A Single Dose Study of the Safety, Blood Levels and Biological Effects of Aes-103 Compared to Placebo in Subjects With Stable Sickle Cell Disease

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of Aes-103 (active ingredient 5-hydroxymethyl-2-furfural [5-HMF]) compared with placebo in subjects with stable sickle cell disease (SCD). Safety will be measured by monitoring adverse events (AEs), electrocardiograms (ECGs), vital signs, and laboratory values. Pharmacokinetics of Aes-103 will be measured over time in plasma, red blood cell hemolysate and binding of Aes-103 to hemoglobin. Pharmacodynamic effects will be assessed by measuring partial pressure of oxygen at which 50% of hemoglobin is saturated with oxygen (p50) while breathing normal air, blood oxygen levels (SpO2), ex-vivo antisickling effects in a hypoxic environment, and by imaging related changes in tissue blood flow and oxygen levels.

Official Title
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A Phase 1, Placebo-Controlled, Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Escalating, Single Oral Doses of Aes-103 in Subjects With Stable Sickle Cell Disease

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Aes-103
* Drug: Aes-103
* Drug: Aes-103
* Drug: Aes-103
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be male or female, aged 18-65 years old, inclusive Have sickle cell disease (SCD) (hemoglobin SS) without hospitalization for pain crises in the 30 days before screening or for any SCD complications on more than two occasions in the past 12 months; subjects are allowed concomitant usage of hydroxyurea (HU) if the dosage is stable for the 2 months before screening and is at a dosage that does not exceed the product's labeling. Have normal laboratory values as defined below: Direct bilirubin 0.1 to 1.0 mg/dL Alanine transaminase (serum glutamic pyruvic transaminase) 6 to 41 IU/L Creatinine for females 0.56 to 1.16 mg/dL and for males 0.77 to 1.19 mg/dL If female, be non-pregnant and non-breastfeeding and be surgically sterile or using an acceptable method of contraception throughout the study and for 30 days after study completion Have successfully completed an outpatient screening visit consisting of medical history, physical examination, 12-lead ECG, vital signs, hematology and chemistry tests, urinalysis, urine drug screen, 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, as judged by the investigator or medical monitor) Be able to understand and have provided written informed consent including signature on an informed consent form approved by an institutional review board Agree to abide by the study schedule and dietary restrictions and to return for the required assessments Be willing to abstain from foods high in 5-HMF (e.g., coffee, malt, barley, balsamic vinegar, dried fruits, and caramel products) for at least 3 days before each dosing Exclusion Criteria: 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 Have been hospitalized in the 14 days before enrollment, for any reason Be currently on regularly scheduled transfusions Have received a transfusion within 2 weeks of administration of study drug Have taken herbal preparations in the 2 weeks before dosing (Note: 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 [including during dosing]. All other medications, including over-the-counter medications used according to the product labeling, administered on an as-needed basis will be permitted except for the 24 hour period before dosing and the day of dosing. Medications for pain management will be allowed as needed [including during dosing.]) Have taken any other investigational drug within 30 days or 5 half-lives before the screening visit, whichever is longer Consumed more than 14 alcoholic drinks per week or more than 3 drinks per day at any point in the past month Have received disulfiram or 4-methylpyrazole within 30 days before dosing Have taken any cough-cold product containing dextrorphan or dextromethorphan within 4 days before dosing Have positive result for urine drug test (cocaine, marijuana, opiates, amphetamines, methamphetamines, benzodiazepines, ethanol) at screening visit. However, use of opiates, amphetamines, or benzodiazepines is allowed if prescribed by a physician. Have engaged in strenuous exercise within 72 hours prior to dosing Be considered not suitable for participation in this study for any reason, as judged by the investigator Have pre-existing allergic or other adverse reactions to orange juice

