Sickle Cell DiseasePhase 2NCT01987908
Evaluation of Different Dose Regimens of Aes-103 Given for 28 Days to Subjects With Stable Sickle Cell Disease
A Phase 2 study testing Aes-103 in people with Sickle Cell Disease, run by Baxalta now part of Shire at 1 site in United Kingdom.
Trial summary
Sickle cell disease (SCD) is a genetic blood disorder characterized by the presence of sickle-shaped red blood cells. In the U.S. and the U.K. this occurs primarily in persons of African origin. Read more about this study
- Who is it for?
- Ages 18 to 60 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
- 35 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 3 Dec 2013to 16 Mar 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Male or female, aged 18-60 years old, inclusive
- Diagnosis of SCD (hemoglobin SS) without hospitalization for pain crises or any other reason in the 14 days before enrollment
- Have normal organ function as defined by direct bilirubin <1.1 mg/dL (19 μmol/L), alanine transaminase (serum glutamic pyruvic transaminase) ≤120 IU/L, and Creatinine ≤1.3 mg/dL (115 μmol/L)
- Have at least one of the following baseline values: hemoglobin level of <10 g/dL, numerical pain rating scale (NPRS) score of ≥ 4, or 6-minute walk distance (6MWD) of <500 m
- If female, be nonpregnant and nonbreastfeeding and be surgically sterile or using an acceptable method of contraception throughout the study and for 3 months after the last dose of study medication
- Have completed an outpatient screening visit consisting of medical history, physical examination, 12-lead electrocardiogram (ECG), vital signs, hematology and chemistry tests, urinalysis, urine drug screen, urine or serum pregnancy test (females), hemoglobin electrophoresis, hepatitis B and C screening, and HIV serology
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- Be able to understand and have provided written informed consent including signature on an informed consent form approved by an institutional review board or independent ethics committee
- Have provided written authorization for use and disclosure of protected health information
- Agree to abide by the study schedule and to return for the required assessments
Who cannot join
- Have been hospitalized in the 14 days before enrollment, for any reason
- 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, or have been hospitalized in the past 6 months as a result of these conditions (for SCD-related morbidity, a minimum of 14 days from the last hospitalization is required)
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Quintiles Ltd. - Quintiles Drug Research Unit, 6 Newcomen Street
London, SE1 1YR
About this study
Official title: A Phase 2, Exploratory, Placebo-Controlled, Multicenter, Double-Blind Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Effects of Two Dose Regimens of Aes-103 Given for 28 Days to Subjects With Stable Sickle Cell Disease
Sickle cell disease (SCD) is a genetic blood disorder characterized by the presence of sickle-shaped red blood cells. In the U.S. and the U.K. this occurs primarily in persons of African origin. There is only one drug (hydroxyurea) approved to manage SCD, but it is not fully efficacious and can produce medically significant side effects. Aes-103 is being evaluated as a novel agent for the long term management of SCD. By directly reducing the sickling process, Aes-103 has a different mechanism of action than hydoxyurea. The active ingredient in Aes-103 is 5-hydroxymethyl furfural, a naturally occurring small molecule that is chemically related to glucose.
This study will evaluate the safety and pharmacokinetic profile of two dosing regimens of Aes-103 for up to 28 days in up to 50 adult subjects with stable SCD compared with subjects receiving placebo.
Read the detailed description
This study will evaluate evaluate in subjects with stable SCD the safety, pharmacokinetic profile, clinical pharmacology actions and clinical activities of two dosing regimens of Aes-103 (1000 mg four times daily in Cohort A and a higher or lower dose given once daily or up to four times daily in Cohort B) given for up to 28 days in adult subjects with stable SCD compared with subjects receiving placebo.
- Conditions
- Sickle Cell Disease
- Being tested
- Aes-103, Placebo
- Keywords
- Pain, Biomarkers, 6 minute walk test, 5-HMF, Pharmacokinetics, Analgesic use, Sickle cell disease, Aes-103, SpO2, Anemia, Hemoglobin
- Medical subject headings
- Anemia, Sickle Cell, Pain, Anemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Aes-103Drug
The active ingredient in Aes-103 is 5-hydroxymethyl furfural (5-HMF). Aes-103 and matching placebo are administered in a liquid oral formulation.
