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    EudraCT Number:2013-001534-18
    Sponsor's Protocol Code Number:Aes-103-003
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-05-03
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2013-001534-18
    A.3Full title of the trial
    A Phase 2, Exploratory, Placebo-Controlled, Multicenter, Double-Blind Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Effects of Five Dose Regimens of Aes-103 Given for 28 Days to Subjects with Stable Sickle Cell Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the effects Aes-103 in patients with Sickle Cell Disease
    A.4.1Sponsor's protocol code numberAes-103-003
    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 SponsorAesRx
    B.1.3.4CountryUnited States
    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 supportTherapeutics and Rare Diseases division of the National Institutes of Health
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportAesRx
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAesRx
    B.5.2Functional name of contact pointWarren Stern
    B.5.3 Address:
    B.5.3.1Street Address275 Grove Street,Suite 2-400
    B.5.3.2Town/ cityNewton
    B.5.3.3Post codeMA 02466
    B.5.3.4CountryUnited States
    B.5.4Telephone number6176881345
    B.5.5Fax number6176636178
    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 No
    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.3.1Product name5-hydroxymethyl 2 furfural
    D.3.2Product code Aes-103
    D.3.4Pharmaceutical form Oral solution
    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 INNINN Not yet proposed
    D.3.9.2Current sponsor codeAes-103
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    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 placeboOral solution
    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
    Sickle Cell Disease
    E.1.1.1Medical condition in easily understood language
    Blood Disorder
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10040644
    E.1.2Term Sickle cell disease
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and pharmacokinetic (PK) profile of four times daily (q.i.d.) dosing of 1000 mg of Aes-103 in Cohort A and up to four additional dosing regimens (to be determined) in Cohort B given for up to 28 days in adult subjects with stable sickle cell disease (SCD) compared with subjects receiving placebo
    E.2.2Secondary objectives of the trial
    To obtain exploratory evidence of pharmacodynamic (PD) and clinical efficacy endpoint changes from baseline in Aes-103-treated subjects compared with those receiving placebo with respect to the magnitude of effect, time course of effect, and relationship to plasma and red blood cell (RBC) concentrations of Aes-103.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Be male or female, aged 18-60 years old, inclusive
    2. Have SCD (hemoglobin SS or S-beta-zero) without hospitalization for any reason in the 14 days before enrollment. Subjects are allowed concomitant usage of HU and other scheduled prescription drugs if the dosage is stable for the 2 months before screening and is at a dosage that does not exceed the product’s labeling. These scheduled prescription medications will be continued during the study. All other medications administered on an as-needed basis, including over-the-counter medications used according to the product labeling, will be permitted except for disulfiram, dextromethorphan, or dextrorphan. Medications for pain management will be allowed as needed.
    3. Have normal organ function as defined below:
    • Direct bilirubin <19 μmol/L
    • Alanine transaminase (serum glutamic pyruvic transaminase) ≤114 IU/L
    • Creatinine ≤115 μmol/L
    • γ-glutamyltransferase ≤110 IU/L
    4. Have at least one of the following baseline values: hemoglobin level of <10 g/dL, numerical pain rating scale (NPRS) score of ≥4, or 6-minute walk distance (6MWD) of ≤500 m
    5. If female, be non-pregnant and non-breast feeding and be surgically sterile or using an acceptable method of contraception throughout the study and for 3 months after the last dose of study medication
    6. Have completed an outpatient screening visit consisting of medical history, physical examination, 12-lead ECG, vital signs, hematology and chemistry tests, urinalysis, urine drug screen, urine or serum pregnancy test (females), hemoglobin electrophoresis, hepatitis B and C screening, and HIV serology (Note: Subjects with abnormal screening values may be eligible if the results are not clinically significant or represent expected manifestations of SCD, as judged by the investigator in agreement with the sponsor or medical monitor.)
    7. Be able to understand and have provided written informed consent including signature on an informed consent form (ICF) approved by an institutional review board (IRB) or independent ethics committee (IEC)
    8. Have provided written authorization for use and disclosure of protected health information (PHI)
    9. Agree to abide by the study schedule and to return for the required assessments
    10. Be willing to abstain from foods high in 5-HMF (e.g., malt, barley, beer, balsamic vinegar, dried fruits, and caramel products) and limit consumption of coffee to 2 cups per day during the study
    11. Subjects with poor venous access who are unlikely to be able to provide repeated blood samples for pharmacokinetic analyses may be enrolled in the study if their venous access is sufficient to provide blood samples for safety assessments of clinical laboratory and hematology measures. (No more than 3 subjects per dose cohort with poor venous access may be enrolled.)
