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
Overview
- Phase
- Phase 2
- Intervention
- Aes-103
- Conditions
- Sickle Cell Disease
- Sponsor
- Baxalta now part of Shire
- Enrollment
- 35
- Locations
- 1
- Primary Endpoint
- 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
- Status
- Terminated
- Last Updated
- 4 years ago
Overview
Brief 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. 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
- •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
Exclusion Criteria
- •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)
Arms & Interventions
Cohort A (Drug)
Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes 103 or placebo for 28 days
Intervention: Aes-103
Cohort A (Placebo)
Subjects randomized 3:1 to receive 4 times daily dosing of 1,000 mg of Aes 103 or placebo
Intervention: Placebo
Cohort B (Drug)
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.
Intervention: Aes-103
Cohort B (Placebo)
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.
Intervention: Placebo
Outcomes
Primary Outcomes
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
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 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 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 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.
Secondary Outcomes
- Oxygen Binding p50/p20 Value - Change From Baseline(During the double-blind treatment period at baseline, Day 1, Day 4 and Day 7)
- Resting Oxygen Saturation as Measured by Oximetry (SpO2) - Change From Baseline(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)
- Plasma Erythropoietin (EPO) Levels - Change From Baseline(At baseline and Day 28 during the double-blind treatment period)
- Hematocrit Levels - Change From Baseline(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(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(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(At baseline, Day 1 and Day 7 during the double-blind treatment period)
- Direct Bilirubin - Change From Baseline(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(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(At baseline, Day 1 and Day 7 during the double-blind treatment period)
- Serum Ferritin Levels - Change From Baseline(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(At baseline, Day 1, Day 7, Day 14 and Day 28 during the double-blind treatment period)
- Body Weight - Change From Baseline(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(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(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)(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](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(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(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(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 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 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 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 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 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 and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments)
- Brief Pain Inventory (BPI): Interference of Pain With Aspects of Life (General Activity) During Double-blind Treatment Period - Change From Baseline(At baseline, Day 7 and Day 28 during the double-blind treatment period)
- Reduction in Sickle Cell-specific Complications(Throughout the study period (approximately 9 weeks))
- Brief Pain Inventory (BPI): Average Pain Level in Last 24 Hours (Double-blind Treatment Period) - Change From Baseline(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(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(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 Post-treatment Observation Period - Change From Baseline(At baseline and Day 49 during the post-treatment observation period)
- Analgesic Use(Throughout the study period (approximately 9 weeks))