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    Clinical Trial Results:
    A Blinded, Placebo-Controlled Extension to Study TRCA-301 to Evaluate the Long-term Safety and Durability of Effect of TRC101 in Subjects with Chronic Kidney Disease and Metabolic Acidosis

    Summary
    EudraCT number
    		 2017-002562-42
    Trial protocol
    		 BG   HU   SI   HR  
    Global end of trial date
    22 Feb 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Jan 2022
    First version publication date
    01 Aug 2020
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Make minor corrections

    Trial information

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    Trial identification
    Sponsor protocol code
    TRCA-301E
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03390842
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Tricida, Inc.
    Sponsor organisation address
    7000 Shoreline Ct, Suite 201, South San Francisco, CA, United States, 94080
    Public contact
    Clinical Operations, Tricida, Inc., 01 4159885120, ystasiv@tricida.com
    Scientific contact
    Clinical Operations, Tricida, Inc., 01 4159885120, ystasiv@tricida.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
    01 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety of TRC101 in chronic kidney disease (CKD) patients with metabolic acidosis. The durability of effect of TRC101 in CKD patients with metabolic acidosis was also evaluated.
    Protection of trial subjects
    The design and conduct of TRCA-301E included appropriate monitoring for safety and risk mitigation. The Medical Monitor was to review safety data on an ongoing basis to identify potential adverse safety trends. A Data Monitoring Committee (DMC), established for the parent study (TRCA-301), continued to review safety during this study. To avoid prolonged periods of serum bicarbonate above the normal range, serum bicarbonate levels were measured at every study visit and the study drug dose was to be interrupted if serum bicarbonate was confirmed to be > 30 mEq/L. In addition, the investigator and Medical Monitor were to discuss subjects whose serum bicarbonate decreased to < 12 mEq/L for possible causes of acute-on-chronic acidosis. All Investigators participating in this study were governed under an appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC). The protocol, informed consent form (ICF) and any information provided to subjects was approved by the responsible IRB/IEC before enrollment of participants in the study at each investigational site. The Investigator was responsible for informing the IRBs/IECs of any reportable serious adverse events (SAEs) or other significant safety concerns, as well as the progress of the study, including completion or termination. This study was conducted in accordance with United States (US) Food and Drug Administration (FDA) regulations, the International Council for Harmonisation (ICH) Guideline E6 (R2), Guideline for Good Clinical Practice (09 Nov 2016), the Declaration of Helsinki and IRB/IEC requirements. The study was also conducted in accordance with the European Union Clinical Trials Directive 2001/20/EC (EU CTD) for sites in the EU and all other applicable local and national laws and regulations governing the conduct of human clinical trials.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovenia: 3
    Country: Number of subjects enrolled
    Ukraine: 22
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Bulgaria: 68
    Country: Number of subjects enrolled
    Georgia: 77
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Serbia: 1
    Worldwide total number of subjects
    196
    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)
    100
    From 65 to 84 years
    95
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects with non-dialysis-dependent CKD who completed the 12-week, randomized, double-blind, placebo-controlled parent study TRCA-301 and who had a serum bicarbonate value of ≥ 12 mEq/L at the TRCA-301 Week 12 Visit were eligible to continue into the 42-week extension study, TRCA-301E.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TRC101 Treatment Arm
    Arm description
    		 TRC101 was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded TRC101 dose they were receiving in the parent study, TRCA-301, as follows: 0, 3, 6 or 9 g TRC101 QD (0, 1, 2 or 3 packets, respectively). Subjects could have a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    veverimer
    Investigational medicinal product code
    Other name
    TRC101
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    TRC101 was orally administered QD as a 3, 6 or 9 g dose (1, 2 or 3 packets, respectively) suspended in approximately 60 – 90 mL of water.

    Arm title
    		 Placebo Treatment Arm
    Arm description
    		 Placebo was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded placebo dose they were receiving in the parent study, TRCA-301, as follows: 0, 1, 2 or 3 placebo packets QD. Subjects could have a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was supplied as a powder for oral suspension in packets. Placebo (1, 2, or 3 packets) was orally administered QD as a suspension in approximately 60 – 90 mL of water.

    Number of subjects in period 1
    		TRC101 Treatment Arm Placebo Treatment Arm
    Started
    114
    82
    Completed
    111
    74
    Not completed
    3
    8
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    -
    1
         Lost to follow-up
    2
    2
         Did not complete treatment period
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TRC101 Treatment Arm
    Reporting group description
    		 TRC101 was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded TRC101 dose they were receiving in the parent study, TRCA-301, as follows: 0, 3, 6 or 9 g TRC101 QD (0, 1, 2 or 3 packets, respectively). Subjects could have a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm.