PlaceboOther
| Study group | Role | What they receive |
|---|---|---|
| Cohort A (Drug) | Experimental | Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes 103 or placebo for 28 days Receives: Drug: Aes-103 |
| Cohort A (Placebo) | Placebo comparator | Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes 103 or placebo Receives: Other: Placebo |
| Cohort B (Drug) | Experimental | In this adaptive design, the dose frequency and the total amount given per day to Cohort B will be adjusted depending on the tolerability, clinical pharmacology and clinical endpoint results of Cohort A. Study terminated prior to completion of Cohort A due to unblinding between study product and placebo groups for participant, site and Sponsor. The study was stopped before initiation of Cohort B. Receives: Drug: Aes-103 |
| Cohort B (Placebo) | Placebo comparator | The dosing regiment of placebo will match that of the Aes-103 treatment in Cohort B. Study terminated prior to completion of Cohort A due to unblinding between study product and placebo groups for participant, site and Sponsor. The study was stopped before initiation of Cohort B. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Adverse Events, Including Sickle Cell-specific Symptoms, During the Double-blind Treatment Period
Number of participants with adverse events (AEs) reported during the double-blind treatment period. AEs included clinically-significant changes in vital signs, ECG, clinical laboratory assessments, physical and neurological examinations. Sickle cell-specific symptoms included the development of new skin ulcers, hospitalization or ambulatory acute care, intravenous analgesics visit for pain episodes (i.e., sickle-cell disease related pain), acute chest syndrome, priapism, and stroke.
Measured: Double-blind treatment period of 28 days (Day 1 to Day 28)
Number of Participants With Adverse Events, Including Sickle-cell Specific Symptoms, During the Placebo lead-in Period
Number of participants with adverse events (AEs) reported during the placebo lead-in period. AEs included clinically-significant changes in vital signs, ECG, clinical laboratory assessments, physical and neurological examinations. Sickle cell-specific symptoms included the development of new skin ulcers, hospitalization or ambulatory acute care, intravenous analgesics visit for pain episodes (i.e., sickle-cell disease related pain), acute chest syndrome, priapism, and stroke.
Measured: Placebo lead-in period of 14 days (Day -14 to Day -1)
Number of Participants With Adverse Events, Including Sickle-cell Specific Symptoms, During the Post-treatment Observation Period
Number of participants with adverse events (AEs) reported during the post-treatment observation period. AEs included clinically-significant changes in vital signs, ECG, clinical laboratory assessments, physical and neurological examinations. Sickle cell-specific symptoms included the development of new skin ulcers, hospitalization or ambulatory acute care, intravenous analgesics visit for pain episodes (i.e., sickle-cell disease related pain), acute chest syndrome, priapism, and stroke.
Measured: Post-treatment observation period of 21 days (Day 29 to Day 49)
Number of Participants With Sickle-Cell Disease-related Symptoms
Measured: Placebo lead-in period of 14 days (Day -14 to Day -1), double-blind treatment period of 28 days (Day 1 to Day 28) and post-treatment observation period of 21 days (Day 29 to Day 49)
Number of Clinically Significant Observations of Vital Signs, 12-lead ECGs, Clinical Laboratory Assessments, and Physical and Neurological Examinations
Vital signs, 12-lead ECGs, clinical laboratory assessments, and physical and neurological examinations that were deemed clinically significant by the investigator in agreement with the sponsor study director.
