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

This study has been completed.
Sponsor:
Collaborators:
Cato Research
ClinPharm Consulting, LLC
Infrared Imaging and Thermometry Unit, Biomedical Engineering and Physical Science Shared Resource (NIBIB)
National Chung Cheng University
QS Pharma
Ricerca Biosciences LLC
SAIC-Frederick, Inc.
Information provided by (Responsible Party):
AesRx, LLC
ClinicalTrials.gov Identifier:
NCT01597401
First received: April 26, 2012
Last updated: July 1, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Anemia, Sickle Cell
Drug: Aes-103
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by AesRx, LLC:

Primary Outcome Measures:
  • 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. [ Time Frame: 32 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Plasma area under the curve (AUC) of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Red blood cell (RBC) hemolysate AUC of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Hemoglobin bound 5-hydroxymethyl-2-furfural (5-HMF) AUC [ Time Frame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Renal elimination of Aes-103 [ Time Frame: predose, 0-4hrs, 4-8hrs, and 8-24hrs ] [ Designated as safety issue: No ]
  • Percentage of hemoglobin bound to Aes-103 [ Time Frame: predose, 1 hr, 2 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Change from baseline in resting oxygen saturation (SpO2) [ Time Frame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Change from baseline in partial pressure of oxygen required to achieve 50% hemoglobin saturation (p50) value [ Time Frame: predose, 1 hr, 2 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Effects of food ingested prior to dosing on plasma AUC of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Percentage of sickled cells under normal ex vivo conditions [ Time Frame: predose, 1 hr, 2 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Change from baseline in blood flow distribution [ Time Frame: predose and .5 to 2 hr ] [ Designated as safety issue: No ]
  • Change from baseline in peripheral arterial tonometry [ Time Frame: predose and .5 to 2 hr ] [ Designated as safety issue: No ]
  • Change from baseline in pain as measured by the Numerical Pain Rating Scale (NPRS) [ Time Frame: -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 ] [ Designated as safety issue: No ]
  • Plasma maximum concentration (Cmax) of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Plasma time to maximum concentration (Tmax) of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Plasma half life (t1/2) of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Plasma AUC of Aes-103's metabolite, 5-hydroxymethyl-2-furoic acid (HMFA) [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Plasma maximum concentration (Cmax) of HMFA [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Plasma time to maximum concentration (Tmax) of HMFA [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Plasma half life (t1/2) of HMFA [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • RBC hemolysate Cmax of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • RBC hemolysate Tmax of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • RBC hemolysate t1/2 of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • RBC hemolysate AUC of HMFA [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • RBC hemolysate Cmax of HMFA [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • RBC hemolysate Tmax of HMFA [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • RBC hemolysate t1/2 of HMFA [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Hemoglobin bound 5-HMF Cmax [ Time Frame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Hemoglobin bound 5-HMF Tmax [ Time Frame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Hemoglobin bound 5-HMF t1/2 [ Time Frame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Renal elimination of HMFA [ Time Frame: predose, 0-4hrs, 4-8hrs, and 8-24hrs ] [ Designated as safety issue: No ]
  • Effects of food ingested prior to dosing on plasma Cmax of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Effects of food ingested prior to dosing on plasma Tmax of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Effects of food ingested prior to dosing on plasma t1/2 of Aes-103 [ Time Frame: 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 ] [ Designated as safety issue: No ]
  • Percentage of sickled cells under hypoxic ex vivo conditions [ Time Frame: predose, 1 hr, 2 hr, 4 hr, and 12 hr ] [ Designated as safety issue: No ]
  • Change from baseline in vasomotion [ Time Frame: predose and .5 to 2 hr ] [ Designated as safety issue: No ]

Enrollment: 19
Study Start Date: May 2012
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Aes-103 300 mg to 1000 mg (Group A)
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
300 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
Drug: Aes-103
1000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
Drug: Placebo
Orange juice vehicle, a solution that is highly similar in appearance to the Aes-103 orange juice solution.
Experimental: Aes-103 2000 mg to 4000 mg (Group B)
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
2000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
Drug: Aes-103
4000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
Drug: Placebo
Orange juice vehicle, a solution that is highly similar in appearance to the Aes-103 orange juice solution.
Experimental: Top Dose Expansion (Group C)
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
4000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
Drug: Placebo
Orange juice vehicle, a solution that is highly similar in appearance to the Aes-103 orange juice solution.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01597401

Locations
United States, Maryland
US National Institutes of Health - National Heart, Lung, and Blood Institute
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
AesRx, LLC
Cato Research
ClinPharm Consulting, LLC
Infrared Imaging and Thermometry Unit, Biomedical Engineering and Physical Science Shared Resource (NIBIB)
National Chung Cheng University
QS Pharma
Ricerca Biosciences LLC
SAIC-Frederick, Inc.
Investigators
Principal Investigator: Gregory Kato, MD US National Institutes of Health - National Heart, Lung, and Blood Institute
  More Information

Publications:

Responsible Party: AesRx, LLC
ClinicalTrials.gov Identifier: NCT01597401     History of Changes
Other Study ID Numbers: Aes-103-002, 1ZIAHL006149-01
Study First Received: April 26, 2012
Last Updated: July 1, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by AesRx, LLC:
Antisickling Agents

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies

ClinicalTrials.gov processed this record on October 29, 2014