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    Clinical Trial Results:
    A 24-week, Phase IIa, Double blind, Randomized, Parallel Group, Placebo controlled, Exploratory Study to Evaluate the Efficacy and Safety of 5 Aminolevulinic Acid Co-administered with Sodium Ferrous Citrate Compared with Placebo in the Treatment of Adult Type 2 Diabetes Mellitus Patients who have not Achieved Adequate Glycaemic Control with Maximum Tolerated Dose of Metformin Daily or Sulfonylurea

    Summary
    EudraCT number
    		 2017-004959-23
    Trial protocol
    		 HU   PL  
    Global end of trial date
    11 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2021
    First version publication date
    04 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NPJ005-DM2-0521
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    neopharma Japan
    Sponsor organisation address
    2nd Floor, PMO Kojimachi, Kojimachi 6-2-6, Chiyoda-ku, Tokyo, Japan, 102-0083
    Public contact
    Clinical Trial Information Desk, neopharma Japan, npjprd@neopharmajp.com
    Scientific contact
    Clinical Trial Information Desk, neopharma Japan, npjprd@neopharmajp.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
    16 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the change from Baseline in Glycated hemoglobin (HbA1c) up to Week 24 between 5 aminolevulinic acid/sodium ferrous citrate (5 ALA/SFC) plus metformin (or sulfonylurea [SU]) and placebo plus metformin (or SU).
    Protection of trial subjects
    Patients were enrolled in the study only after providing informed consent, and undergoing inclusion and exclusion assessments. Rescue therapy for patients in either treatment arm with prandial insulin or oral antidiabetic (OAD) therapy other than Metformin or Sulfonylurea was offered per Investigator’s discretion and in consultation with Medical Monitor from randomization until end of the study, depending on fasting blood glucose values.
    Background therapy
    		 At time of enrollment, patients were treated with a stable maximum tolerated dose (MTD) of metformin (immediate release and extended release) of at least 1500 mg daily or Sulfonylurea (SU) of at least half the maximum dose as per local label, for at least 12 weeks prior to screening visit. Background therapy with metformin or SU remained on the same dose for the duration of the study for both the treatment arms indicated.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Oct 2018
    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
    Ukraine: 19
    Country: Number of subjects enrolled
    Hungary: 31
    Country: Number of subjects enrolled
    Poland: 51
    Worldwide total number of subjects
    101
    EEA total number of subjects
    82
    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)
    60
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 101 patients were enrolled at 18 sites in Hungary, Poland and Ukraine from 25-Oct-2018 to 11-Mar-2020.

    Pre-assignment
    Screening details
    		 174 potential patients underwent a screening period of maximally 4 weeks during which all inclusion/exclusion were checked. 101 patients were randomized to either arm of 5 ALA/SFC 50 mg/39 mg orally twice daily (BID) or a matching placebo in a 2:1 ratio.

    Period 1
    Period 1 title
    Treatment period (24 weeks) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    The appearance, including packaging and labeling of the study treatment (capsules, packaging) was the same for 5-ALA/SFC and the placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 5-ALA-HCl 50 mg/SFC 39 mg + MET/SU
    Arm description
    		 The patients received 5-ALA/SFC at a dose of 50 mg/39 mg (1 capsule each BID), for a total daily dose of 100 mg/78 mg for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-aminolevulinic acid hydrochloride/sodium ferrous citrate (5-ALA-HCl/SFC)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    5-ALA/SFC was administered orally at a dose of 50 mg/39 mg (1 capsule each BID), for a total daily dose of 100 mg/78 mg at least 8 hours apart in the morning and evening, after the meal, for 24 weeks.

    Arm title
    		 Placebo + MET/SU
    Arm description
    		 The patients received an equal number of matching placebo capsules (BID) for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo capsules were administered in the same manner as the test product.

    Number of subjects in period 1
    		5-ALA-HCl 50 mg/SFC 39 mg + MET/SU Placebo + MET/SU
    Started
    68
    33
    Completed
    55
    29
    Not completed
    13
    4
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    5
    1
         Other
    -
    1
         Rescue Criteria Met
    3
    2
         Use of Prohibited Medication
    1
    -
         Noncompliance with protocol
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    5-ALA-HCl 50 mg/SFC 39 mg + MET/SU
    Reporting group description
    		 The patients received 5-ALA/SFC at a dose of 50 mg/39 mg (1 capsule each BID), for a total daily dose of 100 mg/78 mg for 24 weeks.

    Reporting group title
    Placebo + MET/SU
    Reporting group description
    		 The patients received an equal number of matching placebo capsules (BID) for 24 weeks.