Measured: Throughout the study period (approximately 9 weeks)
PK: - Plasma AUC, Cmax, Tmax, and T1/2 of Aes-103 and Its Metabolite, HMFA - RBC Hemolysate AUC (0-8h), Cmax, Tmax, and T1/2 of Aes-103 - Percentage of Hemoglobin Bound to Aes-103
Pharmacokinetic endpoints in the study protocol were as follows:- - Plasma Area under curve (AUC), Maximum plasma concentration (Cmax), time at which Cmax observed (Tmax), and terminal half-life (T1/2) of Aes-103 and its metabolite, 5-hydroxymethyl-2-furoic acid (HMFA) - red blood cell (RBC) hemolysate Area under curve between 0 and 8 hours (AUC [0-8h]), Cmax, Tmax, and T1/2 of Aes-103 - Percentage of hemoglobin bound to Aes-103
Measured: PK blood samples were to be taken within 10 minutes before dosing and 0.5, 1, 2, 4, and 6 hours after the first dose of study product on Days 1 and 7 and at the same time points on Day 28 (or early termination)
Secondary outcomes (33)
Resting Oxygen Saturation as Measured by Oximetry (SpO2) - Change From Baseline
A measure of the amount of oxygen in the blood. Oxygen saturation was determined by pulse oximetry. A pulse oximeter was placed over a nail polish-free finger nail to determine peripheral oxygen saturation (SpO2). Baseline was defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period. A mean change from baseline >0 indicates an increase in oxygen saturation, a mean change <0 indicates a decrease in oxygen saturation. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 4, Day 7, Day 14 and Day 28
Oxygen Binding p50/p20 Value - Change From Baseline
A measure of the ability of hemoglobin to bind oxygen. The p50 is the oxygen level at which 50% of the hemoglobin contains oxygen. The p20 is the oxygen level at which 20% of the hemoglobin contains oxygen. Baseline is defined as the most recent value obtained prior to start of dosing on Day 1 of the double-blind treatment period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: During the double-blind treatment period at baseline, Day 1, Day 4 and Day 7
Plasma Erythropoietin (EPO) Levels - Change From Baseline
Erythropoietin (EPO) is a hormone produced by the kidney that promotes the formation of red blood cells by the bone marrow. EPO can be detected and measured in the blood. Baseline defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: At baseline and Day 28 during the double-blind treatment period
Hematocrit Levels - Change From Baseline
Baseline defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 7, Day 14 and Day 28
Lactate Dehydrogenase (LDH) Levels - Change From Baseline
LDH levels were measured as a biomarker for intravascular hemolysis. The results are based on the LDH Total measurement. Baseline defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 7, Day 14 and Day 28
Hemoglobin Levels - Change From Baseline
A clinical laboratory endpoint that reflects the amount of red blood cells present in the blood. Baseline defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 4, Day 7, Day 14, Day 21 and Day 28
Reticulocyte Percent- Change From Baseline
Category title includes number of participants with available data (n) for participants treated with study product.
Measured: At baseline, Day 1 and Day 7 during the double-blind treatment period
Direct Bilirubin - Change From Baseline
Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 7, Day 14, Day 21 and Day 28
LDH Isoform - Change From Baseline
Measured: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 7, Day 14 and Day 28
C Reactive Protein Levels - Change From Baseline
Category title includes number of participants with available data (n) for participants treated with study product.
Measured: At baseline, Day 1 and Day 7 during the double-blind treatment period
Serum Ferritin Levels - Change From Baseline
Measured: At baseline, Day 1 and Day 7 during the double-blind treatment period
N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels- Change From Baseline
Category title includes number of participants with available data (n) for participants treated with study product.
Measured: At baseline, Day 1, Day 7, Day 14 and Day 28 during the double-blind treatment period
Body Weight - Change From Baseline
A negative change in body weight denotes a weight decrease, a positive change in body weight denotes a weight increase. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 4, Day 7, Day 14, Day 21 and Day 28
Exercise Tolerance: 6-Minute Walk Distance During the Double-blind Treatment Period - Change From Baseline
Functional exercise capacity was evaluated by using the 6-minute walk test (6MWT) which measures the distance that a subject can quickly walk on a flat, hard surface in a period of 6 minutes. Guidelines developed by the American Thoracic Society were used for conducting the test and interpreting the results. Baseline defined as the most recent value obtained prior to the start of dosing on Day 1. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 4, Day 7, Day 14 and Day 28
Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the Post-treatment Observation Period - Change From Baseline
Functional exercise capacity was evaluated by using the 6-minute walk test (6MWT) which measures the distance that a subject can quickly walk on a flat, hard surface in a period of 6 minutes. Guidelines developed by the American Thoracic Society were used for conducting the test and interpreting the results. Baseline defined as the most recent value obtained prior to the start of dosing on Day 1.