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aes-103 300 mg to 1000 mg (Group A)<br>Group A will consist of six subjects receiving a single dose of either a low dose of Aes-103 (300 mg) or placebo without food. After a minimum of a 1- to 2-week washout period and evaluation of blinded safety data, subjects initially randomized to Aes-103 will receive a second, higher dose of Aes-103 (1,000 mg), and subjects initially randomized to placebo will receive a second dose of placebo without food. | Drug: Aes-103<br>* 300 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.<br>Drug: Aes-103<br>* 1000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.<br>Drug: Placebo<br>* Orange juice vehicle, a solution that is highly similar in appearance to the Aes-103 orange juice solution.<br>|
| Experimental: Aes-103 2000 mg to 4000 mg (Group B)<br>Group B will consist of six subjects receiving an initial dose of either Aes 103 (2,000 mg) or placebo without food. After a minimum of a 1- to 2-week washout period and evaluation of blinded safety data, subjects initially randomized to Aes-103 will receive a second, higher dose of Aes-103 (4,000 mg), and subjects initially randomized to placebo will receive a second dose of placebo without food. | Drug: Aes-103<br>* 2000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.<br>Drug: Aes-103<br>* 4000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.<br>Drug: Placebo<br>* Orange juice vehicle, a solution that is highly similar in appearance to the Aes-103 orange juice solution.<br>|
| Experimental: Top Dose Expansion (Group C)<br>Once the top dose (i.e., highest tolerated) of Aes-103 has been determined, the size of this group will be expanded with an additional six subjects (Group C) for a total of 12 at that dose, distributed so that six subjects receiving hydroxyurea (HU) and six subjects not receiving HU (for the past 6 months) will receive study drug (five receiving Aes-103 and one receiving placebo in each of the HU and non-HU treated cohorts). This total of 12 subjects includes the initial six subjects who received the highest dose in the study plus six Group C subjects. These subjects will receive a single dose of the top dose of Aes-103 or placebo without food. After a minimum of a 1- to 2-week washout period and evaluation of blinded safety data, subjects initially randomized to Aes-103 will receive a second dose of the top dose of Aes-103 and subjects initially randomized to placebo will receive a second dose of placebo; all subjects will be administered a pre-dose, high fat, high protein meal. | Drug: Aes-103<br>* 4000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.<br>Drug: Placebo<br>* Orange juice vehicle, a solution that is highly similar in appearance to the Aes-103 orange juice solution.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, as assessed by frequency and severity of adverse events (AEs), and changes in vital signs, 12-lead electrocardiograms (ECGs), and laboratory assessments as compared to baseline. |  | 32 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma area under the curve (AUC) of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Red blood cell (RBC) hemolysate AUC of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Hemoglobin bound 5-hydroxymethyl-2-furfural (5-HMF) AUC |  | predose, .5 hrs, 1 hr, 4 hr, and 12 hr | 
| Renal elimination of Aes-103 |  | predose, 0-4hrs, 4-8hrs, and 8-24hrs | 
| Percentage of hemoglobin bound to Aes-103 |  | predose, 1 hr, 2 hr, 4 hr, and 12 hr | 
| Change from baseline in resting oxygen saturation (SpO2) |  | predose, .5 hrs, 1 hr, 4 hr, and 12 hr | 
| Change from baseline in partial pressure of oxygen required to achieve 50% hemoglobin saturation (p50) value |  | predose, 1 hr, 2 hr, 4 hr, and 12 hr | 
| Effects of food ingested prior to dosing on plasma AUC of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Percentage of sickled cells under normal ex vivo conditions |  | predose, 1 hr, 2 hr, 4 hr, and 12 hr | 
| Change from baseline in blood flow distribution |  | predose and .5 to 2 hr | 
| Change from baseline in peripheral arterial tonometry |  | predose and .5 to 2 hr | 
| Change from baseline in pain as measured by the Numerical Pain Rating Scale (NPRS) |  | -1hr, -.5hrs, -5min, .1hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Plasma maximum concentration (Cmax) of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Plasma time to maximum concentration (Tmax) of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Plasma half life (t1/2) of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Plasma AUC of Aes-103's metabolite, 5-hydroxymethyl-2-furoic acid (HMFA) |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Plasma maximum concentration (Cmax) of HMFA |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Plasma time to maximum concentration (Tmax) of HMFA |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Plasma half life (t1/2) of HMFA |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| RBC hemolysate Cmax of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| RBC hemolysate Tmax of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| RBC hemolysate t1/2 of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| RBC hemolysate AUC of HMFA |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| RBC hemolysate Cmax of HMFA |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| RBC hemolysate Tmax of HMFA |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| RBC hemolysate t1/2 of HMFA |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Hemoglobin bound 5-HMF Cmax |  | predose, .5 hrs, 1 hr, 4 hr, and 12 hr | 
| Hemoglobin bound 5-HMF Tmax |  | predose, .5 hrs, 1 hr, 4 hr, and 12 hr | 
| Hemoglobin bound 5-HMF t1/2 |  | predose, .5 hrs, 1 hr, 4 hr, and 12 hr | 
| Renal elimination of HMFA |  | predose, 0-4hrs, 4-8hrs, and 8-24hrs | 
| Effects of food ingested prior to dosing on plasma Cmax of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Effects of food ingested prior to dosing on plasma Tmax of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Effects of food ingested prior to dosing on plasma t1/2 of Aes-103 |  | predose, .1 hrs, .25 hrs, .5 hrs, .75 hrs, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr | 
| Percentage of sickled cells under hypoxic ex vivo conditions |  | predose, 1 hr, 2 hr, 4 hr, and 12 hr | 
| Change from baseline in vasomotion |  | predose and .5 to 2 hr | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antisickling Agents