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    Summary
    EudraCT Number:2021-006069-39
    Sponsor's Protocol Code Number:LPS16141
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-03-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2021-006069-39
    A.3Full title of the trial
    A Randomized, Double-Blind, Parallel-Group Clinical Trial to Assess the Efficacy of Essentiale on Hepatic Steatosis Added to Standard of Care Versus Placebo Added to Standard of Care, in Non-Alcoholic Fatty Liver
    Disease (NAFLD) Associated with Type 2 Diabetes Mellitus (T2DM) and/or Hyperlipidemia and/or Obesity
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Double-Blind, Parallel-Group Clinical Research Study to Assess the Efficacy of Essentiale on Hepatic Steatosis Added to Standard of Care in comparison to Placebo Added to Standard of Care, in Non-Alcoholic Fatty Liver Disease (NAFLD) Connected with Type 2 Diabetes Mellitus (T2DM) and/or
    abnormally high levels of fats (lipids) in the blood (Hyperlipidemia) and/or abnormal accumulation of body fat (Obesity)
    A.3.2Name or abbreviated title of the trial where available
    Essentiale in NAFLD with T2DM and/or Hyperlipidemia and/or Obesity (EXCEL)
    A.4.1Sponsor's protocol code numberLPS16141
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1244-1278
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSanofi-Aventis Recherche & Développement
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSanofi-Aventis Recherche & Développement
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationA. Nattermann & Cie. GmbH
    B.5.2Functional name of contact pointGlobal Med.Lead,Consumer Healthcare
    B.5.3 Address:
    B.5.3.1Street AddressIndustriepark Höchst - Bldg. K607
    B.5.3.2Town/ cityFrankfurt am Main
    B.5.3.3Post code65926
    B.5.3.4CountryGermany
    B.5.4Telephone number00491736896442
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Essentiale Forte
    D.2.1.1.2Name of the Marketing Authorisation holderOpella Healthcare Romania S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationRomania
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPhosphatidylcholine
    D.3.9.1CAS number 97281-47-5
    D.3.9.3Other descriptive nameDE-OILED ENRICHED PHOSPHOLIPIDS FROM SOYA-BEANS
    D.3.9.4EV Substance CodeSUB130572
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product Yes
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product Yes
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-alcoholic fatty liver disease associated with type 2 diabetes mellitus and/or hyperlipidemia and/or obesity
    E.1.1.1Medical condition in easily understood language
    Fatty liver disease in non-alcoholic patients connected with type 2 diabetes mellitus and/or hyperlipidemia and/or obesity
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 25.0
    E.1.2Level LLT
    E.1.2Classification code 10082249
    E.1.2Term Nonalcoholic fatty liver disease
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of Essentiale added to SoC (lifestyle modification [diet and physical activity/exercise]) compared with placebo added to SoC (lifestyle modification [diet and physical
    activity/exercise]) in patients with NAFLD associated with T2DM and/or hyperlipidemia and/or obesity.
    E.2.2Secondary objectives of the trial
    1. To assess the QoL of patients with NAFLD associated with T2DM and/or hyperlipidemia and/or obesity.

    2. To evaluate severity of 4 major symptoms in patients with NAFLD associated with T2DM and/or
    hyperlipidemia and/or obesity.

    3. To describe the safety of Essentiale and placebo in patients with NAFLD associated with T2DM
    and/or hyperlipidemia and/or obesity.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Is capable of understanding the written informed consent, provides signed written informed consent, is willing and able to complete the electronic diary (eDiary), and agrees to comply with protocol requirements.
    - Is an adult male or female, 18 to 70 years (both inclusive) of age.
    - Was diagnosed with NAFLD.
    - Presents with steatosis score of S1–S3 (defined as CAP score >248 decibels per meter [dB/m], as measured by transient elastography).
    - Presents with liver fibrosis score of F1–F3 (defined as LSM of 5-13 kilopascals [kPa], as measured by transient elastography)
    - Has confirmed diagnosis of at least one of the following associated illnesses:
    o T2DM and has been treated with diabetes medications (eg, metformin,
    insulin) with stable doses for 3 months, as judged by the investigator,
    before the patient enrollment visit, and is willing to continue their
    medications during the trial.
    o Hyperlipidemia (defined as presence of abnormally elevated levels of any
    or all lipids or lipoproteins in the blood) and has been treated with
    hyperlipidemia medications (eg, statins) with stable doses for 3 months, as judged by the investigator, before the patient enrollment visit, and is willing to continue their medications during the trial.
    o Obesity (defined as body mass index [BMI] ≥30 kg/m2) *
    *Body weight and height will be recorded for the calculation of BMI
    (metric: BMI = weight (kg)/[height (m)]2).