Measured: Prior to dosing at baseline and on Day 49 of the post-treatment observation period
Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period (Day 28)
Functional exercise capacity was evaluated by using the 6-minute walk test (6MWT) which measures the distance that a subject can quickly walk on a flat, hard surface in a period of 6 minutes. Guidelines developed by the American Thoracic Society were used for conducting the test and interpreting the results.
Measured: On last day of double-blind treatment period (Day 28) and on Day 49 of the post-treatment observation period
Exercise Tolerance: Cardiopulmonary Exercise Test [CPET]
CPET was optional, based on capacity of participant to complete the test.
Measured: On last day of double-blind treatment period (Day 28)
Patients´ Global Impression of Change (PGIC) During the Double-blind Treatment Period - Change From Baseline
Participants assessed the change in activity limitations, symptoms, emotions, and overall quality of life by using the 1- to 7-point PGIC scale. The question and scale was as follows: Since beginning treatment at this clinic, how would you describe the change in your sickle cell condition? Please circle the number that matches your overall judgment. -3 - much worse -2 - moderately worse -1 - minimally worse 0 - no change +1 - minimally improved +2 - moderately improved +3 - much improved. Baseline defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period. No values available for placebo group for Day 28. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: At baseline and once weekly on Days 7, 14, 21, and 28 during the double-blind treatment period
Patients´ Global Impression of Change (PGIC) During the Post-treatment Observation Period - Change From Baseline
Participants assessed the change in activity limitations, symptoms, emotions, and overall quality of life by using the 1- to 7-point PGIC scale. The question and scale was as follows: Since beginning treatment at this clinic, how would you describe the change in your sickle cell condition? Please circle the number that matches your overall judgment. -3 - much worse -2 - moderately worse -1 - minimally worse 0 - no change +1 - minimally improved +2 - moderately improved +3 - much improved. Baseline defined as the most recent value obtained prior to the start of dosing on Day 1 of the double-blind treatment period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: At baseline and once weekly on Days 35, 42, and 49 during the post-treatment observation period
Patients´ Global Impression of Change (PGIC) During the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period
Participants assessed the change in activity limitations, symptoms, emotions, and overall quality of life by using the 1- to 7-point PGIC scale. The question and scale was as follows: Since beginning treatment at this clinic, how would you describe the change in your sickle cell condition? Please circle the number that matches your overall judgment. -3 - much worse -2 - moderately worse -1 - minimally worse 0 - no change +1 - minimally improved +2 - moderately improved +3 - much improved. Baseline was defined as the most recent value obtained on the last day of the double-blind treatment period. Categories contain Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: At baseline and once weekly on Days 35, 42, and 49 during the post-treatment observation period
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Double-blind Treatment Period - Change From Baseline
Participants assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the average of all measures taken from screening through the period prior to start of dosing on Day 1. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 7, Day 14, Day 21, and Day 28 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Double-blind Treatment Period - AUC
Participants assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the average of all measures taken from screening through the period prior to start of dosing on Day 1. Area under the curve (AUC) was computed using change from baseline in weekly average values at Day 7, Day 14, Day 21. and Day 28.
Measured: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 7, Day 14, Day 21, and Day 28 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - Change From Baseline
Participants assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the average of all measures taken from screening through the period prior to start of dosing on Day 1. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - AUC
Participants assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the average of all measures taken from screening through the period prior to start of dosing on Day 1. Area under the curve (AUC) was computed using change from baseline in weekly average values at Day 7, Day 14, Day 21, Day 28, Day 35, Day 42 and Day 49.
Measured: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period (Day 28)
Participants assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the most recent value obtained on the last day of the double-blind dosing period (Day 28). Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period (Day 28) - AUC
Participants assessed their pain levels by using the 0-10 Numeric Rating Scale: 0 = No pain 1-3 = Mild pain (nagging, annoying, interfering little with activities of daily living [ADLs]) 4-6 = Moderate pain (interferes significantly with ADLs) 7-10 = Severe pain (disabling; unable to perform ADLs A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the most recent value obtained on the last day of the double-blind dosing period (Day 28). Area under the curve (AUC) was computed using change from baseline (Day 28) in weekly average values at Day 35, Day 42 and Day 49.
Measured: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
Brief Pain Inventory (BPI): Average Pain Level in Last 24 Hours (Double-blind Treatment Period) - Change From Baseline
Participants rated the severity of their pain by using the BPI short form. Pain was rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: At baseline, Day 7 and Day 28 during the double-blind treatment period
Brief Pain Inventory (BPI): Worst Pain Level in Last 24 Hours (Double-blind Treatment Period) - Change From Baseline
Participants rated the severity of their pain by using the BPI short form. Pain was rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: At baseline, Day 7 and Day 28 during the double-blind treatment period
Brief Pain Inventory (BPI): Worst Pain Level in Last 24 Hours (Post-treatment Observation Period) - Change From Baseline
Participants rated the severity of their pain by using the BPI short form. Pain was rated on a scale from 0 (no pain) to 10 (pain as bad as you can imagine). A negative mean change denotes a pain decrease. A positive mean change denotes an increase in pain. Baseline was defined as the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period.
Measured: At baseline and Day 49 during the post-treatment observation period
Brief Pain Inventory (BPI): Interference of Pain With Aspects of Life (General Activity) During Double-blind Treatment Period - Change From Baseline
Participants rated the degree to which their pain interfered with various daily functions by using the BPI short form. Interference with general activity was rated on a scale from 0 (does not interfere) to 10 (completely interferes). Baseline was defined as the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period. Category title includes number of participants with available data (n) for participants treated with study product, followed by participants treated with placebo.
Measured: At baseline, Day 7 and Day 28 during the double-blind treatment period
Brief Pain Inventory (BPI): Interference of Pain With Aspects of Life (General Activity) During Post-treatment Observation Period - Change From Baseline
Participants rated the degree to which their pain interfered with various daily functions by using the BPI short form. Interference with general activity was rated on a scale from 0 (does not interfere) to 10 (completely interferes). Baseline was defined as the most recent value obtained prior to the start of the dosing on Day 1 of the double-blind dosing period.
Measured: At baseline and Day 49 during the post-treatment observation period
Analgesic Use
Analgesic use assessed with pain levels by numerical pain rating scale (NPRS) and brief pain inventory (BPI).
Measured: Throughout the study period (approximately 9 weeks)
Reduction in Sickle Cell-specific Complications
Measured: Throughout the study period (approximately 9 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Nov 2013 (estimated)
- Study start3 Dec 2013
- Primary completion16 Mar 2015
- Study completion16 Mar 2015
Why it stopped: Study was terminated early by the Sponsor due to unblinding between study drug and placebo groups at the subject, site and Sponsor levels.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baxalta now part of Shire
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Study Director, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01987908
- Sponsor's protocol ID
- Aes-103-003
- Other IDs
- 321401, 2013-001534-18
- Status last verified
- May 2021
- First submitted
- 29 Oct 2013
- Last updated
- 25 May 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2, Exploratory, Placebo-Controlled, Multicenter, Double-Blind Evaluation of the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Effects of Two Dose Regimens of Aes-103 Given for 28 Days to Subjects With Stable Sickle Cell Disease
- ClinicalTrials.gov ID
- NCT01987908
- Acronym / sponsor ID
- Aes-103-003
- Conditions
- Sickle Cell Disease
- Keywords
- Pain, Biomarkers, 6 minute walk test, 5-HMF, Pharmacokinetics, Analgesic use, Sickle cell disease, Aes-103
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study was terminated early by the Sponsor due to unblinding between study drug and placebo groups at the subject, site and Sponsor levels.
