Sickle Cell DiseasePhase 1NCT01597401

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

A Phase 1 study testing Aes-103 in people with Sickle Cell Disease, run by Baxalta now part of Shire at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Sickle Cell Disease
What is being tested?: Aes-103
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 19 participants
Where: 1 siteUnited States
Study dates: 12 May 2012to 7 Jun 2013
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Show all 11Show fewer

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

Who cannot join

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

Show all 13Show fewer

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

Trial locations and contacts

1 site in 1 country.

United States1 site

US National Institutes of Health - National Heart, Lung, and Blood Institute
Bethesda, Maryland, 20892

Other trials in United States

About this study

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

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.

Conditions: Sickle Cell Disease
Being tested: Aes-103, Placebo
Keywords: Antisickling Agents
Medical subject headings: Anemia, Sickle Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

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

Study groups in NCT01597401
Study group	Role	What they receive
Aes-103 300 mg to 1000 mg (Group A)	Experimental	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. Receives: Drug: Aes-103; Drug: Placebo
Aes-103 2000 mg to 4000 mg (Group B)	Experimental	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. Receives: Drug: Aes-103; Drug: Placebo
Top Dose Expansion (Group C)	Experimental	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. Receives: Drug: Aes-103; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 32 days

Secondary outcomes (35)

Plasma area under the curve (AUC) of Aes-103
Measured: 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
Measured: 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
Measured: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Renal elimination of Aes-103
Measured: predose, 0-4hrs, 4-8hrs, and 8-24hrs
Percentage of hemoglobin bound to Aes-103
Measured: predose, 1 hr, 2 hr, 4 hr, and 12 hr
Change from baseline in resting oxygen saturation (SpO2)
Measured: 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
Measured: predose, 1 hr, 2 hr, 4 hr, and 12 hr
Effects of food ingested prior to dosing on plasma AUC of Aes-103
Measured: 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
Measured: predose, 1 hr, 2 hr, 4 hr, and 12 hr
Change from baseline in blood flow distribution
Measured: predose and .5 to 2 hr
Change from baseline in peripheral arterial tonometry
Measured: predose and .5 to 2 hr
Change from baseline in pain as measured by the Numerical Pain Rating Scale (NPRS)
Measured: -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
Measured: 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
Measured: 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
Measured: 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)
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Hemoglobin bound 5-HMF Tmax
Measured: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Hemoglobin bound 5-HMF t1/2
Measured: predose, .5 hrs, 1 hr, 4 hr, and 12 hr
Renal elimination of HMFA
Measured: predose, 0-4hrs, 4-8hrs, and 8-24hrs
Effects of food ingested prior to dosing on plasma Cmax of Aes-103
Measured: 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
Measured: 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
Measured: 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
Measured: predose, 1 hr, 2 hr, 4 hr, and 12 hr
Change from baseline in vasomotion
Measured: predose and .5 to 2 hr

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

12 May 20127 Jun 2013

First posted14 May 2012 (estimated)
Study start12 May 2012
Primary completion7 Jun 2013
Study completion7 Jun 2013

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (14)Papers the sponsor has linked to this study.
Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 19 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01597401
Sponsor's protocol ID: Aes-103-002
Other IDs: 1ZIAHL006149-01
Status last verified: May 2021
First submitted: 26 Apr 2012
Last updated: 5 May 2021
Results posted: No
Data monitoring committee: No

Publications

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. doi: 10.1111/j.1365-2141.2004.05332.x.
PubMed 15686467
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.
PubMed 19819341
Czok G. [Tolerance of 5-hydroxymethylfurfural (HMF). 2d communication: pharmacologic effects]. Z Ernahrungswiss. 1970 Dec;10(2):103-10. doi: 10.1007/BF02021840. No abstract available. German.
PubMed 5492127
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. doi: 10.1080/15287398709531052.
PubMed 3612837
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. doi: 10.1080/009841099157764.
PubMed 10376886
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. doi: 10.1093/chromsci/35.12.578.
PubMed 9397542
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. doi: 10.1016/j.ejcts.2007.07.016. Epub 2007 Sep 4.
PubMed 17768058
Mitchell BL. Sickle cell trait and sudden death--bringing it home. J Natl Med Assoc. 2007 Mar;99(3):300-5.
PubMed 17393956
Mrochek JE, Rainey WT Jr. Identification and biochemical significance of substituted furans in human urine. Clin Chem. 1972 Aug;18(8):821-8. No abstract available.
PubMed 5043270
Murkovic M, Pichler N. Analysis of 5-hydroxymethylfurfual in coffee, dried fruits and urine. Mol Nutr Food Res. 2006 Sep;50(9):842-6. doi: 10.1002/mnfr.200500262.
PubMed 16917810
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. No abstract available.
PubMed 18367739
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. doi: 10.1021/jf0601113.
PubMed 19127754
Simonian TA. [Toxico-hygienic characteristics of oxymethylfurfural]. Vopr Pitan. 1969 Jan-Feb;28(1):54-8. No abstract available. Russian.
PubMed 4312377
Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health. 2006;29(4):245-54.
PubMed 17718403

