E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040644 |
E.1.2 | Term | Sickle cell disease |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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 |
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E.2.2 | Secondary 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.) |
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E.4 | Principal 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) |
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E.5 End points |
E.5.1 | Primary 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
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary 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
•Hematocrit
• 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 |
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E.5.2.1 | Timepoint(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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | 0 |