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.

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

The initial 6-month treatment period was considered complete when the endpoint assessment (at Visit 9/Month 6 or at early discontinuation) was performed for all patients. All patients who completed the assessments over the initial 6 months of the trial were eligible to continue in an additional 6-month, double-blind, placebo- controlled extension, designed to collect information on the longer-term safety and efficacy of the trial treatments.

Following completion of the 6-month Initial Treatment Period, patients that met all entry criteria were re-randomized and treated as follows:

• Patients originally randomized to one of the two dose levels of EryDex (low dose or high dose; Groups 1 or 2) continued in the same treatment arm.

• Patients originally randomized to the Placebo group (Group 3) were re-allocated as defined at the initial randomization in equal proportions (1:1) and received either the EryDex low dose or high dose as follows:

  • Following 6 months of treatment, one third of the placebo patients were switched to treatment with EryDex, as described above.
  • After 9 months of treatment, another third of the placebo patients were switched to treatment with EryDex, as described above.
  • At 12 months, all remaining placebo patients were eligible to switch to open-label treatment with EryDex, as described above.

Inclusion Criteria:

1. 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.
2. 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).
3. Patient was investigated for the proven genetic diagnosis of A-T (prior documentation or by central laboratory test report).
4. Patient was at least 6 years of age.
5. Body weight was >15 kg.
6. 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

General

1. Females that were:

   1. Pregnant or breast-feeding (for European Union [EU] countries only).
   2. 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.

2. A disability that may have prevented the patient from completing all study requirements.

3. Current participation in another clinical study.

   Medical History and Current Status

4. 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).

5. Loss/removal of 250 mL or more of blood within the past 4 weeks prior to screening.

6. Current neoplastic disease or previous neoplastic disease not in remission for at least 2 years.

7. History of severe impairment of the immunological system.

8. Severe or unstable pulmonary disease.

9. Uncontrolled diabetes.

10. 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.

11. 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.

12. Confirmed hemoglobinopathies, e.g., hemoglobin C disease, sickle cell anemia, or thalassemia.

13. Moderate or severe renal and/or hepatic impairment.

    Prior/Concomitant Medication

14. 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.

15. Chronic condition or prior allergic reaction representing a contraindication to the use of dexamethasone or other steroid drugs.

16. 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.

17. Has participated in a previous trial with EryDex.

18. Requires any concomitant medication prohibited by the protocol.

19. Has taken a drug or treatment known to cause major organ system toxicity during the past year.

20. Used of any drug that is a strong inducer/inhibitor of cytochrome P450 3A4 (CYP3A4) within 4 weeks before baseline.

The Sponsor, Investigator, site staff, and patients were not aware of the treatment assignments.