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

Sickle Cell Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01597401
• Other study ID #: Aes-103-002
• Secondary ID: 1ZIAHL006149-01
• Status: Completed
• Phase: Phase 1
• Start date: May 12, 2012
• Est. completion date: June 7, 2013

Study information

• Verified date: May 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: June 7, 2013
• Est. primary completion date: June 7, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Aes-103
300 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
• Aes-103
1000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
• Aes-103
2000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
• Aes-103
4000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.
• Placebo
Orange juice vehicle, a solution that is highly similar in appearance to the Aes-103 orange juice solution.

Locations

Country	Name	City	State
United States	US National Institutes of Health - National Heart, Lung, and Blood Institute	Bethesda	Maryland

Sponsors (10)

Lead Sponsor	Collaborator
Baxalta now part of Shire	Cato Research, ClinPharm Consulting, LLC, Infrared Imaging and Thermometry Unit, Biomedical Engineering and Physical Science Shared Resource (NIBIB), National Chung Cheng University, National Heart, Lung, and Blood Institute (NHLBI), QS Pharma, Ricerca Biosciences LLC, SAIC-Frederick, Inc., Therapeutics for Rare and Neglected Diseases (TRND)

Country where clinical trial is conducted

United States, 

References & Publications (14)

Abdulmalik O, Safo MK, Chen Q, Yang J, Brugnara C, Ohene-Frempong K, Abraham DJ, Asakura T. 5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells. Br J Haematol. 2005 Feb;128(4):552-61. — View Citation

Buchanan G, Vichinsky E, Krishnamurti L, Shenoy S. Severe sickle cell disease--pathophysiology and therapy. Biol Blood Marrow Transplant. 2010 Jan;16(1 Suppl):S64-7. doi: 10.1016/j.bbmt.2009.10.001. Epub 2009 Oct 9. Review. — View Citation

Czok G. [Tolerance of 5-hydroxymethylfurfural (HMF). 2d communication: pharmacologic effects]. Z Ernahrungswiss. 1970 Dec;10(2):103-10. German. — View Citation

Germond JE, Philippossian G, Richli U, Bracco I, Arnaud MJ. Rapid and complete urinary elimination of [14C]-5-hydroxymethyl-2-furaldehyde administered orally or intravenously to rats. J Toxicol Environ Health. 1987;22(1):79-89. — View Citation

Godfrey VB, Chen LJ, Griffin RJ, Lebetkin EH, Burka LT. Distribution and metabolism of (5-hydroxymethyl)furfural in male F344 rats and B6C3F1 mice after oral administration. J Toxicol Environ Health A. 1999 Jun 11;57(3):199-210. — View Citation

Lo Coco F, Novelli V, Valentini C, Ceccon L. High-performance liquid chromatographic determination of 2-furaldehyde and 5-hydroxymethyl-2-furaldehyde in fruit juices. J Chromatogr Sci. 1997 Dec;35(12):578-83. — View Citation

Matzi V, Lindenmann J, Muench A, Greilberger J, Juan H, Wintersteiger R, Maier A, Smolle-Juettner FM. The impact of preoperative micronutrient supplementation in lung surgery. A prospective randomized trial of oral supplementation of combined alpha-ketoglutaric acid and 5-hydroxymethylfurfural. Eur J Cardiothorac Surg. 2007 Nov;32(5):776-82. Epub 2007 Sep 4. — View Citation

Mitchell BL. Sickle cell trait and sudden death--bringing it home. J Natl Med Assoc. 2007 Mar;99(3):300-5. Review. — View Citation

Mrochek JE, Rainey WT Jr. Identification and biochemical significance of substituted furans in human urine. Clin Chem. 1972 Aug;18(8):821-8. — View Citation

Murkovic M, Pichler N. Analysis of 5-hydroxymethylfurfual in coffee, dried fruits and urine. Mol Nutr Food Res. 2006 Sep;50(9):842-6. — View Citation

Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008 Mar 27;358(13):1362-9. doi: 10.1056/NEJMct0708272. Review. — View Citation

Prior RL, Wu X, Gu L. Identification and urinary excretion of metabolites of 5-(hydroxymethyl)-2-furfural in human subjects following consumption of dried plums or dried plum juice. J Agric Food Chem. 2006 May 17;54(10):3744-9. — View Citation

Simonian TA. [Toxico-hygienic characteristics of oxymethylfurfural]. Vopr Pitan. 1969 Jan-Feb;28(1):54-8. Russian. — View Citation

Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health. 2006;29(4):245-54. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Hemoglobin bound 5-hydroxymethyl-2-furfural (5-HMF) AUC		predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Secondary	Renal elimination of Aes-103		predose, 0-4hrs, 4-8hrs, and 8-24hrs
Secondary	Percentage of hemoglobin bound to Aes-103		predose, 1 hr, 2 hr, 4 hr, and 12 hr
Secondary	Change from baseline in resting oxygen saturation (SpO2)		predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Secondary	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
Secondary	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
Secondary	Percentage of sickled cells under normal ex vivo conditions		predose, 1 hr, 2 hr, 4 hr, and 12 hr
Secondary	Change from baseline in blood flow distribution		predose and .5 to 2 hr
Secondary	Change from baseline in peripheral arterial tonometry		predose and .5 to 2 hr
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Hemoglobin bound 5-HMF Cmax		predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Secondary	Hemoglobin bound 5-HMF Tmax		predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Secondary	Hemoglobin bound 5-HMF t1/2		predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Secondary	Renal elimination of HMFA		predose, 0-4hrs, 4-8hrs, and 8-24hrs
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of sickled cells under hypoxic ex vivo conditions		predose, 1 hr, 2 hr, 4 hr, and 12 hr
Secondary	Change from baseline in vasomotion		predose and .5 to 2 hr