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 5 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT01597401
Acronym / sponsor ID: Aes-103-002
Conditions: Sickle Cell Disease
Keywords: Antisickling Agents
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 19 participants (actual)
Lead sponsor: Baxalta now part of ShireIndustry (pharma, biotech, devices)
Collaborators: SAIC-Frederick, Inc., Therapeutics for Rare and Neglected Diseases (TRND), QS Pharma, National Chung Cheng University, Infrared Imaging and Thermometry Unit, Biomedical Engineering and Physical Science Shared Resource (NIBIB), ClinPharm Consulting, LLC, Ricerca Biosciences LLC, National Heart, Lung, and Blood Institute (NHLBI), Cato Research
Study start: 12 May 2012 (actual)
Primary completion: 7 Jun 2013 (actual)
Study completion: 7 Jun 2013 (actual)
First posted: 14 May 2012 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 3

Arm	Type	Receives
Aes-103 300 mg to 1000 mg (Group A)	Experimental	Drug: Aes-103, Drug: PlaceboGroup 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.
Aes-103 2000 mg to 4000 mg (Group B)	Experimental	Drug: Aes-103, Drug: PlaceboGroup 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.
Top Dose Expansion (Group C)	Experimental	Drug: Aes-103, Drug: PlaceboOnce 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.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (11 listed)

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:
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)

Key exclusion criteria (13 listed)

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.])

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Aes-103300 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.	Drug	Aes-103 300 mg to 1000 mg (Group A)
Aes-1031000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.	Drug	Aes-103 300 mg to 1000 mg (Group A)
Aes-1032000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.	Drug	Aes-103 2000 mg to 4000 mg (Group B)
Aes-1034000 mg Aes-103 powder reconstituted in orange juice to a volume of 100 mL per single dose for oral administration.	Drug	Aes-103 2000 mg to 4000 mg (Group B), Top Dose Expansion (Group C)
PlaceboOrange juice vehicle, a solution that is highly similar in appearance to the Aes-103 orange juice solution.	Drug	Aes-103 2000 mg to 4000 mg (Group B), Aes-103 300 mg to 1000 mg (Group A), Top Dose Expansion (Group C)

Primary outcome

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

35 secondary outcomes

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

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 5 May 2021.
Background: PubMed 15686467Abdulmalik 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. doi: 10.1111/j.1365-2141.2004.05332.x.
Background: PubMed 19819341Buchanan 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.
Background: PubMed 5492127Czok G. [Tolerance of 5-hydroxymethylfurfural (HMF). 2d communication: pharmacologic effects]. Z Ernahrungswiss. 1970 Dec;10(2):103-10. doi: 10.1007/BF02021840. No abstract available. German.
Background: PubMed 3612837Germond 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. doi: 10.1080/15287398709531052.
Background: PubMed 10376886Godfrey 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. doi: 10.1080/009841099157764.
Background: PubMed 9397542Lo 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. doi: 10.1093/chromsci/35.12.578.
Background: PubMed 17768058Matzi 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. doi: 10.1016/j.ejcts.2007.07.016. Epub 2007 Sep 4.
Background: PubMed 17393956Mitchell BL. Sickle cell trait and sudden death--bringing it home. J Natl Med Assoc. 2007 Mar;99(3):300-5.
Background: PubMed 5043270Mrochek JE, Rainey WT Jr. Identification and biochemical significance of substituted furans in human urine. Clin Chem. 1972 Aug;18(8):821-8. No abstract available.
Background: PubMed 16917810Murkovic M, Pichler N. Analysis of 5-hydroxymethylfurfual in coffee, dried fruits and urine. Mol Nutr Food Res. 2006 Sep;50(9):842-6. doi: 10.1002/mnfr.200500262.
Background: PubMed 18367739Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008 Mar 27;358(13):1362-9. doi: 10.1056/NEJMct0708272. No abstract available.
Background: PubMed 19127754Prior 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. doi: 10.1021/jf0601113.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Study Director study director

Takeda

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Aes-103 in people with Sickle Cell Disease, run by Baxalta now part of Shire at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 May 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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. (time frame: 32 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01597401, which also lists 14 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 May 2021.