Genetic Syndrome, Nervous System Disease
Conditions
Keywords
Ataxia Teleangiectasia, AT, EryDex system, Dexamethasone, Dexamethasone sodium phosphate
Brief summary
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.
Detailed description
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.
Interventions
DRUGEryDex Low dose DSP
EDS-EP dose range of \ 5-10 mg DSP/infusion
DRUGEryDex High dose DSP
EDS-EP dose range of \ 14-22 mg DSP/infusion
DRUGPooled Placebo
EDS processed autologous erythrocytes using a sodium chloride \[NaCl\] solution.
Sponsors
Quince Therapeutics S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The Sponsor, Investigator, site staff, and patients were not aware of the treatment assignments.
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified International Cooperative Ataxia Rating Scale (mICARS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) | to Month 6 (Visit 9) | The CGI-C scale assesses the change in the patient's clinical status from baseline using a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. Clinicians were required to conduct a full clinical interview and examination of the patient. The interview and examination assessed various aspects of the patient's appearance (grooming, evidence of falls, etc.), ataxia, cognition (orientation, calculation ability, language, ability to follow commands, memory, etc.), apraxia, dysarthria, extrapyramidal motor symptoms, activities of daily living, and mood. The higher the score the worse the outcome. |
| 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) | The CGI-S scale measures global severity of illness at a given point in time, and is usually rated on a 7-point, Likert-type scale ranging from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). No version of the CGI-S exists which has been specifically adapted for use in patients with A-T; therefore, a 5-point version was developed that considered the severity of the following symptoms of A-T: ataxia (walking), dysarthria, dysmetria, extrapyramidal symptoms (chorea, myoclonus, dystonia, and tremor), and eye movements. Ratings of none (0), mild (1), moderate (2), severe (3), and very severe (4) were selected based on the level of symptomatology. The higher the score the worse the outcome. |
| Change From Baseline of Vineland Adaptive Behavior Scale (VABS-II) Scores - Last Observation Carried Forward (LOCF) | to Visit 9 (Month 6) | VABS-II was a questionnaire to assess adaptive behavior. It contained 4 domains each with 2-3 subdomains, every subdomain contained various items (questions): A) communication (receptive, expressive, written) B) daily living skills (personal, domestic, community) C) socialization (interpersonal relationships, play and leisure time, coping skills) D) motor skills (gross motor, fine motor). The expanded version of the VABS consisted of 540 items, 261 of which used in this trial. The possible score for each item was from 0 to 4 based on whether the patient performed the activity never, rarely, sometimes, often or almost always. At the end of each domain section, a total score (the sum of the score for each item) was calculated. Domain A: min score 0, max score 572. Domain B: 0 - 800. Domain C: 0 - 580. Domain D: 0 - 424. A grand total score (A+B+C+D scores) was provided (range:0-2376) The lower the score the higher the disability at each level (domains and subdomains). |
| Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | to Visit 9 (Month 6) | TEAE = Treatment Emergent Adverse Events were any AEs started on or after the day of the first infusion through the day just prior to the day of the Visit 9 (Month 6) infusion, or \<=60 days after last dose if the subject never continued past this period. |
| Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | to Visit 15 (Month 12) | TEAE = Treatment Emergent Adverse Events were any AEs started on or after the day of the first infusion through the day just prior to the day of the Visit 15 (Month 12) infusion. Placebo patients who switched to EryDex treatment at 6 and 9 months were not added to the Extension Treatment Period safety data so that the results reported here under are for those patients who remained on placebo from the start of the study till the end of it. |
Countries
Australia, Belgium, Germany, India, Israel, Italy, Norway, Poland, Spain, Tunisia, United Kingdom, United States
Participant flow
Recruitment details
176 patients were randomized, and 175 patients received study drug (Safety Population or ITT). There were 164 patients in the mITT and 107 patients in the PP population. Of the 164 patients in the mITT, 54 were randomized to placebo, 56 to low dose, and 54 to high dose EryDex.The PP population excluded 57 patients that were unable to comply with the study treatment interval, mainly due to the COVID-19 pandemic and issues with traveling in India, and who did not meet the definition of the PP.