    E.4Principal exclusion criteria
    1. Have been hospitalized in the 14 days before enrollment, for any reason
    2. Have evidence of clinically significant cardiovascular, respiratory, renal, hepatic, pulmonary, gastrointestinal, hematological, neurological, psychiatric, or other disease that may interfere with the objectives of the study or the safety of the subject, as judged by the investigator in agreement with the sponsor or medical monitor, or have been hospitalized in the past 6 months as a result of these conditions (for SCD-related morbidity, a minimum of 14 days from the last hospitalization is required)
    3. Have a history of development of abnormal liver function test (LFT) values in association with administration of xenobiotic provided the causality relationship of the xenobiotic to the LFT abnormality is judged to be at least probably related.
    4. Be considered not suitable for participation in this study for any reason, as judged by the investigator
    5. Have taken any other investigational drug within 30 days before the screening visit
    6. Consumed more than 21 alcohol units per week in the last month or more than 3 units per day in the last week
    7. Have received disulfiram or 4-methoxypyrazole within 30 days before dosing (may affect PK results due to assay interference)
    8. Have received dextromethorphan or dextrorphan within 7 days before dosing
    9. Have taken herbal preparations in the 2 weeks before dosing
    10. Have positive result for urine drug test (cocaine, opiates [except prescribed], amphetamines, methamphetamines, benzodiazepines [except prescribed]) at screening visit (A positive test for THC will not be an exclusion)
    E.5 End points
    E.5.1Primary end point(s)
    The primary safety endpoints will be assessed by the following:
    •Frequency and severity of AEs, including sickle cell-specific symptoms, such as development of new skin ulcers, hospitalization or ambulatory acute care intravenous analgesics visit for pain episodes, acute chest syndrome, priapism, or stroke.
    •Changes in other SCD-related symptoms
    •Changes in vital signs, 12-lead ECGs, clinical laboratory assessments, and physical and neurological examinations.

    The primary PK endpoints are as follows:
    •Plasma AUC, Cmax, Tmax, and t1/2 of Aes-103 and its metabolite, HMFA
    •RBC hemolysate AUC0-8h, Cmax, Tmax, and t1/2 of Aes-103
    •Percentage of hemoglobin bound to Aes-103
    E.5.1.1Timepoint(s) of evaluation of this end point
    The following safety parameters will be assessed at screening, between 1 and 3 hours before the first dose of lead-in placebo on Day –14, on Days -1, 1, and 4 during the inpatient period, and at each outpatient visit throughout the study unless otherwise specified:
    • AEs, including sickle cell-specific symptoms (recorded as signs and symptoms before first dose of single-blind placebo on Day –14 and continuously throughout the study thereafter)
    • Vital signs at 1 to 3 hours after the morning dose and between 9 pm and 10 pm on all inpatient days (also recorded on Day –1 and daily during the inpatient period)
    • 12-lead ECG at 1 to 3 hours after the morning dose (not conducted on Days -1 or 42)
    Please refer to protocol pages xi and xii for the remaining text.
    E.5.2Secondary end point(s)
    The secondary PD and efficacy endpoints will be change from baseline for each of the two dosing regimens compared to placebo for the following:
    •Resting oxygen saturation as measured by oximetry (SpO2)
    •Oxygen binding p50 value
    •Plasma erythropoietin (EPO) levels
    • LDH total levels, anemia/hemoglobin count, reticulocyte percent, and direct bilirubin
    • LDH isozyme (LDH1, LDH2, LDH3, LDH4, and LDH5) levels
    • C reactive protein levels
    • Serum ferritin levels
    • NT-proBNP levels
    • Body weight
    • Exercise tolerance (6MWT and CPET)
    • Patient Global Impression of Change
    • Pain levels and analgesic use
    • Reduction in sickle cell-specific complications
    E.5.2.1Timepoint(s) of evaluation of this end point
    PD and efficacy samples and measurements will be taken between 1 and 3 hours before the first dose and 1 to 3 hours after the first dose of study medication on Day 1 of the double-blind, inpatient period, 1 to 3 hours after the morning dose on Day 7, 1 to 3 hours after the morning dose on Day 28 (or the last day of dosing during the double-blind, outpatient period, if earlier) and on Day 49 (or the last day of the post-dose observation period, if earlier). The following will be • Whole blood will be drawn for p50/p20 assays between 8 pm and 10 pm on the evening before the first dose (Day –1) and between 8 am and 10 am on Days 1, 4 of the inpatient period (Visit 3) and on Day 7 (Visit 4).
    Please refer to protocol pages x and xi for remaining text.
    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 Yes
    E.6.7Pharmacodynamic Yes
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. trial design description
    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 concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    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 months18
    E.8.9.1In the Member State concerned 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: 100
    F.1.3Elderly (>=65 years) No
    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 No
    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 state100
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 100
    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 Decision2013-06-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-03-16
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