- Enrolment
- 35 participants (actual)
- Lead sponsor
- Baxalta now part of ShireIndustry (pharma, biotech, devices)
- Study start
- 3 Dec 2013 (actual)
- Primary completion
- 16 Mar 2015 (actual)
- Study completion
- 16 Mar 2015 (actual)
- First posted
- 20 Nov 2013 (estimated)
- Results
- Posted 24 Mar 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Sickle cell disease (SCD) is a genetic blood disorder characterized by the presence of sickle-shaped red blood cells. In the U.S. and the U.K. this occurs primarily in persons of African origin. There is only one drug (hydroxyurea) approved to manage SCD, but it is not fully efficacious and can produce medically significant side effects. Aes-103 is being evaluated as a novel agent for the long term management of SCD. By directly reducing the sickling process, Aes-103 has a different mechanism of action than hydoxyurea. The active ingredient in Aes-103 is 5-hydroxymethyl furfural, a naturally occurring small molecule that is chemically related to glucose.
This study will evaluate the safety and pharmacokinetic profile of two dosing regimens of Aes-103 for up to 28 days in up to 50 adult subjects with stable SCD compared with subjects receiving placebo.
Detailed description
This study will evaluate evaluate in subjects with stable SCD the safety, pharmacokinetic profile, clinical pharmacology actions and clinical activities of two dosing regimens of Aes-103 (1000 mg four times daily in Cohort A and a higher or lower dose given once daily or up to four times daily in Cohort B) given for up to 28 days in adult subjects with stable SCD compared with subjects receiving placebo.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Cohort A (Drug) | Experimental | Drug: Aes-103Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes 103 or placebo for 28 days |
| Cohort A (Placebo) | Placebo comparator | Other: PlaceboSubjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes 103 or placebo |
| Cohort B (Drug) | Experimental | Drug: Aes-103In this adaptive design, the dose frequency and the total amount given per day to Cohort B will be adjusted depending on the tolerability, clinical pharmacology and clinical endpoint results of Cohort A. Study terminated prior to completion of Cohort A due to unblinding between study product and placebo groups for participant, site and Sponsor. The study was stopped before initiation of Cohort B. |
| Cohort B (Placebo) | Placebo comparator | Other: PlaceboThe dosing regiment of placebo will match that of the Aes-103 treatment in Cohort B. Study terminated prior to completion of Cohort A due to unblinding between study product and placebo groups for participant, site and Sponsor. The study was stopped before initiation of Cohort B. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- Male or female, aged 18-60 years old, inclusive
- Diagnosis of SCD (hemoglobin SS) without hospitalization for pain crises or any other reason in the 14 days before enrollment
- Have normal organ function as defined by direct bilirubin <1.1 mg/dL (19 μmol/L), alanine transaminase (serum glutamic pyruvic transaminase) ≤120 IU/L, and Creatinine ≤1.3 mg/dL (115 μmol/L)
- Have at least one of the following baseline values: hemoglobin level of <10 g/dL, numerical pain rating scale (NPRS) score of ≥ 4, or 6-minute walk distance (6MWD) of <500 m
- If female, be nonpregnant and nonbreastfeeding and be surgically sterile or using an acceptable method of contraception throughout the study and for 3 months after the last dose of study medication
Key exclusion criteria (2 listed)
- Have been hospitalized in the 14 days before enrollment, for any reason
- 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, or have been hospitalized in the past 6 months as a result of these conditions (for SCD-related morbidity, a minimum of 14 days from the last hospitalization is required)
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-103The active ingredient in Aes-103 is 5-hydroxymethyl furfural (5-HMF). Aes-103 and matching placebo are administered in a liquid oral formulation. | Drug | Cohort A (Drug), Cohort B (Drug) |
| Placebo | Other | Cohort A (Placebo), Cohort B (Placebo) |
Primary outcome
Number of Participants With Adverse Events, Including Sickle Cell-specific Symptoms, During the Double-blind Treatment Period
Time frame: Double-blind treatment period of 28 days (Day 1 to Day 28)
Number of participants with adverse events (AEs) reported during the double-blind treatment period. AEs included clinically-significant changes in vital signs, ECG, clinical laboratory assessments, physical and neurological examinations. Sickle cell-specific symptoms included the development of new skin ulcers, hospitalization or ambulatory acute care, intravenous analgesics visit for pain episodes (i.e., sickle-cell disease related pain), acute chest syndrome, priapism, and stroke.