Participants by arm
| Arm | Count |
|---|---|
| EryDex Low Dose DSP - SAF EDS-EP dose range of \
5-10 mg DSP/infusion: Patients were treated with EryDex prepared using 2.0 mL of the 25 mg/mL DSP solution, plus 11 mL sterile water for injection in the same syringe, for a total of 13.0 mL, corresponding to 50.0 mg of experimental drug which resulted in a mean of 8.23 mg ± 3.30 mg (mean ± standard deviation) of DSP infused to subjects. 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
EryDex Low dose DSP: EDS-EP dose range of \
5-10 mg DSP/infusion | 59 |
| EryDex High Dose DSP - SAF EDS-EP dose range of \
14-22 mg DSP/infusion: Patients were treated with EryDex prepared using 5.0 mL of the 25 mg/mL DSP solution, plus 11 mL sterile water for injection in the same syringe, for a total of 16 mL, corresponding to 125 mg of experimental drug which resulted in a mean of 17.4 ± 5.38 mg (mean ± standard deviation) of DSP infused to subjects. 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
EryDex High dose DSP: EDS-EP dose range of \
14-22 mg DSP/infusion | 57 |
| Pooled Placebo - SAF Patients were 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 was diluted with 11 mL sterile water for injection in the same syringe, for a total of 16 mL.
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).
Pooled Placebo: EDS processed autologous erythrocytes using 5 mL of 0.372% sodium chloride \[NaCl\] solution. | 59 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 | 1 |
| Overall Study | Covid-Related Treatment/Visit Delay | 15 | 13 | 17 |
| Overall Study | Other | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 3 | 4 |
Baseline characteristics
| Characteristic | EryDex Low Dose DSP - SAF | Total | Pooled Placebo - SAF | EryDex High Dose DSP - SAF |
|---|---|---|---|---|
| Age, Categorical <=18 years | 59 Participants | 175 Participants | 59 Participants | 57 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 9.5 years STANDARD_DEVIATION 3.16 | 10.0 years STANDARD_DEVIATION 4.06 | 10.3 years STANDARD_DEVIATION 4.02 | 10.2 years STANDARD_DEVIATION 4.86 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 72 Participants | 27 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 99 Participants | 29 Participants | 36 Participants |
| Region of Enrollment Australia | 1 participants | 5 participants | 1 participants | 3 participants |
| Region of Enrollment Belgium | 1 participants | 3 participants | 0 participants | 2 participants |
| Region of Enrollment Germany | 5 participants | 16 participants | 5 participants | 6 participants |
| Region of Enrollment India | 22 participants | 66 participants | 26 participants | 18 participants |
| Region of Enrollment Israel | 1 participants | 1 participants | 0 participants | 0 participants |
| Region of Enrollment Italy | 1 participants | 4 participants | 1 participants | 2 participants |
| Region of Enrollment Norway | 2 participants | 5 participants | 1 participants | 2 participants |
| Region of Enrollment Poland | 3 participants | 11 participants | 3 participants | 5 participants |
| Region of Enrollment Spain | 7 participants | 13 participants | 4 participants | 2 participants |
| Region of Enrollment Tunisia | 3 participants | 8 participants | 2 participants | 3 participants |
| Region of Enrollment United Kingdom | 2 participants | 11 participants | 6 participants | 3 participants |
| Region of Enrollment United States | 11 participants | 32 participants | 10 participants | 12 participants |
| Sex: Female, Male Female | 29 Participants | 85 Participants | 29 Participants | 27 Participants |
| Sex: Female, Male Male | 30 Participants | 90 Participants | 30 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 57 | 1 / 19 | 0 / 9 | 0 / 9 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 45 / 59 | 50 / 57 | 15 / 19 | 7 / 9 | 8 / 9 | 7 / 11 | 9 / 11 |
| serious Total, serious adverse events | 8 / 59 | 9 / 57 | 4 / 19 | 1 / 9 | 1 / 9 | 1 / 11 | 4 / 11 |
Outcome results
Primary
Change From Baseline in Modified International Cooperative Ataxia Rating Scale (mICARS)
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.