    Reporting group values
    		 5-ALA-HCl 50 mg/SFC 39 mg + MET/SU Placebo + MET/SU Total
    Number of subjects
    		 68 33 101
    Age categorical
    Units: Subjects
        < 65 years
    		 43 17 60
        ≥ 65 years
    		 25 16 41
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.4 ± 6.76 61.2 ± 9.45 -
    Gender categorical
    Units: Subjects
        Female
    		 27 16 43
        Male
    		 41 17 58
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 68 33 101
    Race
    Units: Subjects
        White
    		 68 33 101
    Complication related T2DM (Y/N)
    Units: Subjects
        Yes
    		 19 7 26
        No
    		 49 26 75
    Background medication
    Units: Subjects
        Metformin
    		 64 31 95
        Sulfonylurea
    		 4 2 6
    HbA1c
    Units: Subjects
        < 8%
    		 48 24 72
        ≥ 8%
    		 20 9 29
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 168.71 ± 8.743 169.52 ± 9.501 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 91.28 ± 16.238 93.11 ± 18.341 -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 31.94 ± 4.182 32.16 ± 4.282 -
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 7.61 ± 0.768 7.44 ± 0.716 -
    Duration of T2DM
    Units: years
        arithmetic mean (standard deviation)
    		 8.61 ± 5.937 7.96 ± 5.143 -
    Fasting plasma glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.00 ± 2.190 9.16 ± 2.145 -
    Waist circumference
    Units: cm
        arithmetic mean (standard deviation)
    		 106.9 ± 11.65 108.1 ± 11.63 -
    Systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 137.8 ± 11.34 133.8 ± 9.79 -
    Diastolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 80.4 ± 8.23 78.0 ± 7.26 -
    Fructosamine levels
    Units: μmol/L
        arithmetic mean (standard deviation)
    		 286.1 ± 36.76 278.3 ± 38.53 -
    Serum zinc (≥ lower level)
    The threshold of serum zinc ≥ lower level was 9.2 μmol/L (range: 9.2 to 19.9 μmol/L)
    Units: μmol/L
        arithmetic mean (standard deviation)
    		 13.87 ± 3.006 15.05 ± 4.472 -
    Fasting C-peptide
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 0.947 ± 0.4039 0.983 ± 0.2837 -
    eGFR
    Units: mL/min/1.73 m2
        arithmetic mean (standard deviation)
    		 87.97 ± 23.318 89.14 ± 23.193 -
    CGM
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 98.3 ± 80.23 96.7 ± 65.06 -

    End points

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    End points reporting groups
    Reporting group title
    5-ALA-HCl 50 mg/SFC 39 mg + MET/SU
    Reporting group description
    		 The patients received 5-ALA/SFC at a dose of 50 mg/39 mg (1 capsule each BID), for a total daily dose of 100 mg/78 mg for 24 weeks.

    Reporting group title
    Placebo + MET/SU
    Reporting group description
    		 The patients received an equal number of matching placebo capsules (BID) for 24 weeks.

    Primary: Change from baseline in HbA1c to Week 24

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    End point title
    		 Change from baseline in HbA1c to Week 24
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to Week 24
    End point values
    		 5-ALA-HCl 50 mg/SFC 39 mg + MET/SU Placebo + MET/SU
    Number of subjects analysed
    68
    32
    Units: percent
        least squares mean (standard error)
    -0.12 ± 0.079
    -0.12 ± 0.107
    Statistical analysis title
    		 Primary efficacy
    Statistical analysis description
    Change from baseline HbA1c was analyzed based on Mixed Model for Repeated Measures with treatment, visit as fixed factors, treatment*visit as interaction effects and baseline HbA1c as covariate.
    Comparison groups
    Placebo + MET/SU v 5-ALA-HCl 50 mg/SFC 39 mg + MET/SU
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs (TEAEs) were defined as AEs that first occurred or worsened in severity after the first administration of the study medication, until end of the study.
    Adverse event reporting additional description
    An Adverse Event was any untoward medical occurrence in a patient or subject, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    5-ALA-HCl 50 mg/SFC 39 mg + MET/SU
    Reporting group description
    		 The patients received 5-ALA/SFC at a dose of 50 mg/39 mg (1 capsule each BID), for a total daily dose of 100 mg/78 mg for 24 weeks.

    Reporting group title
    Placebo + MET/SU
    Reporting group description
    		 The patients received an equal number of matching placebo capsules (BID) for 24 weeks.

    Serious adverse events
    		 5-ALA-HCl 50 mg/SFC 39 mg + MET/SU Placebo + MET/SU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 33 (3.03%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Cardiac disorders
    Cardiac failure chronic
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 33 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 5-ALA-HCl 50 mg/SFC 39 mg + MET/SU Placebo + MET/SU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 68 (69.12%)
    22 / 33 (66.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 68 (8.82%)
    1 / 33 (3.03%)
         occurrences all number
    6
    1
    Blood pressure fluctuation
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Investigations
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Tachycardia
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Sciatica
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Transient ischaemic attack
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 68 (8.82%)
    1 / 33 (3.03%)
         occurrences all number
    6
    1
    Abdominal pain
         subjects affected / exposed
    4 / 68 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    5
    0
    Nausea
         subjects affected / exposed
    3 / 68 (4.41%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Noninfective sialoadenitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Dermatitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Rash pruritic
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Urinary tract inflammation
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Thyroid mass
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 68 (4.41%)
    2 / 33 (6.06%)
         occurrences all number
    6
    2
    Arthralgia
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Spinal pain
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 68 (8.82%)
    4 / 33 (12.12%)
         occurrences all number
    7
    5
    Pharyngitis
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Influenza
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    21 / 68 (30.88%)
    10 / 33 (30.30%)
         occurrences all number
    74
    33
    Hypoglycaemia
         subjects affected / exposed
    5 / 68 (7.35%)
    3 / 33 (9.09%)
         occurrences all number
    11
    6
    Obesity
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Overweight
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2018
    Inclusion and exclusion criteria was amended as a result of the feedback received from VHP.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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