Multi-center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Effects of Intra-Erythrocyte Dexamethasone Sodium Phosphate on Neurological Symptoms in Patients With Ataxia Telangiectasia
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 176
- 试验地点
- 22
- 主要终点
- Change From Baseline in Modified International Cooperative Ataxia Rating Scale (mICARS)
研究概览
简要总结
Objectives:
The objective of study was to evaluate the safety and the efficacy of EryDex (Dexamethasone sodium phosphate encapsulated in autologous erythrocytes, using the EryDex System - EDS) at two dose levels (low dose and high dose DSP/infusion), compared to placebo, on Neurological Symptoms in Patients With Ataxia Telangiectasia.
Initial Double-Blind Treatment Period (0 to 6 Months)
Primary Efficacy Objective:
• Evaluate the effect of EryDex at two dose levels (low dose and high dose DSP/infusion), compared to placebo, on central nervous system (CNS) symptoms measured by the change in the Modified International Cooperative Ataxia Rating Scale (mICARS) from baseline to Month 6 (Visit 9) in patients with ataxia telangiectasia (A-T).
Secondary Efficacy Objectives:
- Evaluate the effect of EryDex, compared to placebo, on the Clinical Global Impression of Change (CGI-C) in patients with A-T from baseline to Month 6 (Visit 9).
- Evaluate the effect of EryDex, compared to placebo, on measures of Clinical Global Impression of Severity (CGI-S; structured) in patients with A-T from baseline to Month 6 (Visit 9)
- Evaluate the effect of EryDex, compared to placebo, on measures of Adaptive behavior measures in patients with A-T by the Vineland Adaptive Behavior Scales (VABS) from baseline to Month 6 (Visit 9).
Safety Objectives:
• Evaluate the safety and tolerability of two non-overlapping doses of EryDex, compared to placebo, in patients with A-T over the 12-month double-blind study duration.
Extension Treatment Period (6-12 Months):
Primary Objective:
• Evaluate the efficacy of EryDex at two dose levels (low dose and high dose DSP/infusion) compared to placebo, in treating CNS symptoms in A-T patients during longer-term treatment (up to 12 months), as measured by the mICARS.
Secondary Objectives:
- Evaluate the longer-term (up to 12 months) safety and tolerability of EryDex in A-T patients.
- Compare the effects of EryDex on the CGI-C and CGI-S (structured), VABS, and QoL using the EQ-5D-5L scale.
详细描述
This was an international, multi-center, one-year, randomized, prospective, double-blind, placebo-controlled, phase III study.
This study was divided into three periods: Screening (Days -30 to -1), 6-month Initial Treatment Period (Months 1-6; Visits 1-9), and 6-month Extension Treatment Period (Months 7-12; Visits 10-15).
A total of 175 patients, of the 180 planned, met all selection criteria at baseline, and were randomized in a 1:1:1 fashion to one of the two EDS-EP dose levels or placebo.
These patients were randomly assigned to receive one of the two doses of EDS-EP or placebo, as follows:
- Group 1: EDS-EP dose range of ~5-10 mg DSP/infusion (low dose), 59 pts
- Group 2: EDS-EP dose range of ~14-22 mg DSP/infusion (high dose), 57 pts
- Group 3: Placebo EDS infusion, 59 pts
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
The Sponsor, Investigator, site staff, and patients were not aware of the treatment assignments.
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient met clinical criteria for diagnosis of A-T. The neurological signs of A-T (incoordination of the head and eyes in lateral gaze deflection, gait ataxia associated with an inappropriately narrow base) must have been documented. Such signs of A-T illustrated the body systems in which changes were confirmed, but the listed changes were examples and other changes in those systems may have been observed and documented to confirm the diagnosis of A-T.
- •Patient was in autonomous gait or was helped by periodic use of a support (i.e., score for Item 1 of the full ICARS - Walking Capacities between 0 and 4, included).
- •Patient was investigated for the proven genetic diagnosis of A-T (prior documentation or by central laboratory test report).
- •Patient was at least 6 years of age.
- •Body weight was >15 kg.
- •The patient and parent/caregiver (if below the age of consent), or a legal representative, provided written informed consent to participate. If consent was provided solely by the caregiver in accordance with local regulations, the patient must have provided assent to participate in the study.
- •Exclusion criteria
- •Females that were:
- •Pregnant or breast-feeding (for European Union [EU] countries only).
- •Of childbearing potential, pregnant, or breast-feeding (for US and Rest of World countries) not using adequate birth control, as determined by their Healthcare Provider.
- •A disability that may have prevented the patient from completing all study requirements.
- •Current participation in another clinical study.
