Evaluation of Different Dose Regimens of Aes-103 Given for 28 Days to Subjects With Stable Sickle Cell Disease

NCT01987908 | Terminated Phase 2 Results

• 3 other identifiers: Aes-103-0033214012013-001534-18
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

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.

Conditions

Sickle Cell Disease

Keywords

Pain; Biomarkers; 6 minute walk test; 5-HMF; Pharmacokinetics; Analgesic use; Sickle cell disease; Aes-103; SpO2; Anemia; Hemoglobin

Outcome Measures

Primary Outcomes (6)

• 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.

  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.

  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.

  Post-treatment observation period of 21 days (Day 29 to Day 49)

• Number of Participants With Sickle-Cell Disease-related Symptoms

  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.

  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

  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

  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

  During the double-blind treatment period at baseline, Day 1, Day 4 and Day 7

• 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

Study Arms (4)

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

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

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.

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.

Other: Placebo

Interventions

Aes-103 DRUG

The active ingredient in Aes-103 is 5-hydroxymethyl furfural (5-HMF). Aes-103 and matching placebo are administered in a liquid oral formulation.

Cohort A (Drug); Cohort B (Drug)

Placebo OTHER

Cohort A (Placebo); Cohort B (Placebo)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Baxalta now part of Shire: lead

Study Sites (1)

Quintiles Ltd. - Quintiles Drug Research Unit, 6 Newcomen Street

London, SE1 1YR, United Kingdom

Location

MeSH Terms

Conditions

Anemia, Sickle Cell; Pain; Anemia

Interventions

5-hydroxymethylfurfural

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

PK data not determined as the assay collection method was found to be faulty rendering all samples unevaluable. Study was terminated early by the Sponsor due to unblinding between study drug and placebo groups at the subject, site and Sponsor levels.

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@shire.com

+1 866 842 5335

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2013
• First Posted: November 20, 2013
• Study Start: December 3, 2013
• Primary Completion: March 16, 2015
• Study Completion: March 16, 2015
• Last Updated: May 25, 2021
• Results First Posted: March 24, 2017

Record last verified: 2021-05

Locations

GB (1)