Time frame: to Month 6 (Visit 9)
Population: Modified Intention to Treat population - mITT: ll randomized patients who received at least one dose of study medication and had at least one post-baseline efficacy assessment of the primary efficacy variable
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EryDex Low Dose DSP - mITT | Change From Baseline in Modified International Cooperative Ataxia Rating Scale (mICARS) | 0.8 score on a scale | Standard Deviation 3.56 |
| EryDex High Dose DSP - mITT | Change From Baseline in Modified International Cooperative Ataxia Rating Scale (mICARS) | 1.0 score on a scale | Standard Deviation 3.32 |
| Placebo - mITT | Change From Baseline in Modified International Cooperative Ataxia Rating Scale (mICARS) | 2.3 score on a scale | Standard Deviation 5.03 |
Comparison: Least squares means, and p-values are derived from a mixed model repeated measures analysis with baseline modified ICARS value as covariate and the fixed effects of treatment, age, sex, region and visit and the interaction term treatment-by-visit.p-value: 0.084795% CI: [-2.932, 0.19]Mixed model for repeated measures
Comparison: Least squares means, and p-values are derived from a mixed model repeated measures analysis with baseline modified ICARS value as covariate and the fixed effects of treatment, age, sex, region and visit and the interaction term treatment-by-visit.p-value: 0.076595% CI: [-2.957, 0.152]Mixed model for repeated measures
Secondary
Change From Baseline of Vineland Adaptive Behavior Scale (VABS-II) Scores - Last Observation Carried Forward (LOCF)
VABS-II was a questionnaire to assess adaptive behavior. It contained 4 domains each with 2-3 subdomains, every subdomain contained various items (questions): A) communication (receptive, expressive, written) B) daily living skills (personal, domestic, community) C) socialization (interpersonal relationships, play and leisure time, coping skills) D) motor skills (gross motor, fine motor). The expanded version of the VABS consisted of 540 items, 261 of which used in this trial. The possible score for each item was from 0 to 4 based on whether the patient performed the activity never, rarely, sometimes, often or almost always. At the end of each domain section, a total score (the sum of the score for each item) was calculated. Domain A: min score 0, max score 572. Domain B: 0 - 800. Domain C: 0 - 580. Domain D: 0 - 424. A grand total score (A+B+C+D scores) was provided (range:0-2376) The lower the score the higher the disability at each level (domains and subdomains).
Time frame: to Visit 9 (Month 6)
Population: Modified Intention to Treat population - mITT: ll randomized patients who received at least one dose of study medication and had at least one post-baseline efficacy assessment of the primary efficacy variable
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EryDex Low Dose DSP - mITT | Change From Baseline of Vineland Adaptive Behavior Scale (VABS-II) Scores - Last Observation Carried Forward (LOCF) | 42.6 score on a scale | Standard Deviation 125.95 |
| EryDex High Dose DSP - mITT | Change From Baseline of Vineland Adaptive Behavior Scale (VABS-II) Scores - Last Observation Carried Forward (LOCF) | -26.5 score on a scale | Standard Deviation 214.52 |
| Placebo - mITT | Change From Baseline of Vineland Adaptive Behavior Scale (VABS-II) Scores - Last Observation Carried Forward (LOCF) | 57.5 score on a scale | Standard Deviation 200.37 |
Comparison: Least squares means difference, associated statistics, and p-values derived using ANCOVA, with age (at 2 levels: \<10 years, \>=10 years), sex, treatment, region, and baseline VABS score as fixed effects.p-value: 0.702995% CI: [-82.261, 55.601]ANCOVA
Comparison: Least squares means difference, associated statistics, and p-values derived using ANCOVA, with age (at 2 levels: \<10 years, \>=10 years), sex, treatment, region, and baseline VABS score as fixed effects.p-value: 0.032895% CI: [-148.201, -6.421]ANCOVA
Secondary
Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12
TEAE = Treatment Emergent Adverse Events were any AEs started on or after the day of the first infusion through the day just prior to the day of the Visit 15 (Month 12) infusion. Placebo patients who switched to EryDex treatment at 6 and 9 months were not added to the Extension Treatment Period safety data so that the results reported here under are for those patients who remained on placebo from the start of the study till the end of it.
Time frame: to Visit 15 (Month 12)
Population: Safety Population: all patients who received any amount of randomized treatment (also referred to as the ITT population). Placebo patients who switched to EryDex treatment at 6 and 9 months were not added to the Extension Treatment Period safety data so that the results reported are for those patients who remained on placebo from the start of the study (N=19)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE Leading to Discontinuation | 1 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Serious TEAE | 8 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Serious Treatment-related TEAE | 1 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE Leading to Death | 0 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Treatment-related TEAE | 19 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE | 45 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Serious TEAE | 9 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE | 50 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Treatment-related TEAE | 25 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Serious Treatment-related TEAE | 1 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE Leading to Discontinuation | 2 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE Leading to Death | 0 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Treatment-related TEAE | 5 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE Leading to Death | 0 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE Leading to Discontinuation | 0 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Serious TEAE | 4 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any TEAE | 15 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12 | Patients With Any Serious Treatment-related TEAE | 1 Participants |
Secondary
Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6
TEAE = Treatment Emergent Adverse Events were any AEs started on or after the day of the first infusion through the day just prior to the day of the Visit 9 (Month 6) infusion, or \<=60 days after last dose if the subject never continued past this period.
Time frame: to Visit 9 (Month 6)
Population: Safety Population (SAF): all patients who received any amount of randomized treatment (also referred to as the ITT population).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE | 43 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Serious Treatment-related TEAE | 0 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Serious TEAE | 6 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Pre- treatment AE | 14 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE Leading to Death | 0 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE Leading to Discontinuation | 0 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Treatment-related TEAE | 15 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Serious TEAE | 7 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Pre- treatment AE | 16 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE | 47 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Treatment-related TEAE | 21 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Serious Treatment-related TEAE | 1 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE Leading to Discontinuation | 2 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE Leading to Death | 0 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Serious Treatment-related TEAE | 0 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE | 43 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE Leading to Death | 0 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any TEAE Leading to Discontinuation | 0 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Serious TEAE | 7 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Any Treatment-related TEAE | 15 Participants |
| Placebo - mITT | Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6 | Patients With Pre- treatment AE | 14 Participants |
Secondary
Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C)
The CGI-C scale assesses the change in the patient's clinical status from baseline using a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. Clinicians were required to conduct a full clinical interview and examination of the patient. The interview and examination assessed various aspects of the patient's appearance (grooming, evidence of falls, etc.), ataxia, cognition (orientation, calculation ability, language, ability to follow commands, memory, etc.), apraxia, dysarthria, extrapyramidal motor symptoms, activities of daily living, and mood. The higher the score the worse the outcome.
Time frame: to Month 6 (Visit 9)
Population: Modified Intention to Treat population - mITT: ll randomized patients who received at least one dose of study medication and had at least one post-baseline efficacy assessment of the primary efficacy variable
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EryDex Low Dose DSP - mITT | Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) | Improvement (Scores 1-3) | 19 Participants |
| EryDex Low Dose DSP - mITT | Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) | Stable or Worsening (Scores 4-7) | 37 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) | Improvement (Scores 1-3) | 27 Participants |
| EryDex High Dose DSP - mITT | Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) | Stable or Worsening (Scores 4-7) | 27 Participants |
| Placebo - mITT | Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) | Improvement (Scores 1-3) | 19 Participants |
| Placebo - mITT | Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) | Stable or Worsening (Scores 4-7) | 35 Participants |
Comparison: Logistic regression modeling (0/1), where 0 = No change or worsening and 1= improvement, with age (at 2 levels: \<10 years, ≥10 years), sex, treatment, region as fixed effects.p-value: 0.891995% CI: [0.426, 2.099]Regression, Logistic
Comparison: Logistic regression modeling (0/1), where 0 = No change or worsening and 1= improvement, with age (at 2 levels:~\<10 years, ≥10 years), sex, treatment, region as fixed effects.p-value: 0.125595% CI: [0.842, 4.053]Regression, Logistic
Secondary
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
The CGI-S scale measures global severity of illness at a given point in time, and is usually rated on a 7-point, Likert-type scale ranging from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). No version of the CGI-S exists which has been specifically adapted for use in patients with A-T; therefore, a 5-point version was developed that considered the severity of the following symptoms of A-T: ataxia (walking), dysarthria, dysmetria, extrapyramidal symptoms (chorea, myoclonus, dystonia, and tremor), and eye movements. Ratings of none (0), mild (1), moderate (2), severe (3), and very severe (4) were selected based on the level of symptomatology. The higher the score the worse the outcome.
Time frame: to Visit 9 (Month 6)
Population: Modified Intention to Treat population - mITT: ll randomized patients who received at least one dose of study medication and had at least one post-baseline efficacy assessment of the primary efficacy variable
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EryDex Low Dose DSP - mITT | 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 | CGI-S Score - 4 | 0 Participants |
| EryDex Low Dose DSP - mITT | 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 | CGI-S Score - 0 | 0 Participants |
| EryDex Low Dose DSP - mITT | 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 | CGI-S Score - 2 | 29 Participants |
| EryDex Low Dose DSP - mITT | 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 | CGI-S Score - 1 | 15 Participants |
| EryDex Low Dose DSP - mITT | 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 | CGI-S Score - 3 | 12 Participants |
| EryDex High Dose DSP - mITT | 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 | CGI-S Score - 1 | 16 Participants |
| EryDex High Dose DSP - mITT | 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 | CGI-S Score - 4 | 0 Participants |
| EryDex High Dose DSP - mITT | 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 | CGI-S Score - 3 | 12 Participants |
| EryDex High Dose DSP - mITT | 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 | CGI-S Score - 0 | 0 Participants |
| EryDex High Dose DSP - mITT | 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 | CGI-S Score - 2 | 26 Participants |
| Placebo - mITT | 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 | CGI-S Score - 4 | 0 Participants |
| Placebo - mITT | 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 | CGI-S Score - 0 | 0 Participants |
| Placebo - mITT | 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 | CGI-S Score - 1 | 17 Participants |
| Placebo - mITT | 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 | CGI-S Score - 3 | 13 Participants |
| Placebo - mITT | 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 | CGI-S Score - 2 | 24 Participants |
Comparison: Odds ratio, confidence limits, and p-value derived using a proportional odds ordinal logistic regression analysis, with age (at 2 levels: \<10 years, ≥10 years), sex, treatment, region, visit, baseline CGI-S score, and treatment-by- visit interaction as fixed effects.p-value: 0.458395% CI: [0.597, 3.144]Ordinal Logistic Regression Analysis
Comparison: Odds ratio, confidence limits, and p-value derived using a proportional odds ordinal logistic regression analysis, with age (at 2 levels: \<10 years, ≥10 years), sex, treatment, region, visit, baseline CGI-S score, and treatment-by- visit interaction as fixed effects.p-value: 0.458595% CI: [0.595, 3.16]Ordinal Logistic Regression Analysis