EDS in Ataxia Telangiectasia Patients

Study Overview
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Brief Summary
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This is an international, multi-center, one-year, randomized, prospective, double-blind, placebo-controlled, phase III study, designed to assess the effect of two non-overlapping dose ranges of EDS EP, administered by IV infusion once per month, on neurological symptoms of patients with Ataxia Telangiectasia.

Detailed Description
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All patients who complete the assessments as designed over the initial 6 months of the trial will be eligible to continue in an additional 6-month, double-blind, placebo-controlled extension designed to collect information on the long-term safety and efficacy of the trial treatments. Upon completion of all screening assessments for eligibility patients meeting all selection criteria at baseline will be randomized in a 1:1:1 fashion to one of the two EDS-EP dose levels or placebo. A minimization procedure will be employed to ensure that the proportions of male and female, and younger (6 to <10 years) and older (≥10 years), patients are comparable across the three treatment groups. Every attempt will be made to ensure the same balance is achieved across different regions. A minimum of 180 patients will be enrolled, hence, each group will consist of 60 patients 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 D SP/infusion, Group 2: EDS-EP dose range of  14-22 mg D SP/infusion, Group 3: Placebo EDS infusion. The initial 6-month treatment period will be considered complete when the endpoint assessment (at Visit 9/Month 6 or at early discontinuation) has been performed for all patients. Patients who are not experiencing severe side-effects, or have deteriorated significantly while on the treatment and provide informed consent will be eligible to continue treatment for an additional 6 months in a double-blind, placebo-controlled extension treatment period. Patients meeting all entry criteria will be treated as follows: Patients originally randomized to EDS-EP treatment groups (Group 1 or Group 2) will continue on the same treatment; Patients originally randomized to the Placebo group (Group 3) will be re-randomized in equal proportions (1:1) to receive either the EDS-EP  5-10 mg DSP/infusion or  14-22 mg DSP/infusion, as follows: Following 6 months of treatment, one third of the originally randomized placebo patients will be re-randomized to treatment with EDS-EP, as described above; After 9 months of treatment, one third of the originally randomized placebo patients will be re-randomized to treatment with EDS-EP, as described above; At 12 months, all remaining placebo patients who continue open-label treatment will receive treatment with EDS-EP, as described above. The ICARS will be administered by a site rater and scoring verified by a central remote qualified rater, based on a video recording of the assessment at the site. The scores provided by the central remote raters will be used for the primary analysis of the 'Modified' ICARS (primary efficacy endpoint). The site ICARS rater will not be involved in the rating of the CGI- S and CGI-C, VABS, or QoL scale. The CGI rater will not have access to the ICARS ratings, but may refer to other scales in scoring the CGI. All patients who complete 12 months of treatment in the trial, complete the study assessments, and provide informed consent will be eligible to continue treatment with EDS-EP in an open-label, extension study (IEDAT-03-2016). Retrieved drop-outs (RDO), i.e. patients who discontinued treatment prematurely but completed the final (Visit 15/Month 12) efficacy assessments will also be eligible to enter the open-label extension study. Patients will continue on the dose of EDS-EP they were receiving at the end of Study IEDAT-02, or if on placebo, the patient will be randomly switched (1:1) to one of the two doses of EDS-EP.

Official Title
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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

Conditions
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Nervous System Disease, Genetic Syndrome

Intervention / Treatment
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* Drug: EDS-EP dose range of  5-10 mg DSP/infusion
* Drug: EDS-EP dose range of  14-22 mg DSP/infusion
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Patient meets clinical criteria for diagnosis of AT. The neurological signs of AT (incoordination of the head and eyes in lateral gaze deflection, gait ataxia associated with an inappropriately narrow base) must be documented. Patient is in autonomous gait or is helped by periodic use of a support. Patient will be investigated for the proven genetic diagnosis of AT (prior documentation or by central laboratory test report). Patient is at least 6 years of age, of either sex Body weight > 15 kg. The patient and his/her parent/caregiver (if below the age of consent), or a legal representative, has provided written informed consent to participate. If consent is provided solely by the caregiver in accordance with local regulations, the patient must provide assent to participate in the study. Main Exclusion Criteria: General Females that are pregnant, or are breast-feeding (for EU countries only); of childbearing potential, pregnant, or are breast-feeding (for US and Rest of World countries). Females of childbearing potential using adequate birth control, as determined by their Health Care Provider, will be eligible. A disability that may prevent the patient from completing all study requirements. Current participation in another clinical study. Medical History and Current Status 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 increases 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. Patients with diabetes that has been stabilized (i.e. no hypoglycemic or hyperglycemic episodes in the past 3 months) will be eligible. Any other severe, unstable, or serious disease or condition that in the Investigator's opinion would 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 will be 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 EDS. 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. Use of any drug that is a strong inducer/inhibitor of CYP3A4 within 4 weeks before baseline.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EDS-EP dose range of  5-10 mg DSP/infusion<br>Drug: EDS-EP dose range of  5-10 mg DSP/infusion EDS-EP dose range of  5-10 mg DSP/infusion: A DSP loading quantity of 50.0 mg will be added to the EDS process, by using 2.0 mL of the 25 mg/mL DSP solution to deliver an EDS dose range of  5-10 mg. DSP is diluted with 11 mL sterile water for injection in the same syringe, for a total of 13.0 mL. Other Names: EryDex System end product | Drug: EDS-EP dose range of  5-10 mg DSP/infusion<br>* infusion<br>* Other names: EryDex System end product;|
| Experimental: EDS-EP dose range of  14-22 mg DSP/infusion<br>Drug: DSP/infusion EDS-EP dose range of  14-22 mg DSP/infusion DSP/infusion EDS-EP dose range of  14-22 mg DSP/infusion: A DSP loading quantity of 125 mg will be added to the EDS process, by using 5.0 mL of the 25 mg/mL DSP solution to deliver an EDS dose range of 14-22 mg. DSP is diluted with 11 mL sterile water for injection in the same syringe, for a total of 16 mL. Other Names: EryDex System end product | Drug: EDS-EP dose range of  14-22 mg DSP/infusion<br>* infusion<br>* Other names: EryDex System end product;|
| Placebo Comparator: Placebo EDS infusion<br>Patients will be treated with autologous erythrocytes prepared with the EDS process using a placebo solution (5 mL of 0.372% NaCl solution) instead of experimental drug (DSP). Placebo is diluted with 11 mL sterile water for injection in the same syringe, for a total of 16 mL. | Drug: Placebo<br>* infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified International Cooperative Ataxia Rating Scale (mICARS) | Change from baseline analyzed using a Mixed Model Repeated Measures (MMRM) approach | 3 months, 6 months, 9 months, 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression of Change (CGI-C) key secondary outcome measure | Change from baseline analyzed using ANCOVA | 3 months, 6 months, 9 months, 12 months | 
| Clinical Global Impression of Severity (CGI-S) of neurological symptoms of AT | Change from baseline | 3 months, 6 months, 9 months, 12 months | 
| Vineland Adaptive Behavior Scales (VABS) | Change from baseline | 3 months, 6 months, 9 months, 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ataxia Teleangiectasia, AT, EryDex system, Dexamethasone, Dexamethasone sodium phosphate