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
Phase: PHASE3
Conditions: Nervous System Disease, Genetic Syndrome
Sponsor: Quince Therapeutics S.p.A.

CLINICAL STUDY PROTOCOL 
Protocol Number 
IEDAT-02-2015 
Study 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  
Short Study Title - Acronym 
Ataxia Telangiectasia Treatment with EryDex SysTem - 
ATTEST 
Phase 
Phase III 
EudraCT Number 
2015-005241-31 
IND Number 
115929 
Date of Protocol 
Version 1.0: 09 May 2015, Final 
Version 2.1: 16 November 2015, Final 
Version 3.0: 1 February 2016, Final 
Version 3.1: 28 April 2016, Final 
Version 3.2: 25 May 2016, Final 
Version 4.0: 29 November 2016, Final 
Version 5.0: 20 September 2017 (Site-specific), Final 
Version 6.0: 29 September 2017, Final 
Version 7.1: 13 March 2018, Final 
Version 8.0: 23 April 2018, Final 
Version 8.1 – Country specific (Germany): 24 October 2018 
Version 9.0: 11 April 2019, Final 
Version 10.0: 16 April 2019, Final 
Version 11.0: 24 June 2020, Final 
Author 
 
Sponsor 
EryDel S.p.A. 
Via Meucci 3 
20091 Bresso (MI), Italy 
: +39 02 36504472 
: +39 02 36504474 
Trial Protocol Version 
Version 11.0; 24 June 2020, Final 
GCP Statement 
This study will be performed in compliance with Good Clinical Practice (GCP),  
the Declaration of Helsinki (with amendments) and local legal and regulatory requirements. 
CONFIDENTIALITY 
The information contained herein is the property of EryDel S.p.A. and may not be reproduced, published 
or disclosed to others without written authorisation of EryDel S.p.A 
EryDel S.p.A., Via Meucci 3, 20091 Bresso (MI) (Italy) 
PPD

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 2 of 121 
1 
SYNOPSIS 
Title of the Study 
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 
Protocol Number 
IEDAT-02-2015 
Phase of Development 
III 
Center(s)/ Country(ies) 
20-25 centers in North America, Europe, Africa, Asia and Australia
Planned Trial Period  
(first subject enrolled - 
last subject out) 
First Subject In (FSI): 15th of March 2017 
Last Subject In (LSI): 30th of March 2020 
Last Subject Last Visit (LSLV): 1st Quarter 2021 
Study Objectives 
Initial Treatment Period (6 months) 
Primary Efficacy Objective: 
•
To evaluate the effect of two dose ranges (~5-10 and ~14-22 mg
DSP/infusion) of EryDex System end product [EDS-EP; the EDS is a
combination product that is used to load dexamethasone sodium phosphate
(DSP) into autologous erythrocytes, creating the EDS end product, which
is infused into the patient], compared to placebo, on central nervous system
(CNS) symptoms measured by the ‘Modified’ International Cooperative
Ataxia Rating Scale (mICARS) in patients with ataxia telangiectasia (AT).
Key Secondary Efficacy Objective: 
•
To evaluate the effect of EDS-EP, compared to placebo, in this population
on the Clinical Global Impression of Change from baseline (CGI-C).
Safety Objective: 
•
To evaluate the safety and tolerability of EDS-EP compared to placebo in
AT patients, based on the occurrence of Treatment-Emergent Adverse
Events (TEAEs), including Serious AEs and discontinuations due to AEs,
and changes in vital signs, laboratory parameters, ECGs and
physical/neurological examination findings.
Secondary Efficacy Objectives: 
•
To evaluate the effect of EDS-EP, compared to placebo, in this population
on the following efficacy measures:
o
Clinical Global Impression of Severity (CGI-S) of neurological
symptoms of AT;
o
Adaptive behavior measured by the Vineland Adaptive
Behavior Scales (VABS);
Tertiary Objectives: 
•
To evaluate the effect of EDS-EP on health-related Quality of Life (QoL)
using the EQ-5D-5L scale;
•
To assess the pharmacokinetic and pharmacodynamic relationships between
dexamethasone administered through EDS-EP and safety, tolerability, and
demographic variables.
•
To evaluate the pharmacokinetic (PK) profile of dexamethasone
administered through EDS-EP at two dose levels based on pooled data
from all patients in each treatment group.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 3 of 121 
A determination of individual PK parameters will be performed for patients with 
an adequate number of PK blood samples after the initial infusion.  
Exploratory Objective: 
•
To collect data on the use of the A-T NEST concurrent with the ICARS,
CGI-S and CGI-C, as well as its use in languages other than English, and
to compare it with the data from the scales referenced to assess the
psychometric properties of the A-T NEST.
Extension Treatment Period (6 months) 
Primary Objective: 
•
To evaluate the efficacy of two dose ranges (~5-10 and ~14-22 mg
DSP/infusion) of EDS-EP compared to placebo in treating CNS symptoms
in AT patients during long-term treatment (up to 12 months), as measured
by the ‘Modified’ ICARS.
Secondary Objectives: 
•
To evaluate the long-term (up to 12 months) safety and tolerability of EDS-
EP in AT patients;
•
To compare the effects of the two dose ranges of EDS-EP on the clinician’s
global impression (CGI-C and CGI-S), adaptive behavior (VABS), and
QoL (EQ-5D-5L scale).
Study Design 
This is an international (North America, Europe, Africa, Asia and Australia), 
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 AT. 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 were anticipated to  be enrolled, then the last subject 
was enrolled on the 30th of March 2020, with 175 enrolled patients, due to the 
Covid-19 outbreak. Each group will consist of 60 patients randomly assigned to 
receive one of the two dose ranges of EDS-EP or placebo, as follows: 
•
Group 1: EDS-EP low dose range of ~5-10 mg DSP/infusion,
•
Group 2: EDS-EP high dose range of ~14-22 mg DSP/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.   

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 4 of 121 
As a results of the COVID-19 pandemic, temporary changes to the protocol have 
been implemented. These changes are described in Appendix 14.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 (or longer, in case a patient is willing to be enrolled in the open-
label study IEDAT-03-2018, but the study has not yet received IRB/EC approval 
at the time the patient reaches Visit 15/Month 12). 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:
o
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;
o
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;
o
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, QoL or 
A-T NEST 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-03-2018). In case a 
patient is willing to be enrolled in the open-label study IEDAT-03-2018, but the 
study has not yet received IRB/EC approval at the time the patient reaches Visit 
15/Month 
12, 
the 
patient 
may 
undergo 
unscheduled 
monthly 
assessments/infusions (according to the assigned blinded treatment) starting from 
the time Visit 15/Month 12 should be performed, and continuing until the site has 
been initiated for the open-label study IEDAT-03-2018 and he/she has been 
evaluated for eligibility for the study. All patients, including those previously 
treated with placebo, who meet all of the selection criteria will receive monthly 
infusions of EDS-EP (dose range of ~14-22 mg DSP/infusion).  
Planned Number of 
Patients  
A minimum of 180 patients meeting all selection criteria were anticipated to be 
enrolled and randomized to one of the 3 treatment groups (approximately 60 
patients per group). Due to the Covid-19 outbreak, the enrollment was closed with 
175 randomized patients. 
Inclusion and Exclusion 
Criteria 
Inclusion Criteria 
1.
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

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 5 of 121 
associated with an inappropriately narrow base) must be documented. Such 
signs of AT illustrate the body systems in which changes shall be confirmed 
but the listed changes are examples and other changes in those systems may 
be observed and documented to confirm the diagnosis of AT. 
2.
Patient is in autonomous gait or is helped by periodic use of a support (i.e.
local ICARS score for Item 1 – Walking Capacities between 0 and 4,
included).
3.
Patient will be investigated for the proven genetic diagnosis of AT (prior
documentation or by central laboratory test report).
4.
Patient is at least 6 years of age, of either sex
5.
Body weight > 15 kg.
6.
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.
Exclusion Criteria 
General 
1.
Females that are
a.
pregnant, or are breast-feeding (for EU countries only);
b.
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.  
2.
A disability that may prevent the patient from completing all study
requirements.
3.
Current participation in another clinical study.
Medical History and Current Status 
4.
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).
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.
Patients with diabetes that has been stabilized (i.e. no hypoglycemic or
hyperglycemic episodes in the past 3 months) will be eligible.
10. 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.
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
will be 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.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 6 of 121 
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 EDS.
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. Use of any drug that is a strong inducer/inhibitor of CYP3A4 within 4 weeks
before baseline.
Schedule of Visits and 
Assessments: Screening 
period (Days -30 to -1) 
Every potential patient will provide informed consent or assent prior to the 
initiation of any screening procedure. During the 30-day screening period, any 
previous treatments with other corticosteroid compounds will be withdrawn 
(washout from previous treatment). The following screening evaluations will be 
conducted:  
•
Medical history and demographics
•
Physical examination
•
Vital signs (including height and weight in triplicate)
•
Neurological examination
•
ICARS (administered by the qualified site-specific rater.
•
CGI-S
•
Electrocardiogram (ECG)
•
Routine laboratory tests: hematology, biochemistry, urinalysis
•
Special laboratory tests: HbA1c, CD4+ lymphocytes count,
-fetoprotein, CRP, and RBC antibodies (IgG, IgM and Qualitative
Direct Coombs test)
•
Blood collected to assess RBC osmotic resistance (in selected centers)
•
Serum pregnancy test (women of childbearing potential)
•
Plasma cortisol – sample to be collected before 8:00 AM and prior to
randomization at baseline. If the basal cortisol level is within the
reference normal range, the patient can be enrolled in the study. If the
8:00 AM cortisol level is below 3-5 µg/dL (depending on assay)
regardless of symptoms, or the patient exhibits signs or symptoms of
adrenal insufficiency (see Appendix 12) and has a cortisol <10 µg/dL,
the patient will receive a high dose ACTH stimulation test, regardless of
weight, within 24 hours. If the ACTH stimulation test is normal, the
patient can be enrolled after the effects of the ACTH have dissipated
(e.g., 30 days after ACTH administered).  If the patient fails the ACTH
stimulation test they will be excluded from the study and referred to a
pediatric endocrinologist, with a recommendation to prescribe stress
dose steroids.
•
Sample for AT genetic assay, if not previously reported (test results must
be obtained from a certified lab, but do not need to be available before
baseline).

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 7 of 121 
•
Mini-ATM detection - 2.5 mL of blood collected
•
Assessment of prior and concomitant medications
•
Assessment of AEs
If any abnormal laboratory test results, vital sign measurements, or ECG findings 
of clinical significance are noted at the screening visit, these must be repeated 
during the 30-day screening period and the results made available prior to making 
the final decision on a patient’s eligibility for the study at Baseline. Adverse 
events, reported by the patient or observed by the investigator, and the use of 
concomitant medication will be recorded from the time of signing of informed 
consent through the end of the study.  
Schedule of Visits and 
Assessments: Baseline 
(Day 0/1) 
The following assessments will be performed on Day 0 and Day 1 before 
administration of study treatment: 
•
Physical examination
•
Vital signs (including height and weight in triplicate)
•
Neurological examinations
•
Review of all eligibility criteria.
•
ICARS once on Day 0 (~24 hr before dosing; video recording required)
and once on Day 1 (baseline assessment; video recording required).
•
CGI-S
•
Vineland Adaptive Behavior Scale (VABS)
•
Quality of life (QoL): EQ-5D-5L
•
Columbia-Suicide Severity Rating Scale (C-SSRS)
•
ECG, only if repeated due to abnormal findings at the screening visit
•
Routine laboratory tests on the diverted blood sample (see Section 11.6):
only if repeated due to abnormal parameters at the screening visit
•
Special laboratory tests on the diverted blood sample (see Section 11.6):
HbA1c, CD4+ lymphocytes count, and CRP
•
Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total
and conjugated), LDH]
•
Urine and serum pregnancy test (women of childbearing potential) on
the diverted blood sample (see Section 11.6).
•
Assessment of physical development, sexual maturation, and the effect
of treatment with dexamethasone on these aspects (Tanner scale;
Marshall and Tanner 1969, 1970). Tanner staging of the breasts in pre-
menarchal females and of the scrotum in males who have not completed
puberty, will be performed. Post-menarchal females and males who have
completed puberty will be excluded from this growth analysis.
•
Bone mineral density
•
Assessment of concomitant medications
•
Assessment of AEs
•
Blood sample (0 hr) for dexamethasone pharmacokinetics (PK) just
before the infusion.
Following randomization using the IVRS/IWRS, study treatment will be prepared 
and administered as follows:  
•
1 mL blood collected, after blood diversion (see Section 11.6), for
aerobic culture.
•
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 8 of 121 
•
Addition of randomized study medication (DSP or placebo) to the EDS
process
•
After completion of the IV infusion of the study treatment the following 
assessments will be performed on Day 1: 
•
Blood samples for dexamethasone PK 1, and 4 hr after the end of the
infusion. If all samples are taken, the total blood volume collected for
PK within the first 24 hours would be 9 mL.
•
Free plasma hemoglobin (1 hr post infusion)
•
Vital signs
•
Physical examination
•
Assessment of AEs
Schedule of Visits and 
Assessments: Day 2 
At Day 2 the following assessments will be performed: 
•
A-T NEST (in selected centers)
•
Blood sample for dexamethasone PK 24 hr after the infusion
•
Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total
and conjugated), CBC, LDH, urinalysis]
•
Assessment of concomitant medications
•
Assessment of AEs
Schedule of Visits and 
Assessments: Day 15 
At Day 15 the following assessments will be performed: 
•
Blood sample for dexamethasone PK
•
Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total
and conjugated), CBC, LDH, urinalysis]
•
Assessment of concomitant medications
•
Assessment of AEs
Schedule of Visits and 
Assessments: Months 1, 2, 
4, 5, 7, 8, 10, and 11 
At Months 1, 2, 4, 5, 7, 8, 10, and 11 the following assessments will be performed: 
•
Blood sample for dexamethasone PK before infusion on the diverted
blood sample (Months 1, 2, 4 and 5 only)
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 9 of 121 
•
Laboratory tests on the diverted blood sample: serum creatinine
•
Urine pregnancy test will be performed before every infusion (for
women of childbearing potential)
•
A-T NEST (in selected centers) (Months 1, 4, 7, and 10 only)
•
C-SSRS
•
Mini-ATM detection on the diverted blood sample, only on Day 60
(Month 2)
•
Upon completion of the EDS process, fill the satellite sample bag with
approximately 6 mL of EDS-EP by gravity (approximately 2mL if no
other samples but the ones for sterility culture test will be collected). A
1-mL sterile sample of the EDS-EP will be stored under refrigeration as
a "Retention Sample".
•
Study treatment administration by IV infusion, once all assessments
have been completed.
•
After completion of the IV infusion of the study treatment the following 
assessments will be performed 
•
Physical examination and vital signs 1-2 hr after the end of infusion
•
Blood sample for dexamethasone PK 1 hr after the end of infusion
(Months 2, 4 and 5 only).
•
Assessment of AEs and concomitant medications.
Schedule of Visits and 
Assessments: Months 3, 6, 
9 and 12 
At Months 3, 6, 9 and 12 the following assessments will be performed before 
treatment administration (unless specified otherwise):  
•
Informed consent/assent at Month 6 for patients continuing treatment
•
Physical examination
•
Vital signs
•
Neurological examinations
•
ICARS (video recording required)
•
CGI-S
•
CGI-C
•
VABS
•
EQ-5D-5L
•
C-SSRS
•
ECG
•
Routine laboratory tests on the diverted blood sample
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 10 of 121 
•
Special laboratory tests on the diverted blood sample: HbA1c, CD4+
lymphocytes count, -fetoprotein, CRP, and RBC antibodies (IgG, IgM,
Qualitative Direct Coombs test), only on Months 6 and 12.
•
Mini-ATM detection on the diverted blood sample, only on Month 6.
•
Serum pregnancy test (women of childbearing potential) on the diverted
blood sample, only Month 6 and Month 12.
•
Urine pregnancy test will be performed before every infusion for women
of childbearing potential.
•
Assessment of physical development, sexual maturation, and the effect
of treatment with dexamethasone on these aspects. Tanner staging of the
breasts in pre-menarchal females and of the scrotum in males who have
not completed puberty, will be performed at Months 6 and 12. Post-
menarchal females and males who have completed puberty will be
excluded from this growth analysis.
•
Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total
and conjugated), LDH] (Months 3, 6 and 9 only)
•
Bone mineral density [on Months 6 and 12 only]
•
Assessment of concomitant medications
•
Assessment of AEs
•
Blood sample for dexamethasone PK (Months 3 and 6 only) just before
the infusion
•
Upon completion of the EDS process, fill the satellite sample bag with
approximately 6 mL of EDS-EP by gravity (approximately 2 mL if no
other samples but the ones for sterility culture test will be collected). A
1-mL sterile sample of the EDS-EP will be stored under refrigeration as
a "Retention Sample".
•
Upon completion of the EDS process 5 mL of the EDS from the
EryKit_01 bowl at the end of the process will be collected to assess RBC
osmotic resistance (in selected centers)
•
Study treatment administration by IV infusion, once all assessments
have been completed.
•
After completion of the IV infusion of the study treatment the following 
assessments will be performed: 
•
Physical examination and vital signs 1-2 hr after infusion
•
Blood sample for dexamethasone PK 1 hr after infusion (Month 3 only)
•
Free plasma hemoglobin (1 hr post infusion) (Months 3, 6 and 9 only)
•
Assessment of concomitant medications
•
Assessment of AEs
In case a patient is willing to be enrolled in the open-label study IEDAT-03-2018, 
but the study has not yet received IRB/EC approval at the time the patient reaches 
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 11 of 121 
Visit 15/Month 12, the patient may undergo unscheduled monthly 
assessments/infusions (according to the assigned blinded treatment) starting from 
the time Visit 15/Month 12 should be performed, and continuing until the site has 
been initiated for the open-label study IEDAT-03-2018 and he/she has been 
evaluated for eligibility for the study. 
•
Laboratory tests on the diverted blood sample: serum creatinine
•
Urine pregnancy test will be performed before every infusion (for
women of childbearing potential)
•
C-SSRS
•
Upon completion of the EDS process, fill the satellite sample bag with
approximately 6 mL of EDS-EP by gravity (approximately 2mL if no
other samples but the ones for sterility culture test will be collected). A
1-mL sterile sample of the EDS-EP will be stored under refrigeration as
a "Retention Sample".
•
Study treatment administration by IV infusion, once all assessments
have been completed.
•
After completion of the IV infusion of the study treatment the following 
assessments will be performed: 
•
Physical examination and vital signs 1-2 hr after the end of infusion
•
Assessment of AEs and concomitant medications.
The assessments on Month 12, the last or end-of-study visit (Visit 15), is to be 
performed upon completion of the study or at premature withdrawal from the 
study. 
Safety Follow-up Visit 
All patients who discontinue prematurely or who complete the 12-month 
treatment period, but don’t continue in the open-label study will be required to 
return for a Safety Follow-up Visit (Visit 16) 30 days after their final assessment 
or at least 60 days after their last infusion, whichever is longer. At this visit, the 
A-T NEST will be assessed and the occurrence of any AEs or Serious AEs (SAEs)
reported by the patient/caregiver or observed by the Investigator since the
previous visit will be recorded.
Investigational Medicinal 
Product(s): dose, mode of 
administration, and 
dosing schedule 
The study treatment consists of one of two dose ranges of dexamethasone sodium 
phosphate (DSP) administered via ex vivo encapsulation into autologous 
erythrocytes (EDS), or an infusion of erythrocytes prepared using a placebo 
solution instead of a DSP solution, that are infused into the patient with AT. 
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 12 of 121 
Autologous whole blood (50 ± 5 mL) to be used for the EDS process will be 
collected by peripheral venipuncture into heparinized collection tubes. 
•
Group 1: EDS-EP low dose range of ~5-10 mg DSP/infusion: 
•
Group 2: EDS-EP high dose range of ~14-22 mg DSP/infusion: 
•
Group 3: Placebo: Patients will be treated with autologous erythrocytes
prepared with the EDS process using a placebo solution 
Study treatment will be administered by IV infusion once per month for 12 
consecutive months (6 months initial treatment + 6 months extension treatment; 
additional blinded unscheduled treatments will be performed in case a patient is 
willing to be enrolled in the open-label study IEDAT-03-2018, but the study has 
not yet received IRB/EC approval at the time the patient reaches Visit 15/Month 
12; these unscheduled infusions will be started from the time Visit 15/Month 12 
should be performed, and continuing until the site has been initiated for the open-
label study IEDAT-03-2018 and he/she has been evaluated for eligibility for the 
study). 
 
 
Reference Therapy: 
For patients randomized to the Placebo group, 
 
  
 
 
 
  
Planned Treatment 
Duration per Patient 
The study will consist of a 30-day Screening Period followed by two sequential 
(each one approximately 180-day long) treatment periods, for a total treatment 
duration of approximately 360 days. Patients completing the Initial Treatment 
Period that are doing well on their assigned treatment will have the option of 
continuing treatment in the Extension Treatment Period. One third of patients 
randomized to the Placebo group (Group 3) in the initial period that continue in 
the extension period will continue to receive placebo throughout the treatment 
CCI
CCI
CCI
CCI
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 13 of 121 
period, while one third of the originally randomized placebo group will be 
switched to EDS at the start of the extension period, and another third will be 
switched to EDS after completing 9 months of treatment. All patients who 
complete 12 (or more) months of treatment in the combined Initial and Extension 
Treatment Periods will be eligible for continuing treatment with EDS in a 
12-month, open-label, extension study (Study IEDAT-03-2018). In case a patient
is willing to be enrolled in the open-label-study IEDAT-03-2018, but the study
has not yet received IRB/EC approval at the time the patient reaches Visit
15/Month 
12, 
the 
patient 
may 
undergo 
unscheduled 
monthly
assessments/infusions (according to the assigned blinded treatment) starting from
the time Visit 15/Month 12 should be performed, and continuing until the site has
been initiated for the open-label study IEDAT-03-2018 and he/she has been
evaluated for eligibility for the study.
Statistical Methods 
(including sample size 
calculation) 
Sample Size 
Based on the very low prevalence of AT, as well as the high disability, morbidity 
and mortality, the number of patients available for prospective studies is 
extremely limited.  Furthermore, only aggregate Phase II study results are 
available for the ICARS; no data are available for the ‘Modified’ ICARS. 
Sample size calculations are based on the analysis of the primary efficacy variable 
(i.e., ‘Modified’ ICARS) under the following assumptions.  
•
For aggregate ICARS, a treatment difference of 3.7 - 4.2 for the ~14-22 mg
dose versus placebo with respect to ICARS measurements is expected, with
a standard deviation of 5.0 - 7.4 (IEDAT-ERY01-2010 Clinical Study
Report).
•
For ‘Modified’ ICARS, the treatment difference is expected to be less than
the aggregate ICARS, therefore instead of examining a treatment difference
between 3.7 and 4.2, the range between 3.0 and 3.7 was examined.  The
decrease in treatment difference is expected given that most of the questions
in the Kinetic Function domain are not included in the ‘Modified’ ICARS
and Chessa et al (2014) reported this domain as demonstrating the greatest
overall improvement.
•
For ‘Modified’ ICARS, the standard deviation is expected to be more than
the aggregate ICARS, therefore instead of examining a standard deviation
between 5.0 and 7.4, the range between 5.0 and 8.0 was examined.  This
increase is expected given that removing questions from health assessment
instruments can decrease precision and increase standard deviations (Awad,
2008; McHorney et al, 1992; McHorney, 1997).
•
The primary efficacy variable will be tested, comparing ~14-22 mg dose
versus placebo at the 0.05 two-sided significance level. Testing of the ~5-10
mg dose versus placebo will only proceed if the ~14-22 mg dose is
significant. Consequently, no adjustment for multiplicity is needed for testing
the two dose levels.
Results from a power analysis identified that a sample size of 54 provides 
sufficient power for a study design with two repeated measures to assess the 
primary efficacy endpoint of change from baseline in ‘Modified’ ICARS between 
two groups with a two-sided 0.05 significance level, when the treatment 
difference ranges between 3.0 and 3.7, and the standard deviation ranges between 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 14 of 121 
5.0 and 7.0 (PASS®, Module “Tests for Two Means in a Repeated Measures 
Design”). 
The final sample size will be adjusted for 10% loss to follow-up, for a final sample 
size of 60 per group. It is anticipated that the screen failure rate will be 
approximately 25%; therefore, at least 240 patients would need to be screened to 
enroll 180 eligible patients. Due to the Covid-19 outbreak, the enrollment was 
closed with 175 randomized patients as of the 30th of March 2020. Statistical 
guidance determined that 175 patients (versus the goal of 180 patients) would not 
materially change the power of the study. 
Efficacy Analysis – Initial Treatment Period 
Efficacy analyses will be performed on the Full Analysis Set (defined below). 
The primary efficacy variable, change from baseline in ‘Modified’ ICARS total 
score, will be analyzed using a Mixed Model Repeated Measures (MMRM) 
approach, with the baseline value as covariate and age, treatment, region, baseline 
value and treatment interaction, visit and treatment-by-visit interaction as fixed 
effects. The primary MMRM analysis will assume missing at random (MAR) as 
a means of handling missing data. Sensitivity analyses will be performed to 
evaluate the MAR assumption. These will utilize ANCOVA models with missing 
data imputed using LOCF, OC, and OC + RDO.  
The analysis of the key secondary efficacy measure, CGI-C, will be performed 
using ANCOVA, with age, sex, treatment, region, visit and treatment-by-visit 
interaction as fixed effects. For the primary ANCOVA analysis, missing data will 
be imputed using LOCF. For sensitivity analyses, missing data will be imputed 
using OC and OC + RDO. 
For the other secondary and tertiary efficacy variables, the VABS, CGI-S, and 
QoL (EQ-5D-5L), the change from Baseline to Month 6 in the total score will be 
analyzed using either one of the two approaches described for the primary 
efficacy parameter and key secondary efficacy parameter, as appropriate, for the 
distribution of the variable being analyzed.  
For the CGI-C, the proportion of patients with improvement (scores of 1, 2 or 3), 
vs. those with no change or worsening (scores of 4, 5, 6 or 7), will also be 
compared between groups at Month 6.  
Hierarchical Testing Procedure to Control the Type I Error (FWER). 
The primary endpoint will be tested at the 0.05 two-sided significance level. A 
sequential testing strategy will then proceed as indicated in the flowchart in the 
protocol. As long as a significance test is positive, testing will continue to the next 
indicated test in the sequence.  
Efficacy Analysis – Extension Treatment Period 
For the Extension Treatment Period, the comparisons will be made for the 
‘Modified’ ICARS, CGI-S, VABS, and QoL [EQ-5D-5L] using either one of the 
two approaches for the primary efficacy parameter and key secondary efficacy 
parameter, as appropriate, for the distribution of the variable being analyzed. 
The CGI-C rating at Months 9 and 12 will be analyzed using ANCOVA, and the 
categorical ratings for the CGI-C (any improvement vs. no change or worsening) 
will be analyzed using a Logistic Regression Model with fixed effects for 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 15 of 121 
treatment and country, comparing the two EDS dose ranges (~5-10 and~14-22 
mg DSP/infusion) vs. placebo (as above).  
The blind will be broken after all patients have completed the 6-month, double-
blind, Initial Treatment Period, and the database for this period has been locked, 
so that the primary efficacy analysis can be performed.  Therefore, procedures 
will be implemented to ensure that the blind is maintained for the 6-month, 
double-blind, Extension Treatment Period, so that the analyses of the data 
collected in this extension period are valid (See Section 16.2.8 for details). 
Safety Analysis 
All AEs will be summarized by body system and preferred term and treatment 
group. The incidence (%) of SAEs, AEs that are newly occurring or worsened 
after administration of study medication, and AEs leading to discontinuation 
(ADOs) will also be summarized. The intensity of AEs and relationship to the 
study medication, as assessed by the investigators, will also be presented. Results 
from vital signs, ECGs and laboratory tests, and physical and neurological 
examination findings will be summarized descriptively, with abnormal and 
clinically notable values/findings being identified. The change from baseline to 
endpoint in the C-SSRS will be analyzed using ANCOVA. 
Data Safety Monitoring Board (DSMB) 
An independent Data Safety Monitoring Board (DSMB) will review safety and 
tolerability data from the trial. The DSMB will receive unblinded safety data for 
review at specified intervals and will have the authority to modify or stop the trial 
if significant safety concerns are detected.  
The DSMB will review all of the safety data on an ongoing basis, with special 
emphasis on the incidence and severity of steroid-related events, new infections, 
and serious AEs and deaths, in addition to the standard safety parameters  
Pharmacokinetics (PK) 
A population PK analysis will be performed for dexamethasone administered via 
EDS, based on the pooled data for dexamethasone plasma concentrations from all 
samples obtained from patients in each of the EDS treatment groups. In addition, 
for a sub-group of patients for which >80% of planned samples are collected after 
the first infusion (i.e. at least 5 of 6 post-dose samples are collected through Day 
30 [Month 1]), the following PK parameters will be calculated for each patient, 
based on plasma levels of dexamethasone: Cmax, tmax, AUC, apparent half-life. A 
mean, standard deviation, median, and range (minimum, maximum) for each of 
these parameters will be calculated and compared between the two dose groups 
for EDS.  
Details of the planned PK analyses will be provided in a separate document. 
Analysis Populations 
The following analysis sets will be used: 
1) Intention-to-treat population (ITT): All randomized patients.
2) Full Analysis Set (FAS) (Also referred to as MITT): All 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.
3) Per Protocol Population (PP): All patients enrolled into the study who
received at least one dose of randomized treatment, fulfilled all
Inclusion/Exclusion criteria, did not have any major protocol violations, and

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 16 of 121 
completed the Initial Treatment Period of the study as planned (i.e. returned for a 
final evaluation).  
4) Safety Population (SP): All patients who received at least one dose of
randomized treatment.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 28Apr2016; Version 3.2 (Amend. 3), 
25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 
7.1), Final 13 March 2018, Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 (Amend. 11), Final 24 
Jun 2020 
Page 17 of 121 
Schedule of Visits and Assessments: 6-Month Initial Treatment Period 
Visit (V) (z) Screening 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Study Day or Month (D/M) # D -30 to -1 D0/1 
D2 
D15 
M1 
M2 
M3 
M4 
M5 
M6 (a,b) 
Procedure (§) 
Pre(c) 
Post(c) 
Pre(c) 
Post(c) 
Informed Consent Signature 
X 
Medical History/Demographics 
X 
Inclusion/Exclusion Criteria (v) 
X 
X 
EDS-EP Infusion (h) 
1 
2 
3 
4 
5 
6 
Culture-based sterility test (aa) 
X 
X 
X 
X 
X 
X 
Neurological Examination 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Scale 
X 
X 
Vital Signs (x) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X(d) 
X 
X 
Routine Laboratory Tests (e) 
X 
X(d) 
X 
X 
Serum creatinine 
X(w) 
X(w) 
X(w) 
X(w) 
Bone Mineral Density 
X 
X 
Serum($)/Urine(*) Pregnancy Test (o) 
X($) 
X($,*) 
X(*) 
X(*) 
X(*) 
X(*) 
X(*) 
X($) 
ICARS (with video recording) 
X(n) 
X(n) 
X 
X 
CGI-C 
X 
X 
CGI-S 
X 
X 
X 
X 
VABS 
X 
X 
X 
Quality of Life (EQ-5D-5L) 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
A-T NEST (in selected centers) 
X 
X 
X 
RBC osmotic resistance (t) 
X  
X 
X 
Special Laboratory Tests (m) 
X(f,g) 
X(f) 
X(f) 
Hemolysis Panel (s) 
X 
X 
X 
X 
X 
X 
Genetic AT diagnosis (q) 
X 
Mini-ATM detection 
X 
X 
X 
Dexamethasone PK sample 
X(i) 
X(i) 
X(j) 
X(k) 
X(l) 
X(l) 
X(l) 
X(l) 
X(l) 
X(l) 
X(l) 
EDS end product sample (u) 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Treatments 
Throughout the duration of the study 
Adverse Events 
Throughout the duration of the study 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 28Apr2016; Version 3.2 (Amend. 3), 
25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 
7.1), Final 13 March 2018, Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 (Amend. 11), Final 24 
Jun 2020 
Page 18 of 168 
Schedule of Visits and Assessments: 6-Month Extension Treatment Period 
Visit (V) (z) 
V9 
V10 
V11 
V12 
V13 
V14 
Unscheduled 
Visit (£) 
V15 
V16 
Study Day or Month (D/M) # 
M6 (b) 
M7 
M8 
M9 
M10 
M11 
M12(y) 
Safety 
Procedure (§) 
Pre(c) 
Post(c) 
Pre(c) 
Post(c) 
Follow-up (p) 
Informed Consent Signature 
X 
X 
Re-Randomization (r) 
X 
X 
EDS-EP Infusion (h) 
7 
8 
9 
10 
11 
12 
# 
Culture-based sterility test (aa) 
X 
X 
X 
X 
X 
X 
X 
Neurological Examination 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Scale 
X 
Vital Signs (x) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
Routine Laboratory Tests (e) 
X 
X 
Serum creatinine 
X(w) 
X(w) 
X(w) 
X(w) 
X 
Bone Mineral Density  
X 
Serum($)/Urine(*) Pregnancy Test (o) 
X(*) 
X(*) 
X(*) 
X(*) 
X(*) 
X(*) 
X(*) 
X($) 
ICARS (with video recording) 
X 
X 
CGI-C 
X 
X 
CGI-S 
X 
X 
VABS 
X 
X 
Quality of Life (EQ-5D-5L) 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
A-T NEST (in selected centers) 
X 
X 
X 
RBC osmotic resistance (t) 
X 
X 
Special Laboratory Tests (m) 
X(f) 
Hemolysis Panel (s) 
X 
X 
X 
X 
EDS end product sample (u) 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Treatments 
Throughout the duration of the study 
Adverse Events 
Throughout the duration of the study 
X 
a)
Efficacy evaluations on Month 6 (Visit 9) will be used as the Endpoint assessments for all efficacy measures.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 28Apr2016; Version 3.2 (Amend. 3), 
25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 
7.1), Final 13 March 2018, Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 (Amend. 11), Final 24 
Jun 2020 
 
b) 
Month 6 (Visit 9; Endpoint) evaluations should be performed for all patients that complete the Initial Treatment Period, as well as patients that discontinue prematurely; 
these evaluations will be used as the baseline assessments for the double-blind, Extension Treatment Period.  
c) 
Procedures to be done before (Pre) and after (Post) the EDS-EP infusion. 
d) 
These evaluations will be repeated only if abnormalities requiring follow-up were noted at the Screening evaluation; results from the repeat assessments must be available 
at baseline to confirm eligibility before the patient can be randomized to treatment.  
e) 
Routine laboratory assessments to include complete hematology, biochemistry, and urinalysis. 
f) 
Special laboratory tests include HbA1c, CD4+ lymphocytes count, –fetoprotein (not repeated at baseline), CRP, and RBC antibodies (IgG, IgM, Qualitative Direct 
Coombs test – not repeated at baseline).   
g) 
A sample will be collected before 8:00 AM for measurement of plasma cortisol during the screening period, prior to randomization at baseline. If the basal cortisol level is 
within the reference normal range, the patient can be enrolled in the study. If the 8:00 AM cortisol level is below 3-5 µg/dL (depending on assay) regardless of symptoms, 
or the patient exhibits signs or symptoms of adrenal insufficiency (see Appendix 12) and has a cortisol <10 µg/dL, the patient will receive a high dose ACTH stimulation 
test, regardless of weight, within 24 hours. If the ACTH stimulation test is normal, the patient can be enrolled after the effects of the ACTH have dissipated (e.g., 30 days 
after ACTH administered).  If the patient fails the ACTH stimulation test they will be excluded from the study and referred to a pediatric endocrinologist, with a 
recommendation to prescribe stress dose steroids.  
h) 
Assigned study treatment: Group 1: EDS-EP dose range ~5-10 mg DSP/infusion; Group 2: EDS-EP dose range ~14-22 mg DSP/infusion; and Group 3: placebo. 
i) 
Samples to be collected before infusion (0 min), and 1,and 4 hr after the end of the infusion.  
j) 
Single sample to be collected 24 hr post-infusion (Day 2). 
k) 
Single blood sample to be taken in the morning.  
l) 
Blood samples to be collected prior to (trough) and 1 hour after (peak) the infusion, except in Months 1 (Visit 4) and Months 6 (Visit 9); only trough levels will be collected. 
m) Blood sample to be collected before 8:00 AM for measurement of plasma cortisol at the following times: (1) during the screening period (prior to randomization), (2) when 
patients are symptomatic, and (3) when patients are at most risk for adrenal insufficiency and adrenal crisis, such as following discontinuation or interruptions of 
dexamethasone dosing (i.e., loading failures and following discontinuation of the study drug).   
n) 
Video recording will not be required at the screening visit. The ICARS will be performed twice at Baseline, 24 hours apart (Days 0 and 1); the rating on Day 1 (pre-dose) 
will be used as the baseline value for statistical analyses. ICARS video recording will be required for both the Day 0 and Day 1 (baseline) assessments. 
o) 
For women of childbearing potential only.  The test results must be negative at screening (serum) and baseline (urine) for the patient to be eligible for the study. Urine 
pregnancy test will be performed before every infusion.  
p) 
A Safety Follow-up assessment will be performed 30 days after the final evaluation or at least 60 days after the final infusion, whichever is longer; at this visit, the 
occurrence of any AEs or Serious AEs since the final evaluation will be reported.   
q) 
If the genetic test for AT has not been performed previously, the test will be done by the central laboratory.  For patients who require genetic testing to confirm the diagnosis, 
test results do not need to be available before baseline.   
r) 
Patients originally randomized to placebo will be re-randomized to receive one of the two doses of EDS-EP, with one third of patients being switched at 6 months and 
another third at 9 months.  
s) 
Hemolysis panel: free plasma hemoglobin, haptoglobin, bilirubin (total and conjugated), CBC (Day 2 and 15 only), LDH, and urinalysis (Day 2 and 15 only). On Day 1, 
M3, M6 (b) and M9, only free plasma hemoglobin will be measured, 1 hr post-infusion.  
t) 
RBC osmotic resistance to be measured on a blood sample taken at screening and on a sample from the EryKit_01 bowl at the end of the process in selected centers only.  

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 28Apr2016; Version 3.2 (Amend. 3), 
25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 
7.1), Final 13 March 2018, Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 (Amend. 11), Final 24 
Jun 2020 
 
Page 20 of 168 
u) 
Upon completion of the EDS process, the remaining sample in the satellite sample bag or, if this is not available, a sample collected from another EDS-EP sampling point, 
will be used for determination of DSP content and CBC.  
v) 
Patients meeting all selection criteria at Baseline will be randomized (1:1:1) to one of the three treatment groups.  
w) Blood sample for serum creatinine measurement to be taken before infusion. 
x) 
Vital signs to include height and weight measurements in triplicate at screening, baseline and each monthly visit (pre-dose).  
y) 
Month 12 (Visit 15; Endpoint) evaluations should be performed for all patients that complete the Extension Treatment Period, as well as patients that discontinue 
prematurely. 
z) 
The monthly infusions should be performed every 21-28 days. A window of ± 7 days will be permitted on the Day 15 visit and of + 10 days on each of the scheduled 
monthly post-baseline visits (Months 1 - 12). However, no EDS-EP infusion should be performed less than 21 days after the previous infusion. The window between an 
infusion and the subsequent one should be kept as regular as possible throughout the study, avoiding fluctuations in administration windows. The date of an infusion is not 
bound to the date of the initial treatment but to the date of the previous IMP administration. . 
aa) 1 mL blood collected, after blood diversion, for aerobic culture, before EDS process (see “Revised Study Procedures on Sterility Testing for Study IEDAT-02-2015 
(ATTeST)”; Appendix 13). Moreover, a sample of the EDS-EP (approximately 1 ml per inoculum for a total of 2 mL) will be collected from the satellite sample bag to 
perform a culture-based sterility test.  A 1-mL sterile sample of the EDS-EP will be stored under refrigeration as a "Retention Sample". 
(£)  In case a patient is willing to be enrolled in the open-label study IEDAT-03-2018, but the study has not yet received IRB/EC approval at the time the patient reaches Visit 
15/Month 12, the patient may undergo unscheduled monthly assessments/infusions (according to the assigned blinded treatment) starting from the time Visit 15/Month 12 
should be performed, and continuing until the site has been initiated for the open-label study IEDAT-03-2018 and he/she has been evaluated for eligibility for the study. 
An additional Informed Consent Form must be signed prior to the 1st unscheduled visit/infusion. 
(§) As a results of the COVID-19 pandemic, temporary additional safety assessments may be requested at some visits. These changes are described in Appendix 14. 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
Page 22 of 168 
Signature Pages (cont’d) 
 
 
Investigator 
 
Center No. ____________ 
 
I agree to conduct the clinical trial in accordance with this Protocol and in compliance with Good Clinical 
Practice and all applicable regulatory requirements. 
 
 
 
________________________________________ 
____________________________________ 
Investigator’s Name (Printed) 
Title  
 
 
 
________________________________________ 
____________________________________ 
Signature 
Date of Signature  (dd / mm / yyyy) 
 
 
 
The Sponsor has transferred all responsibilities for the conduct of the trial to the CRO or other designated 
vendors for specific services.  
 
 
 
PPD

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
Page 23 of 168 
3 
TABLE OF CONTENTS 
1 
SYNOPSIS ........................................................................................................................................... 2 
2 
SIGNATURE PAGE .......................................................................................................................... 21 
3 
TABLE OF CONTENTS ................................................................................................................... 23 
4 
ABBREVIATIONS AND DEFINITIONS OF TERMS .................................................................... 26 
5 
TITLE OF STUDY ............................................................................................................................. 29 
6 
PROTOCOL NUMBER ..................................................................................................................... 29 
7 
BACKGROUND AND STUDY RATIONALE ................................................................................ 29 
 
Background Information ............................................................................................................. 29 
 
Overview of the EryDex System (EDS) ......................................................................................... 29 
 
Non-Clinical Trials with EDS ......................................................................................................... 29 
 
Summary of Human Clinical Trials with EDS ............................................................................. 30 
 
Drug Product and Delivery System ............................................................................................. 39 
 
Study Rationale ........................................................................................................................... 40 
8 
STUDY OBJECTIVES ...................................................................................................................... 49 
9 
INVESTIGATIONAL PLAN ............................................................................................................. 50 
 
Study Design ............................................................................................................................... 50 
 
Study Population ......................................................................................................................... 50 
 
Inclusion Criteria ............................................................................................................................ 50 
 
Exclusion Criteria ........................................................................................................................... 51 
 
Documentation of Randomization ............................................................................................... 52 
 
Premature Discontinuation .......................................................................................................... 52 
 
Record of Study Participants and Screening Failures ................................................................. 53 
10 
STUDY MEDICATION ..................................................................................................................... 53 
 
Description, Labeling and Packaging .......................................................................................... 53 
 
Description of the Supplies ............................................................................................................. 53 
 
Packaging ......................................................................................................................................... 54 
 
Labeling ............................................................................................................................................ 54 
 
Dose and Administration ............................................................................................................. 55 
 
Storage ......................................................................................................................................... 56 
 
Blinding and Randomization ....................................................................................................... 56 
 
Accountability ............................................................................................................................. 57 
 
Overdose ...................................................................................................................................... 57 
 
Occupational Safety .................................................................................................................... 57 
11 
Evaluations and Procedures ................................................................................................................ 58 
 
Written Informed Consent ........................................................................................................... 58 
 
Study Conduct ............................................................................................................................. 58 
 
Schedule of Visits and Assessments............................................................................................ 62 
 
Visit Schedule and Assessments – Initial Treatment Period ....................................................... 67 
 
Screening (Days -30 to -1) ............................................................................................................... 67 
 
Day 0/1 (Visit 1): Pre-Infusion (Baseline) ...................................................................................... 68 
 
Day 1 (Visit 1): Post-Infusion ......................................................................................................... 69 
 
Day 2 (Visit 2; 24 hours post-infusion) .......................................................................................... 69 
 
Day 15 (Visit 3) ................................................................................................................................ 69 
 
Day 30 (Month 1; Visit 4) ............................................................................................................... 70 
 
Month 2 (Visit 5) .............................................................................................................................. 70 
 
Month 3 (Visit 6) .............................................................................................................................. 71 
 
Month 4 (Visit 7) .............................................................................................................................. 72 
 
Month 5 (Visit 8) .............................................................................................................................. 73 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
Page 24 of 168 
 
Month 6 (Visit 9; Endpoint Evaluation for Efficacy) ................................................................... 73 
 
Visit Schedule and Assessments – Extension Treatment Period ................................................. 74 
 
Month 6 (Visit 9) .............................................................................................................................. 74 
 
