
    Anaemia
         subjects affected / exposed
    20 / 141 (14.18%)
         occurrences all number
    24
    Nervous system disorders
    Headache
         subjects affected / exposed
    32 / 141 (22.70%)
         occurrences all number
    40
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    31 / 141 (21.99%)
         occurrences all number
    35
    Fatigue
         subjects affected / exposed
    52 / 141 (36.88%)
         occurrences all number
    59
    Asthenia
         subjects affected / exposed
    18 / 141 (12.77%)
         occurrences all number
    19
    Pyrexia
         subjects affected / exposed
    24 / 141 (17.02%)
         occurrences all number
    81
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    23 / 141 (16.31%)
         occurrences all number
    26
    Depression
         subjects affected / exposed
    15 / 141 (10.64%)
         occurrences all number
    17
    Mood altered
         subjects affected / exposed
    9 / 141 (6.38%)
         occurrences all number
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    26 / 141 (18.44%)
         occurrences all number
    29
    Diarrhoea
         subjects affected / exposed
    11 / 141 (7.80%)
         occurrences all number
    12
    Vomiting
         subjects affected / exposed
    10 / 141 (7.09%)
         occurrences all number
    12
    Constipation
         subjects affected / exposed
    10 / 141 (7.09%)
         occurrences all number
    10
    Abdominal pain upper
         subjects affected / exposed
    8 / 141 (5.67%)
         occurrences all number
    10
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    14 / 141 (9.93%)
         occurrences all number
    23
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    25 / 141 (17.73%)
         occurrences all number
    30
    Pruritus
         subjects affected / exposed
    26 / 141 (18.44%)
         occurrences all number
    33
    Alopecia
         subjects affected / exposed
    14 / 141 (9.93%)
         occurrences all number
    14
    Dry skin
         subjects affected / exposed
    11 / 141 (7.80%)
         occurrences all number
    11
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    20 / 141 (14.18%)
         occurrences all number
    26
    Arthralgia
         subjects affected / exposed
    12 / 141 (8.51%)
         occurrences all number
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 141 (12.06%)
         occurrences all number
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2012
    There were 3 substantial and 2 non-substantial amendments to the original protocol, dated 26 May 2011. In addition, there were 4 country-specific amendments for Israel. The second general protocol amendment, dated 10 January 2012, was considered substantial and was based on feedback from the Health Authorities. A strong correlation between SVR12 and SVR24 was demonstrated in completed SMV Phase 2b studies (C205 and C206), and in telaprevir and boceprevir Phase 3 studies. Health Authorities agreed that the primary efficacy endpoint for ongoing and future SMV Phase 3 studies could be changed from SVR24 to SVR12. SVR24 became a secondary endpoint. It was clarified that the thyroid function of the subjects should be adequately controlled and that subjects with abnormal thyroid-stimulating hormone (TSH) levels would be excluded from the study or should stop treatment. The antinuclear antibody (ANA) titer and TSH levels were added to exclusion criterion 10. Specific management of pancreatic amylase or lipase elevations, gastrointestinal nausea (with or without vomiting) and diarrhea were deleted from the specific toxicities section and general guidelines on management of graded AEs and laboratory abnormalities considered at least possibly related to SMV. The platelet and absolute neutrophil count in exclusion criteria 13 was revised to facilitate enrollment of African American subjects in the study. It was clarified that the Roche Cobas TaqMan HCV Test v2.0, for use with the High Pure System was used as the assay to determine HCV RNA levels. The performance characteristics of the assay reported by the manufacturer as well as the internal assay performance validation document were added to the reference list. A liver biopsy inclusion criterion was added to the protocol. A liver biopsy was the required method for all subjects without a contraindication for this procedure.
    18 Apr 2013
    The protocol was amended to update the RGT duration criteria and the treatment stopping rules based on the Phase 3 results. Virologic stopping rules were modified so that subjects with HCV RNA ?25 IU/mL at Week 4 discontinued all treatment. Indeed, results from Phase 3 studies showed that the best predictor of achieving SVR with SMV plus PegIFN/RBV therapy is the Week 4 response, which is therefore considered an optimal and early time point for a decision regarding continuing or discontinuing therapy with the objective to terminize unnecessary exposure to treatment in subjects with very low likelihood of achieving SVR. Total treatment duration rules in eligible subjects (ie, subjects with viral relapse or breakthrough during prior PegIFN/RBV therapy in the control arm of SMV Phase 2/3 studies) were modified in line with the observations from Phase 3 studies, so that only subjects with undetectable HCV RNA at Week 4 and 12 could complete all treatment at Week 24, whereas subjects with HCV RNA <25 IU/mL detectable at Week 4 and undetectable at Week 12 were to receive 48 weeks of PegIFN?-2a/RBV treatment. The stopping rule at Week 12 was adapted: Subjects with detectable HCV RNA at Week 12 discontinued all treatment in line with analysis from the Phase 2b C206 study in prior nonresponders and Phase 3 studies in treatment naïve and prior relapse subjects, showing that subjects not achieving undetectable HCV RNA at Week 12 had a very low chance of achieving SVR. This modified stopping rule (ie, confirmed detectable HCV RNA) was also applicable at Week 24 and Week 36. The management of laboratory abnormalities and management of specific toxicities was updated and clarified based on the results from Phase 3 studies. It was determined that it was not necessary to discontinue study medication for isolated grade 4 abnormalities in bilirubin.
    17 Sep 2013
    It includes phase 1 photosensitivity study C125 had concluded that the photosensitizing potential of SMV is similar to that of placebo. Accordingly, formal recommendations for sun protective measures were removed from the ongoing SMV studies at the time that these results became available, and not included in future SMV study protocols. After analysis of the Phase 3 (C208/C216/HPC3007) studies, in which subjects were dosed with SMV prior to removal of recommendation for sun-protective measures, photosensitivity conditions were nevertheless identified as adverse drug reaction of SMV as detailed in the updated IB edition 7, issued in June 2013.34 As a follow-up to a recommendation by the United States (US) Food and Drug Administration (FDA), it was decided to reintroduce the same recommendations initially included in Phase 3 studies (C208/C216/HPC3007), in SMV studies where subjects were still being dosed with SMV and in any future SMV study. Therefore, the protocol was amended to reintroduce the precautionary language on photosensitivity.

    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 low sample size in the Phase 1 group was considered a study limitation by the sponsor.
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