Number of Participants With Adverse Events, Including Sickle-cell Specific Symptoms, During the Placebo lead-in Period
Time frame: Placebo lead-in period of 14 days (Day -14 to Day -1)
Number of participants with adverse events (AEs) reported during the placebo lead-in period. AEs included clinically-significant changes in vital signs, ECG, clinical laboratory assessments, physical and neurological examinations. Sickle cell-specific symptoms included the development of new skin ulcers, hospitalization or ambulatory acute care, intravenous analgesics visit for pain episodes (i.e., sickle-cell disease related pain), acute chest syndrome, priapism, and stroke.
Number of Participants With Adverse Events, Including Sickle-cell Specific Symptoms, During the Post-treatment Observation Period
Time frame: Post-treatment observation period of 21 days (Day 29 to Day 49)
Number of participants with adverse events (AEs) reported during the post-treatment observation period. AEs included clinically-significant changes in vital signs, ECG, clinical laboratory assessments, physical and neurological examinations. Sickle cell-specific symptoms included the development of new skin ulcers, hospitalization or ambulatory acute care, intravenous analgesics visit for pain episodes (i.e., sickle-cell disease related pain), acute chest syndrome, priapism, and stroke.
Number of Participants With Sickle-Cell Disease-related Symptoms
Time frame: Placebo lead-in period of 14 days (Day -14 to Day -1), double-blind treatment period of 28 days (Day 1 to Day 28) and post-treatment observation period of 21 days (Day 29 to Day 49)
Number of Clinically Significant Observations of Vital Signs, 12-lead ECGs, Clinical Laboratory Assessments, and Physical and Neurological Examinations
Time frame: Throughout the study period (approximately 9 weeks)
Vital signs, 12-lead ECGs, clinical laboratory assessments, and physical and neurological examinations that were deemed clinically significant by the investigator in agreement with the sponsor study director.
PK: - Plasma AUC, Cmax, Tmax, and T1/2 of Aes-103 and Its Metabolite, HMFA - RBC Hemolysate AUC (0-8h), Cmax, Tmax, and T1/2 of Aes-103 - Percentage of Hemoglobin Bound to Aes-103
Time frame: PK blood samples were to be taken within 10 minutes before dosing and 0.5, 1, 2, 4, and 6 hours after the first dose of study product on Days 1 and 7 and at the same time points on Day 28 (or early termination)
Pharmacokinetic endpoints in the study protocol were as follows:- - Plasma Area under curve (AUC), Maximum plasma concentration (Cmax), time at which Cmax observed (Tmax), and terminal half-life (T1/2) of Aes-103 and its metabolite, 5-hydroxymethyl-2-furoic acid (HMFA) - red blood cell (RBC) hemolysate Area under curve between 0 and 8 hours (AUC [0-8h]), Cmax, Tmax, and T1/2 of Aes-103 - Percentage of hemoglobin bound to Aes-103
33 secondary outcomes
Resting Oxygen Saturation as Measured by Oximetry (SpO2) - Change From Baseline
Time frame: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 4, Day 7, Day 14 and Day 28
Oxygen Binding p50/p20 Value - Change From Baseline
Time frame: During the double-blind treatment period at baseline, Day 1, Day 4 and Day 7
Plasma Erythropoietin (EPO) Levels - Change From Baseline
Time frame: At baseline and Day 28 during the double-blind treatment period
Hematocrit Levels - Change From Baseline
Time frame: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 7, Day 14 and Day 28
Lactate Dehydrogenase (LDH) Levels - Change From Baseline
Time frame: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 7, Day 14 and Day 28
Hemoglobin Levels - Change From Baseline
Time frame: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 4, Day 7, Day 14, Day 21 and Day 28
Reticulocyte Percent- Change From Baseline
Time frame: At baseline, Day 1 and Day 7 during the double-blind treatment period
Direct Bilirubin - Change From Baseline
Time frame: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 7, Day 14, Day 21 and Day 28
LDH Isoform - Change From Baseline
Time frame: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 7, Day 14 and Day 28
C Reactive Protein Levels - Change From Baseline
Time frame: At baseline, Day 1 and Day 7 during the double-blind treatment period
Serum Ferritin Levels - Change From Baseline
Time frame: At baseline, Day 1 and Day 7 during the double-blind treatment period
N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels- Change From Baseline
Time frame: At baseline, Day 1, Day 7, Day 14 and Day 28 during the double-blind treatment period