- •Medical History and Current Status
- •Cluster differential 4 positive (CD4+) lymphocytes count <400/mm3 (for patients 6 years of age) or <150/mm3 (for patients >6 years). In presence of oral infections, like oral candidiasis, documented at the screening or recurrent as per medical history documentation, the limit increased to <200/mm3 (for patients >6 years).
- •Loss/removal of 250 mL or more of blood within the past 4 weeks prior to screening.
- •Current neoplastic disease or previous neoplastic disease not in remission for at least 2 years.
- •History of severe impairment of the immunological system.
- •Severe or unstable pulmonary disease.
- •Uncontrolled diabetes.
- •Any other severe, unstable, or serious disease or condition that in the Investigator's opinion put the patient at risk for imminent life-threatening morbidity, need for hospitalization, or mortality.
- •Any clinically significant abnormality on standard laboratory examinations (hematology, biochemistry, urinalysis) at screening that remains abnormal on repeat testing. Eligibility of patients with abnormal laboratory test values was determined by the Investigator in consultation with the Medical Monitor.
- •Confirmed hemoglobinopathies, e.g., hemoglobin C disease, sickle cell anemia, or thalassemia.
- •Moderate or severe renal and/or hepatic impairment.
- •Prior/Concomitant Medication
- •Any previous oral or parenteral steroid use within 4 weeks before Baseline. Treatment with inhaled or intranasal steroids for asthma or allergies, as well as use of topical steroids will be permitted.
- •Chronic condition or prior allergic reaction representing a contraindication to the use of dexamethasone or other steroid drugs.
- •Has participated in any other trial with an investigational drug and received a dose within 30 days or 10 half-lives (whichever is greater) from the start of the 30-day Screening Period.
- •Has participated in a previous trial with EryDex.
- •Requires any concomitant medication prohibited by the protocol.
- •Has taken a drug or treatment known to cause major organ system toxicity during the past year.
- •Used of any drug that is a strong inducer/inhibitor of cytochrome P450 3A4 (CYP3A4) within 4 weeks before baseline.
排除标准
- 未提供
研究组 & 干预措施
EryDex Low Dose DSP
EDS-EP dose range of ~5-10 mg DSP/infusion. This study treatment was to be administered by IV infusion once per month for 12 consecutive months (6 months Initial Treatment Period + 6 months Extension Treatment Period). Each patient underwent a 30-day Screening Period, during which any previous treatments with other corticosteroid compounds were withdrawn (washout from previous treatment).
Other Names:
EryDex System end product Low dose DSP
干预措施: EryDex Low dose DSP (Drug)
EryDex High Dose DSP
EDS-EP dose range of ~14-22 mg DSP/infusion. This study treatment was to be administered by IV infusion once per month for 12 consecutive months (6 months Initial Treatment Period + 6 months Extension Treatment Period). Each patient underwent a 30-day Screening Period, during which any previous treatments with other corticosteroid compounds were withdrawn (washout from previous treatment).
Other Names:
EryDex System end product High dose DSP
干预措施: EryDex High dose DSP (Drug)
Placebo
Patients were treated with autologous erythrocytes prepared with the EDS process using a placebo solution. Placebo was to be administered by IV infusion once per month for 12 consecutive months (6 months Initial Treatment Period + 6 months Extension Treatment Period).
Each patient underwent a 30-day Screening Period, during which any previous treatments with other corticosteroid compounds were withdrawn (washout from previous treatment).
干预措施: Pooled Placebo (Drug)
结局指标
主要结局
Change From Baseline in Modified International Cooperative Ataxia Rating Scale (mICARS)
时间窗: to Month 6 (Visit 9)
The International Cooperative Ataxia Rating Scale (ICARS) was an assessment of the degree of impairment in patients with cerebellar ataxia and was administered in its entirety; however, the primary efficacy assessment was based on the modified (m)ICARS, which excluded the Oculomotor domain (items 17 to 19) and items 8 to 12 of the Kinetic Functions domain of the ICARS. The mICARS was a 54 points maximum score (min 0) questionnaire divided into 3 sections: * Posture and Gait Disturbance section-7 items (min score 0, max score 34) * Kinetic Function-2 items (min score 0, max score 12) * Speech Disorder- 2 items (min score 0, max score 8). The assessment was designed to be completed within 30 minutes, and higher scores - both for total and subscores - indicate a higher level of disease impairment. The subscores are added to give the total score.
次要结局
- Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C)(to Month 6 (Visit 9))
- Number of Patients With None to Severe (0 to 4) Scores in Clinical Global Impression of Severity (CGI-S)-Structured of Neurological Symptoms of AT(to Visit 9 (Month 6))
- Change From Baseline of Vineland Adaptive Behavior Scale (VABS-II) Scores - Last Observation Carried Forward (LOCF)(to Visit 9 (Month 6))
- Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6(to Visit 9 (Month 6))
- Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12(to Visit 15 (Month 12))