EDS in Ataxia Telangiectasia Patients - IEDAT-02 (ATTeST)
Research type
Research Study
Full title
A 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
IRAS ID
191352
Contact name
William Whitehouse
Contact email
Sponsor organisation
EryDel S.p.A.
Eudract number
2015-005241-31
Clinicaltrials.gov Identifier
115929 , IND number
Duration of Study in the UK
2 years, 2 months, days
Research summary
Summary of Research
This is an international, multi-centre, one-year, randomised, prospective, double-blind, placebo-controlled, phase III study. It was designed to assess the effect of two non-overlapping dose ranges of dexamethasone sodium phosphate (DSP), administered by IV infusion by a new way - the EryDex system (EDS). The EDS uses a special procedure to place the DSP (or placebo) into red blood cells (RBCs) previously taken from the patient. The RBCs plus DSP or placebo are then transfused back into the patient once per month, and the impact on the neurological symptoms of patients with Ataxia Telangiectasia (AT) assessed.
At least 180 patients will be randomised to two different doses of treatment or placebo (1 in 3). AT is a rare disease and there is no approved drug to treat the disease or to slow down the progression of the debilitating disability and mortality associated with this illness. Neurological degeneration is the major risk involved in a severe outcome. Earlier studies have suggested that long term treatment with steroids can offer some benefit. The EDS provides the benefit of low and constant drug delivery with a lower incidence of associated steroid side effects despite long term use.
After 6 months of treatment, the two active treatment groups will continue their doses while one third of the placebo group will be randomised to receive treatment (1:1) with one of the two doses. At month 9, another third of the placebo group will be randomly assigned to drug in the same way. At the end of the study, an optional open-label extension study will allow patients who are doing well to continue on treatment. Efficacy will be measured by the International Cooperative Ataxia Rating Scale (ICARS). Patients will be expected to undergo monthly visits for evaluations, blood tests and study drug administration.Summary of Results
SUMMARY – CONCLUSIONS
EFFICACY RESULTS:
Of the 239 patients screened, 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 (reimbursement procedure
for patients) in India, and who did not meet the definition of the PP population.
The analysis of the primary efficacy endpoint (mICARS, mITT) showed a numerical trend in favor of
the low and high dose groups relative to placebo; however, these assessments did not reach statistical
significance (least squares mean [LSM] -1.37, p=0.085 and LSM -1.40, p=0.077, respectively). The
sensitivity analysis of the ICARS and the RmICARS showed similar results.
Subgroup analyses were performed for age, sex, region, and genetic disease diagnosis in the mITT
population. At Month 6, there was a statistically significant difference for mICARS in 6 to 9-year-olds
in the high dose group when compared to placebo (LSM -2.79, p=0.0185). There was no statistical
difference observed for mICARS in 6 to 9-year-olds in the low dose group or in patients who were
≥10 years of age. These findings suggest treating patients as early as possible may slow disease
progression.
In a pre-specified PP population analysis (N=107), a statistically significant difference was observed
for the mICARS for both doses (LSM -2.80, p=0.0037 for the low dose group and LSM -2.21, p=0.019
for the high dose group). The sensitivity analyses for the RmICARS and full ICARS showed similar,
consistent results. The relevance of these results is supported by the PK profile of dexamethasone
reported in the population PK model (based on data collected in the Phase 1 Study IED-PK01-2013
and patients with A-T in the current investigation) that dexamethasone is still detectable 20 to 30 days
after dosing, but at lower levels. Collectively, these data emphasize the importance of adherence to the
prescribed treatment interval and how the COVID-19 pandemic which, in some regions led to delays in
treatment due to travel restrictions and/or increased restrictions at hospitals, impacted the overall
results of the ATTeST study.
Results of the key secondary endpoint (CGI-C at Month 6) demonstrated a favorable trend for the
EryDex high dose versus placebo (50% vs 35.2%). The responder analysis of the 6 to 9-year-olds
subgroup showed a statistically significant effect for the high dose versus placebo (51.7% vs 27.6%;
p=0.028). There was no statistically significant difference between the low dose and placebo groups in
the proportion of patients who showed improvement (p=0.6373) or in patients who were ≥10 years of
age.
The analysis (LOCF) of the change from baseline to Month 6 of the quality-of-life instrument (EQ-5D-
5L) showed improvements for the high dose group versus placebo for the mobility domain (p=0.03)
and the self-care domain (p=0.024); comparable, statistically significant results were obtained with the
OC analysis. For the high dose, a treatment effect approaching statistical significance was also
observed for the visual analog scale when compared to placebo (p=0.058); similar results were
observed with the OC analysis (p=0.0503). Overall, the assessments of self-care and preserved
mobility using the EQ-5D-5L instrument suggest that EryDex treatment was associated with
improvements of quality-of-life for patients with A-T.
SAFETY RESULTS:
A total of 175 patients received at least one dose of EryDex. The median duration (min, max) of active
treatment for the low and high dose groups was 333 days (34, 867 days) and 365 days (1,627 days),
respectively, for those who remained in their initial treatment groups.
EryDex treatment was generally well tolerated, with most adverse events (AEs) being mild to moderate
and transient. No patterns of clinically relevant AEs were observed. The proportion of patients who
Clinical Study Report
IEDAT-02-2015 (ATTeST)
12
CONFIDENTIAL
experienced at least 1 Treatment Emergent Adverse Event (TEAE) was comparable across the three
arms through 12 months of treatment. Serious TEAEs were reported by 8 (13.6%) patients in the lowdose
group, 9 (15.8%) patients in the high-dose group, and 4 (21.1%) patients in the placebo group for
the Extension Treatment Period. There was 1 death that occurred approximately 11 months (Day 335)
following the last study treatment (placebo). Three patients discontinued from the study, 1 patient in
the low dose group had an SAE of B-cell lymphoma (unlikely treatment-related) and 2 patients in the
high dose group who had TEAEs of pyrexia and tachycardia (1 patient, probably treatment-related) and
pain and pruritus (1 patient, possibly treatment-related).
Assessment of potential steroid-induced side effects indicated a greater proportion of patients reported
pyrexia and pruritus in the EryDex treatment groups compared to placebo. Other potential steroid
induced TEAEs that were reported by a greater proportion of patients (>5%) in the EryDex groups
compared to placebo included influenza and nasopharyngitis during the Initial Treatment Period, and
upper respiratory tract infection, weight increase, and osteoporosis over the entire treatment period.
Critically, overall there was no increase in the proportion of patients who demonstrated TEAEs
indicative of adrenal insufficiency. EryDex did not appear to have an impact on growth and
development, including meaningful changes in BMD and Tanner Staging assessments. Furthermore,
none of the laboratory parameters of special interest (i.e., alpha fetoprotein, C-reactive protein, and
HbA1c) showed a clinically significant shift from baseline over the course of the study. Overall, there
were no clear, clinically significant differences in potential steroid-induced side effects observed
between the treated and placebo groups. This interpretation was supported following review of the
independent Data Safety Monitoring Board (DSMB) at its regular meetings throughout the study.
There were no clear or consistent patterns of change or clinically significant shifts from baseline in
hematology measures, clinical chemistry measures, urinalysis measures, vital signs, ECG findings,
physical examination, or neurological examination.
CONCLUSION:
ATTeST Study (IEDAT-02-2015) did not show a statistically significant difference in the primary
efficacy endpoint of improvement of CNS symptoms as measured by mICARS in the mITT
population. However, based on analyses using the PP population, there was an apparent treatment
effect of EryDex at both dose levels when compared to placebo. In conjunction with the PK profile of
EryDex, these data emphasize the importance of adherence to the prescribed treatment interval and
how the COVID-19 pandemic which, in some regions led to delays in treatment due to travel
restrictions and/or increased restrictions at hospitals, impacted the overall results of this study.
Furthermore, observations from the efficacy subgroup analyses, particularly in 6 to 9-year-olds, and in
light of the available natural history data, suggest treating patients as early as possible.
Overall, the safety and tolerability profile of EryDex was favorable, with no clear, clinically significant
difference in potential steroid-induced side effects.
The safety and preliminary efficacy results from study IEDAT-02-2015 support the continued
development of EryDex as a potential treatment for patients with A-T, a rare, devastating progressive
disorder for which there are currently no viable treatment options.REC name
East Midlands - Nottingham 2 Research Ethics Committee
REC reference
16/EM/0258
Date of REC Opinion
28 Jul 2016
REC opinion
Further Information Favourable Opinion