    Reporting group title
    Placebo Treatment Arm
    Reporting group description
    		 Placebo was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded placebo dose they were receiving in the parent study, TRCA-301, as follows: 0, 1, 2 or 3 placebo packets QD. Subjects could have a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm.

    Reporting group values
    		 TRC101 Treatment Arm Placebo Treatment Arm Total
    Number of subjects
    		 114 82 196
    Age categorical
    Age (years) was calculated as the number of years between date of birth and date of informed consent, expressed as an integer.
    Units: Subjects
        < 65 years
    		 56 44 100
        ≥ 65 years
    		 58 38 96
    Age continuous
    Age (years) was calculated as the number of years between date of birth and date of informed consent, expressed as an integer.
    Units: years
        arithmetic mean (standard deviation)
    		 62.9 ( 12.07 ) 61.7 ( 11.88 ) -
    Gender categorical
    Units: Subjects
        Female
    		 46 31 77
        Male
    		 68 51 119
    History of Hypertension
    Units: Subjects
        Yes
    		 110 79 189
        No
    		 4 3 7
    History of Diabetes Mellitus
    Units: Subjects
        Yes
    		 70 57 127
        No
    		 44 25 69
    History of Congestive Heart Failure
    Units: Subjects
        Yes
    		 34 28 62
        No
    		 80 54 134
    Baseline eGFR
    Baseline eGFR is defined as the average of values of eGFR collected at the Screening 1 Visit, Screening 2 Visit, and Baseline Visit (i.e., Day 1 pre-dose) in the parent study TRCA-301, as measured by the central laboratory, based on serum creatinine values using the CKD-EPI formula.
    Units: mL/min/1.73m2
        arithmetic mean (standard deviation)
    		 29.4 ( 6.41 ) 27.9 ( 5.42 ) -
    Baseline Bicarbonate
    Baseline Bicarbonate is defined as the average of the values of serum bicarbonate collected at the Screening 1 Visit, Screening 2 Visit, and Baseline Visit (i.e., Day 1 pre-dose) in the parent study TRCA-301, measured onsite using an i-STAT point-of-care device.
    Units: mEq/L
        arithmetic mean (standard deviation)
    		 17.21 ( 1.429 ) 17.13 ( 1.501 ) -

    End points

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    End points reporting groups
    Reporting group title
    TRC101 Treatment Arm
    Reporting group description
    		 TRC101 was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded TRC101 dose they were receiving in the parent study, TRCA-301, as follows: 0, 3, 6 or 9 g TRC101 QD (0, 1, 2 or 3 packets, respectively). Subjects could have a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm.

    Reporting group title
    Placebo Treatment Arm
    Reporting group description
    		 Placebo was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded placebo dose they were receiving in the parent study, TRCA-301, as follows: 0, 1, 2 or 3 placebo packets QD. Subjects could have a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm.

    Primary: Incidence of adverse events, serious adverse events and adverse events leading to withdrawal

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    End point title
    		 Incidence of adverse events, serious adverse events and adverse events leading to withdrawal [1]
    End point description
    The incidence of adverse events (AEs), serious adverse events (SAEs) and AEs leading to withdrawal. For incidence of AEs and SAEs, see Adverse Events Section. For incidence of AEs leading to withdrawal, see endpoint values below.
    End point type
    Primary
    End point timeframe
    Week 12 Visit in the parent study, TRCA-301, to the Week 54 Visit in the extension study, TRCA-301E.
    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 protocol and statistical analysis plan did not prespecify any hypothesis testing.
    End point values
    		 TRC101 Treatment Arm Placebo Treatment Arm
    Number of subjects analysed
    112
    81
    Units: percent
        number (not applicable)
    0
    1.2
    No statistical analyses for this end point

    Secondary: Subjects with change from baseline in serum bicarbonate of ≥ 4 mEq/L or serum bicarbonate within the normal range

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    End point title
    		 Subjects with change from baseline in serum bicarbonate of ≥ 4 mEq/L or serum bicarbonate within the normal range
    End point description
    Percent of subjects having a change from baseline in serum bicarbonate of at least 4 mEq/L or bicarbonate in the normal range (22 – 29 mEq/L) at the end of treatment (Week 52).
    End point type
    Secondary
    End point timeframe
    Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E.
    End point values
    		 TRC101 Treatment Arm Placebo Treatment Arm
    Number of subjects analysed
    110
    74
    Units: percent
        number (confidence interval 95%)
    62.7 (53.0 to 71.8)
    37.8 (26.8 to 49.9)
    Attachments
    		 Untitled (Filename: TRCA-301E_Secondary Endpoint 1 Chart.pdf)
    Statistical analysis title
    		 % Subjects Who Met Endpoint: TRC101-Placebo
    Comparison groups
    Placebo Treatment Arm v TRC101 Treatment Arm
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015
    Method
    		 Fisher exact
    Parameter type
    		 Difference in % of subjects
    Point estimate
    24.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.2
         upper limit
    		 38.7
    Statistical analysis title
    		 % Subjects ≥4mEq/L Change from Baseline:TRC101-PBO
    Comparison groups
    TRC101 Treatment Arm v Placebo Treatment Arm
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015
    Method
    		 Fisher exact
    Parameter type
    		 Treatment difference in % of subjects
    Point estimate
    24.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.7
         upper limit
    		 38.2
    Statistical analysis title
    		 % Subjects within Normal Range: TRC101-PBO
    Comparison groups
    TRC101 Treatment Arm v Placebo Treatment Arm
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Treatment difference in % of subjects
    Point estimate
    30.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.6
         upper limit
    		 43.7

    Secondary: Change from baseline in serum bicarbonate at the end of treatment

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    End point title
    		 Change from baseline in serum bicarbonate at the end of treatment
    End point description
    Change from baseline in serum bicarbonate at the end of treatment (Week 52).
    End point type
    Secondary
    End point timeframe
    Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E.
    End point values
    		 TRC101 Treatment Arm Placebo Treatment Arm
    Number of subjects analysed
    114
    82
    Units: mEq/L
        least squares mean (standard error)
    4.70 ( 0.335 )
    2.71 ( 0.403 )
    Attachments
    		 Untitled (Filename: TRCA-301E_Secondary Endpoint 2 Chart.pdf)
    Statistical analysis title
    		 Mean Change from Baseline: TRC101-Placebo
    Comparison groups
    TRC101 Treatment Arm v Placebo Treatment Arm
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Mixed-effect repeated measures model
    Parameter type
    		 Treatment difference in LS means
    Point estimate
    1.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 3.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.524

    Secondary: Change from baseline in the total score of the KDQOL-PFD at the end of treatment

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    End point title
    		 Change from baseline in the total score of the KDQOL-PFD at the end of treatment
    End point description
    Change from baseline in the total score of the Kidney Disease Quality of Life Physical Function Domain (KDQOL-PFD) at the end of treatment. The KDQOL is a validated, kidney disease-specific measure of health-related quality of life. For study TRCA-301E, and parent study TRCA-301, the 10-question Item 3 of the KDQOL, also known as the SF-36 Physical Function subscale, was selected to measure physical functioning and is referenced herein as the KDQOL-PFD. The KDQOL-PFD was chosen as a patient-reported outcome measurement to evaluate the effects of TRC101 on daily activities that may be adversely affected by loss of muscle caused by metabolic acidosis. The minimum score for each of the 10 questions is 0 (physical activity highly limited) and the maximum is 100 (physical activity not limited). The total KDQOL-PFD score is calculated by adding the scores for all 10 questions, for a minimum and maximum possible total KDQOL-PFD score of 0 or 100, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E.
    End point values
    		 TRC101 Treatment Arm Placebo Treatment Arm
    Number of subjects analysed
    113
    78
    Units: KDQOL-PFD total score
        arithmetic mean (standard error)
    11.42 ( 2.201 )
    -0.71 ( 2.268 )
    Attachments
    		 Untitled (Filename: TRCA-301E_Secondary Endpoint 3 Chart.pdf)
    Statistical analysis title
    		 Mean Change from Baseline in KDQOL-PFD: TRC101-PBO
    Comparison groups
    TRC101 Treatment Arm v Placebo Treatment Arm
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - p-value based on analysis of covariance model with rank of change from baseline in total score as dependent variable; treatment (PBO or TRC101) as a fixed effect; and baseline total score, Baseline eGFR, Baseline Bicarbonate as continuous covariates.

    Secondary: Change from baseline in the duration of repeated chair stand test at the end of treatment

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    End point title
    		 Change from baseline in the duration of repeated chair stand test at the end of treatment
    End point description
    Change from baseline in the duration of repeated chair stand test at the end of treatment (Week 52). The five-times repeated chair stand test was used as a measure of lower extremity muscle strength. In this test, the time it took for a subject to repeatedly stand from a chair five times was recorded. This test among the group of measures (gait speed, chair stand, and balance tests) comprising the Short Physical Performance Battery (SPPB), which has been used as a predictive tool for possible disability and for monitoring physical functioning in older people.
    End point type
    Secondary
    End point timeframe
    Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E.
    End point values
    		 TRC101 Treatment Arm Placebo Treatment Arm
    Number of subjects analysed
    112
    77
    Units: seconds
        arithmetic mean (standard error)
    -4.28 ( 1.240 )
    -1.42 ( 1.248 )
    Attachments
    		 Untitled (Filename: TRCA-301E_Secondary Endpoint 4 Chart.pdf)
    Statistical analysis title
    		 Change from Baseline for RCST: TRC101-Placebo
    Statistical analysis description
    Change from Baseline in the Time to Complete the Repeated Chair Stand Test (RCST) at Week 52
    Comparison groups
    TRC101 Treatment Arm v Placebo Treatment Arm
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 12 visit in the parent study, TRCA-301, to the Week 54 follow-up visit in the extension study, TRCA-301E.
    Adverse event reporting additional description
    The TRCA-301E Safety Analysis Set included all subjects who received any amount of study drug (TRC101 or PBO) in TRCA-301E. Three subjects were excluded (2 TRC101, 1 PBO) because they entered TRCA-301E on a dose hold and remained on the dose hold for the duration of the study because their bicarbonate levels remained within the normal range.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    TRC101 Treatment Arm
    Reporting group description
    		 TRC101 was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded TRC101 dose they were receiving in the parent study, TRCA-301, as follows: 0, 3, 6 or 9 g TRC101 QD (0, 1, 2 or 3 packets, respectively). Subjects could have a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm.

    Reporting group title
    Placebo Treatment Arm
    Reporting group description
    		 Placebo was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded placebo dose they were receiving in the parent study, TRCA-301, as follows: 0, 1, 2 or 3 placebo packets QD. Subjects could have a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm.

    Serious adverse events
    		 TRC101 Treatment Arm Placebo Treatment Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 112 (1.79%)
    4 / 81 (4.94%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    2
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Azotaemia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic kidney disease
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperkalaemia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TRC101 Treatment Arm Placebo Treatment Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 112 (69.64%)
    39 / 81 (48.15%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 112 (15.18%)
    20 / 81 (24.69%)
         occurrences all number
    19
    22
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 112 (5.36%)
    1 / 81 (1.23%)
         occurrences all number
    6
    1
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    8 / 112 (7.14%)
    5 / 81 (6.17%)
         occurrences all number
    8
    5
    Diarrhoea
         subjects affected / exposed
    7 / 112 (6.25%)
    5 / 81 (6.17%)
         occurrences all number
    8
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 112 (6.25%)
    3 / 81 (3.70%)
         occurrences all number
    7
    3
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    5 / 112 (4.46%)
    7 / 81 (8.64%)
         occurrences all number
    5
    7
    Infections and infestations
    Influenza
         subjects affected / exposed
    12 / 112 (10.71%)
    6 / 81 (7.41%)
         occurrences all number
    13
    6
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    16 / 112 (14.29%)
    8 / 81 (9.88%)
         occurrences all number
    19
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Dec 2017
    Original protocol. Note: 68 subjects were enrolled under the original protocol.
    28 Feb 2018
    Protocol Amendment 1: The protocol was amended to remove reference to the eligible age range for the parent study, TRCA-301, which was revised to increase the upper limit to 85 years. The amendment also clarified that the adverse event reporting period begins when subjects are enrolled in Study TRCA-301E. Adverse events with an onset time prior to enrollment in the extension study were reported in the parent study, TRCA-301. Note: 128 subjects were enrolled under Protocol Amendment 1.
    05 Jul 2018
    Protocol Amendment 2: The protocol was amended to add Kidney Disease and Quality of Life (KDQOL) questions and the repeated chair stand test to the tests and procedures performed at the Week 40 Visit. In addition, the study drug titration algorithm was simplified for subjects with blood bicarbonate in the normal range. Additional minor revisions were also made to correct typographical errors and provide updated administrative information. Note: All subjects had been enrolled in the trial when Protocol Amendment 2 was implemented.
    08 Nov 2018
    Protocol Amendment 3: The protocol was revised to add clarification regarding statistical methodology to be used for mixed-effect model repeated measures (MMRM) and analysis of covariance (ANCOVA) analyses of the durability of effect endpoints. In the event that the residuals from the MMRM or ANCOVA models were not normally distributed, alternative statistical analyses were to be used instead; these were to be specified in the Statistical Analysis Plan. Note: All subjects had been enrolled in the trial when Protocol Amendment 3 was implemented.

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31248662
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