Clinical trial NCT01987908: Evaluation of Different Dose Regimens of Aes-103 Given for 28 Days to Subjects With Stable Sickle Cell Disease
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Sickle Cell Disease
Keywords: Pain
Biomarkers
6 minute walk test
5-HMF
Pharmacokinetics
Analgesic use
Sickle cell disease
Aes-103
SpO2
Anemia
Hemoglobin
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2013-11-20
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Number of Participants With Adverse Events, Including Sickle Cell-specific Symptoms, During the Double-blind Treatment Period
timeFrame: Double-blind treatment period of 28 days (Day 1 to Day 28)
measure: Number of Participants With Adverse Events, Including Sickle-cell Specific Symptoms, During the Placebo lead-in Period
timeFrame: Placebo lead-in period of 14 days (Day -14 to Day -1)
measure: Number of Participants With Adverse Events, Including Sickle-cell Specific Symptoms, During the Post-treatment Observation Period
timeFrame: Post-treatment observation period of 21 days (Day 29 to Day 49)
measure: Number of Participants With Sickle-Cell Disease-related Symptoms
timeFrame: 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)
measure: Number of Clinically Significant Observations of Vital Signs, 12-lead ECGs, Clinical Laboratory Assessments, and Physical and Neurological Examinations
timeFrame: Throughout the study period (approximately 9 weeks)
measure: 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
timeFrame: 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:
measure: Resting Oxygen Saturation as Measured by Oximetry (SpO2) - Change From Baseline
timeFrame: 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
measure: Oxygen Binding p50/p20 Value - Change From Baseline
timeFrame: During the double-blind treatment period at baseline, Day 1, Day 4 and Day 7
measure: Plasma Erythropoietin (EPO) Levels - Change From Baseline
timeFrame: At baseline and Day 28 during the double-blind treatment period
measure: Hematocrit Levels - Change From Baseline
timeFrame: 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
measure: Lactate Dehydrogenase (LDH) Levels - Change From Baseline
timeFrame: 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
measure: Hemoglobin Levels - Change From Baseline
timeFrame: 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
measure: Reticulocyte Percent- Change From Baseline
timeFrame: At baseline, Day 1 and Day 7 during the double-blind treatment period
measure: Direct Bilirubin - Change From Baseline
timeFrame: 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
measure: LDH Isoform - Change From Baseline
timeFrame: 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
measure: C Reactive Protein Levels - Change From Baseline
timeFrame: At baseline, Day 1 and Day 7 during the double-blind treatment period
measure: Serum Ferritin Levels - Change From Baseline
timeFrame: At baseline, Day 1 and Day 7 during the double-blind treatment period
measure: N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels- Change From Baseline
timeFrame: At baseline, Day 1, Day 7, Day 14 and Day 28 during the double-blind treatment period
measure: Body Weight - Change From Baseline
timeFrame: 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
measure: Exercise Tolerance: 6-Minute Walk Distance During the Double-blind Treatment Period - Change From Baseline
timeFrame: 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
measure: Exercise Tolerance: 6-Minute Walk Distance on Day 49 of the Post-treatment Observation Period - Change From Baseline
timeFrame: Prior to dosing at baseline and on Day 49 of the post-treatment observation period
measure: 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)
timeFrame: On last day of double-blind treatment period (Day 28) and on Day 49 of the post-treatment observation period
measure: Exercise Tolerance: Cardiopulmonary Exercise Test [CPET]
timeFrame: On last day of double-blind treatment period (Day 28)
measure: Patients´ Global Impression of Change (PGIC) During the Double-blind Treatment Period - Change From Baseline
timeFrame: At baseline and once weekly on Days 7, 14, 21, and 28 during the double-blind treatment period
measure: Patients´ Global Impression of Change (PGIC) During the Post-treatment Observation Period - Change From Baseline
timeFrame: At baseline and once weekly on Days 35, 42, and 49 during the post-treatment observation period
measure: Patients´ Global Impression of Change (PGIC) During the Post-treatment Observation Period - Change From Last Day of Double-blind Treatment Period
timeFrame: At baseline and once weekly on Days 35, 42, and 49 during the post-treatment observation period
measure: Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Double-blind Treatment Period - Change From Baseline
timeFrame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 7, Day 14, Day 21, and Day 28 assessments
measure: Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Double-blind Treatment Period - AUC
timeFrame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 7, Day 14, Day 21, and Day 28 assessments
measure: Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - Change From Baseline
timeFrame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
measure: Numerical Pain Rating Scale (NPRS): Worst Pain (Weekly Average) in the Post-treatment Observation Period - AUC
timeFrame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
measure: 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)
timeFrame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
measure: 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
timeFrame: Participants assessed and recorded their pain level daily. Weekly averages were calculated for the Day 35, Day 42 and Day 49 assessments
measure: Brief Pain Inventory (BPI): Average Pain Level in Last 24 Hours (Double-blind Treatment Period) - Change From Baseline
timeFrame: At baseline, Day 7 and Day 28 during the double-blind treatment period
measure: Brief Pain Inventory (BPI): Worst Pain Level in Last 24 Hours (Double-blind Treatment Period) - Change From Baseline
timeFrame: At baseline, Day 7 and Day 28 during the double-blind treatment period
measure: Brief Pain Inventory (BPI): Worst Pain Level in Last 24 Hours (Post-treatment Observation Period) - Change From Baseline
timeFrame: At baseline and Day 49 during the post-treatment observation period
measure: Brief Pain Inventory (BPI): Interference of Pain With Aspects of Life (General Activity) During Double-blind Treatment Period - Change From Baseline
timeFrame: At baseline, Day 7 and Day 28 during the double-blind treatment period
measure: Brief Pain Inventory (BPI): Interference of Pain With Aspects of Life (General Activity) During Post-treatment Observation Period - Change From Baseline
timeFrame: At baseline and Day 49 during the post-treatment observation period
measure: Analgesic Use
timeFrame: Throughout the study period (approximately 9 weeks)
measure: Reduction in Sickle Cell-specific Complications
timeFrame: Throughout the study period (approximately 9 weeks)
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Quintiles Ltd. - Quintiles Drug Research Unit, 6 Newcomen Street
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: