Clinical trial NCT01597401: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Sickle Cell Disease
Keywords: Antisickling Agents
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: SAIC-Frederick, Inc.
name: Therapeutics for Rare and Neglected Diseases (TRND)
name: QS Pharma
name: National Chung Cheng University
name: Infrared Imaging and Thermometry Unit, Biomedical Engineering and Physical Science Shared Resource (NIBIB)
name: ClinPharm Consulting, LLC
name: Ricerca Biosciences LLC
name: National Heart, Lung, and Blood Institute (NHLBI)
name: Cato Research
First posted: 2012-05-14
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: 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.
timeFrame: 32 days
Secondary outcomes:
measure: Plasma area under the curve (AUC) of Aes-103
timeFrame: 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
measure: Red blood cell (RBC) hemolysate AUC of Aes-103
timeFrame: 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
measure: Hemoglobin bound 5-hydroxymethyl-2-furfural (5-HMF) AUC
timeFrame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
measure: Renal elimination of Aes-103
timeFrame: predose, 0-4hrs, 4-8hrs, and 8-24hrs
measure: Percentage of hemoglobin bound to Aes-103
timeFrame: predose, 1 hr, 2 hr, 4 hr, and 12 hr
measure: Change from baseline in resting oxygen saturation (SpO2)
timeFrame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
measure: Change from baseline in partial pressure of oxygen required to achieve 50% hemoglobin saturation (p50) value
timeFrame: predose, 1 hr, 2 hr, 4 hr, and 12 hr
measure: Effects of food ingested prior to dosing on plasma AUC of Aes-103
timeFrame: 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
measure: Percentage of sickled cells under normal ex vivo conditions
timeFrame: predose, 1 hr, 2 hr, 4 hr, and 12 hr
measure: Change from baseline in blood flow distribution
timeFrame: predose and .5 to 2 hr
measure: Change from baseline in peripheral arterial tonometry
timeFrame: predose and .5 to 2 hr
measure: Change from baseline in pain as measured by the Numerical Pain Rating Scale (NPRS)
timeFrame: -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
measure: Plasma maximum concentration (Cmax) of Aes-103
timeFrame: 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
measure: Plasma time to maximum concentration (Tmax) of Aes-103
timeFrame: 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
measure: Plasma half life (t1/2) of Aes-103
timeFrame: 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
measure: Plasma AUC of Aes-103's metabolite, 5-hydroxymethyl-2-furoic acid (HMFA)
timeFrame: 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
measure: Plasma maximum concentration (Cmax) of HMFA
timeFrame: 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
measure: Plasma time to maximum concentration (Tmax) of HMFA
timeFrame: 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
measure: Plasma half life (t1/2) of HMFA
timeFrame: 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
measure: RBC hemolysate Cmax of Aes-103
timeFrame: 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
measure: RBC hemolysate Tmax of Aes-103
timeFrame: 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
measure: RBC hemolysate t1/2 of Aes-103
timeFrame: 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
measure: RBC hemolysate AUC of HMFA
timeFrame: 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
measure: RBC hemolysate Cmax of HMFA
timeFrame: 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
measure: RBC hemolysate Tmax of HMFA
timeFrame: 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
measure: RBC hemolysate t1/2 of HMFA
timeFrame: 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
measure: Hemoglobin bound 5-HMF Cmax
timeFrame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
measure: Hemoglobin bound 5-HMF Tmax
timeFrame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
measure: Hemoglobin bound 5-HMF t1/2
timeFrame: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
measure: Renal elimination of HMFA
timeFrame: predose, 0-4hrs, 4-8hrs, and 8-24hrs
measure: Effects of food ingested prior to dosing on plasma Cmax of Aes-103
timeFrame: 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
measure: Effects of food ingested prior to dosing on plasma Tmax of Aes-103
timeFrame: 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
measure: Effects of food ingested prior to dosing on plasma t1/2 of Aes-103
timeFrame: 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
measure: Percentage of sickled cells under hypoxic ex vivo conditions
timeFrame: predose, 1 hr, 2 hr, 4 hr, and 12 hr
measure: Change from baseline in vasomotion
timeFrame: predose and .5 to 2 hr
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: US National Institutes of Health - National Heart, Lung, and Blood Institute
state: Maryland
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
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