Body Weight - Change From Baseline
Time frame: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 1, Day 4, Day 7, Day 14, Day 21 and Day 28
Exercise Tolerance: 6-Minute Walk Distance During the Double-blind Treatment Period - Change From Baseline
Time frame: Prior to, during and after the end of dosing in the double-blind treatment period, i.e., at baseline, Day 4, Day 7, Day 14 and Day 28
Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the Post-treatment Observation Period - Change From Baseline
Time frame: Prior to dosing at baseline and on Day 49 of the post-treatment observation period
Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period (Day 28)
Time frame: On last day of double-blind treatment period (Day 28) and on Day 49 of the post-treatment observation period
Exercise Tolerance: Cardiopulmonary Exercise Test [CPET]
Time frame: On last day of double-blind treatment period (Day 28)
Patients´ Global Impression of Change (PGIC) During the Double-blind Treatment Period - Change From Baseline
Time frame: At baseline and once weekly on Days 7, 14, 21, and 28 during the double-blind treatment period
Patients´ Global Impression of Change (PGIC) During the Post-treatment Observation Period - Change From Baseline
Time frame: At baseline and once weekly on Days 35, 42, and 49 during the post-treatment observation period
Patients´ Global Impression of Change (PGIC) During the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period
Time frame: At baseline and once weekly on Days 35, 42, and 49 during the post-treatment observation period
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Double-blind Treatment Period - Change From Baseline
Time frame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 7, Day 14, Day 21, and Day 28 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Double-blind Treatment Period - AUC
Time frame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 7, Day 14, Day 21, and Day 28 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - Change From Baseline
Time frame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - AUC
Time frame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period (Day 28)
Time frame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period (Day 28) - AUC
Time frame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
Brief Pain Inventory (BPI): Average Pain Level in Last 24 Hours (Double-blind Treatment Period) - Change From Baseline
Time frame: At baseline, Day 7 and Day 28 during the double-blind treatment period
Brief Pain Inventory (BPI): Worst Pain Level in Last 24 Hours (Double-blind Treatment Period) - Change From Baseline
Time frame: At baseline, Day 7 and Day 28 during the double-blind treatment period
Brief Pain Inventory (BPI): Worst Pain Level in Last 24 Hours (Post-treatment Observation Period) - Change From Baseline
Time frame: At baseline and Day 49 during the post-treatment observation period
Brief Pain Inventory (BPI): Interference of Pain With Aspects of Life (General Activity) During Double-blind Treatment Period - Change From Baseline
Time frame: At baseline, Day 7 and Day 28 during the double-blind treatment period
Brief Pain Inventory (BPI): Interference of Pain With Aspects of Life (General Activity) During Post-treatment Observation Period - Change From Baseline
Time frame: At baseline and Day 49 during the post-treatment observation period
Analgesic Use
Time frame: Throughout the study period (approximately 9 weeks)
Reduction in Sickle Cell-specific Complications
Time frame: Throughout the study period (approximately 9 weeks)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 May 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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 2 study testing Aes-103 in people with Sickle Cell Disease, run by Baxalta now part of Shire at 1 site in United Kingdom.
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 9 inclusion and 2 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: stopped early, as of the sponsor's last update on 25 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 Kingdom. 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. Some participants in this study may receive a placebo. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Mar 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Number of Participants With Adverse Events, Including Sickle Cell-specific Symptoms, During the Double-blind Treatment Period (time frame: Double-blind treatment period of 28 days (Day 1 to Day 28)). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 25 May 2021.