    - Is willing to follow lifestyle modification (diet and physical activity/exercise), as recommended by the investigator, and agrees to maintain these modifications during the trial period.
    (Note: In order to encourage stable and sustainable lifestyle modification among patients during the conduct of this trial, sites will be encouraged to apply site - and disease-specific SOC or apply 2016 European Association for the Study of the Liver [EASL] guidelines (EASL et al 2016). In either case, SOC refers to lifestyle modification, whose common denominator across trial sites potentially could be summarized as a measure to decrease body fat and weight.)
    E.4Principal exclusion criteria
    Patients meeting any of the following criteria (at the patient enrollment visit) will be excluded from the trial:
    - Has other causes of liver disease or abnormal laboratory results (AST ≥4 × upper limit of normal [ULN], ALT ≥4 × ULN, bilirubin ≥2 × ULN), or cirrhosis within 3 months before the patient enrollment visit.
    - Has current viral hepatitis.
    - Has been diagnosed with type 1 diabetes mellitus (T1DM).
    - Has an HbA1c >10.0% within 3 months before the patient enrollment visit.
    - Has severe heart disease (eg, heart failure), according to New York Heart Association (NYHA) Functional Classification (Class II–IV; The Criteria Committee of the New York Heart Association 1994) or severe renal impairment, as defined by estimated glomerular filtration rate of <15 mL/min/1.73 m2.
    - Has current or known history of drug abuse within 6 months before the patient enrollment visit.
    - Has current or known history of alcohol consumption >20 g per day in women or >30 g per day in men.
    - Is enrolled in another clinical trial or has taken other investigational drug(s) within
    1 month before the patient enrollment visit.
    - Is not suitable for participation, whatever the reason, as judged by the investigator,
    including medical or clinical conditions, or potentially is at risk of noncompliance to trial procedures.
    - Has hypersensitivity to Essentiale or its components or any of its excipients that, in
    the opinion of the investigator, contraindicates participation in the trial.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable (change in steatosis, as measured by transient elastography [CAP score] from baseline to 6 months) will be analyzed using an analysis of covariance (ANCOVA) model with treatment arms, country, and CAP score at baseline as covariates. Difference between treatment arms and two-sided 95% CIs will be estimated within the framework of ANCOVA. As the ANCOVA only uses data information that includes patients with evaluable scores at baseline and 6 months, the actual population used in this analysis will be a subset of the mITT by default.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline to 6 months.
    E.5.2Secondary end point(s)
    The secondary endpoints will be analyzed and summarized using descriptive statistics based on the mITT. There will be no sensitivity analysis for the secondary endpoints. The Holm procedure will be applied to address multiplicity issues while performing 5 statistical tests in total for 5 secondary endpoints. The corresponding 100*(1- 0.05/(m-(i-1))) CI will be provided. Note that the primary endpoint needs to be significant in order to interpret the tests related to secondary endpoints (hierarchical approach between the primary endpoint family and the secondary endpoints family).
    For each secondary endpoint listed below, the same approach as for the primary endpoint will
    be used on the mITT, except that the CAP score at baseline in the MMRM will be replaced
    by either the QoL total score at baseline or the symptom evaluation score at baseline
    (asthenia, feeling depressed, abdominal pain/discomfort, or fatigue), depending on which
    secondary endpoint is considered:
    • Change from baseline to 6 months in QoL total score of the CLDQ-NAFLD/NASH.
    • Change from baseline to 6 months in asthenia symptom score.
    • Change from baseline to 6 months in feeling depressed symptom score.
    • Change from baseline to 6 months in abdominal pain/discomfort symptom evaluation.
    • Change from baseline to 6 months in fatigue symptom score.
    E.5.2.1Timepoint(s) of evaluation of this end point
    From baseline to 6 months- 9 months (AEs, SAEs, including adverse events of special
    interest (AESIs).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Germany
    Russian Federation
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial is defined as the date of the last visit of the last patient in the trial globally.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state87
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 190
    F.4.2.2In the whole clinical trial 190
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-06-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-06-26
    P. End of Trial
    P.End of Trial StatusOngoing
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