Months 7, 8, 10 and 11 (Visits 10, 11, 13 and 14) .......................................................................... 75 
 
Month 9 (Visit 12) ............................................................................................................................ 75 
 
Unscheduled Visit(s) ........................................................................................................................ 77 
 
Month 12 (Visit 15; Final Visit) ...................................................................................................... 77 
 
Safety Follow-up Visit (Visit 16) .................................................................................................... 78 
 
Visit Windows .................................................................................................................................. 78 
 
Laboratory Sample Collection ..................................................................................................... 78 
 
Measurement of Dexamethasone Sodium Phosphate and Other Analytes in Infusion Bag Sample
 
80 
 
Concomitant Medications ............................................................................................................ 81 
12 
EFFICACY EVALUATIONS ............................................................................................................ 83 
 
ICARS ......................................................................................................................................... 83 
 
Description of the ICARS ............................................................................................................... 83 
 
Validity of ICARS in AT Patient Population ................................................................................ 83 
 
Standardization of Ratings and Use of Central Remote Rater ................................................... 84 
 
Clinical Global Impression (CGI-C and CGI-S) ......................................................................... 84 
 
Vineland Adaptive Behaviors Scale (VABS) .............................................................................. 85 
 
Quality of Life Scale ................................................................................................................... 85 
 
Rater Requirements and Training ................................................................................................ 86 
 
Order of Test Performance .......................................................................................................... 86 
 
Exploratory Efficacy Measure ..................................................................................................... 86 
 
A-T NEST ........................................................................................................................................ 86 
13 
SAFETY EVALUATIONS ................................................................................................................ 88 
 
Physical and Neurological Examinations .................................................................................... 88 
 
Vital Signs ................................................................................................................................... 88 
 
Electrocardiogram (ECG) ............................................................................................................ 89 
 
Standard Laboratory Evaluations and Screening Tests ............................................................... 89 
 
Special Laboratory Evaluations ................................................................................................... 91 
 
Sterility Testing of EDS-EP ........................................................................................................ 92 
 
Columbia Suicide Severity Rating Scale (C-SSRS) .................................................................... 92 
 
Bone Mineral Density (BMD) ..................................................................................................... 93 
 
Tanner Staging ............................................................................................................................ 93 
14 
REPORTING SAFETY INFORMATION ......................................................................................... 94 
 
Adverse Events ............................................................................................................................ 94 
 
Glossary ............................................................................................................................................ 94 
 
Data Collection ................................................................................................................................ 95 
 
Subject Follow-up ............................................................................................................................ 97 
 
Reporting Serious Adverse Events (SAEs) .................................................................................... 97 
 
Safety Reporting to Investigators, IRBs/IECs, and Regulatory Authorities ............................... 98 
 
Reporting Overdose ..................................................................................................................... 98 
 
Pregnancy .................................................................................................................................... 98 
 
Breaking the Study Blind by the Investigator ............................................................................. 99 
 
Independent Data Safety Monitoring Board ................................................................................ 99 
15 
SUBJECT COMPLETION AND DISCONTINUATION ............................................................... 100 
 
Definitions ................................................................................................................................. 100 
 
Procedures for Handling Withdrawals ...................................................................................... 100 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
Page 25 of 168 
16 
STATISTICAL METHODS ............................................................................................................. 102 
 
Analysis of Efficacy .................................................................................................................. 102 
 
Statistical Methods .................................................................................................................... 102 
 
Sample Size .................................................................................................................................... 102 
 
Populations for Analysis ............................................................................................................... 104 
 
Background and Demographic Characteristics.......................................................................... 104 
 
Study Medication .......................................................................................................................... 104 
 
Concomitant Medications and Therapy ...................................................................................... 104 
 
Safety Evaluations ......................................................................................................................... 104 
 
Efficacy Analyses ........................................................................................................................... 105 
 
Randomization ............................................................................................................................... 106 
17 
ETHICS ............................................................................................................................................ 112 
 
Ethical Considerations ............................................................................................................... 112 
 
IEC/IRB Approval ..................................................................................................................... 112 
18 
ADMINISTRATIVE CONSIDERATIONS .................................................................................... 113 
 
Regulatory Requirements: Sponsor/Investigator Obligations ................................................... 113 
 
Curriculum Vitae ....................................................................................................................... 113 
 
Investigator and Study Administrative Structure ...................................................................... 113 
 
Investigator’s Statement ............................................................................................................ 113 
 
Monitoring Procedures .............................................................................................................. 113 
 
Study Monitoring .......................................................................................................................... 113 
 
Case Report Forms (CRFs) .......................................................................................................... 114 
 
Auditing/Inspecting ....................................................................................................................... 114 
 
Archiving of Records ................................................................................................................ 114 
 
Final Clinical Study Report ....................................................................................................... 114 
 
Study Documentation and Publication of Results ..................................................................... 115 
 
Financial Agreement ................................................................................................................. 115 
 Termination of Study ................................................................................................................. 116 
 
Study Discontinuation by the Sponsor ........................................................................................ 116 
 
Study Discontinuation by the Investigator .................................................................................. 116 
 Insurance Policy ........................................................................................................................ 116 
 Financial Disclosure .................................................................................................................. 116 
19 
REFERENCES ................................................................................................................................. 118 
APPENDICES ........................................................................................................................................... 122 
Appendix 1: Declaration of Helsinki ................................................................................................. 122 
Appendix 2: ICH GCP - Investigator’s Responsibilities ................................................................. 128 
Appendix 3: Investigator Statement .................................................................................................. 134 
Appendix 4: Clinically Notable Values ............................................................................................. 136 
Appendix 5: Description of the EryDex System (EDS) .................................................................... 140 
Appendix 6: Sample Study Solution and Medication Labels .......................................................... 147 
Appendix 7: Encapsulation Procedure Checklist............................................................................. 152 
Appendix 8: Method for Measuring Dexamethasone Sodium Phosphate in Samples Taken from 
Satellite Sample Bag or any other EDS-EP Sampling Point ........................................................... 158 
Appendix 9: Procedure for Collection of Blood Samples for Laboratory Measurement of Free 
Plasma Hemoglobin (Hemolysis Panel) ............................................................................................. 159 
Appendix 10: 14-day sterility test using a culture-based method – Sampling procedure ............ 160 
Appendix 11: Action Plan in Case of Positive Post-Release Sterility Test Results........................ 162 
Appendix 12: Signs and Symptoms of Adrenal Insufficiency .............................................................. 164 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 26 of 121 
Appendix 13: Aseptic procedures for prevention of contamination of EDS-EP sterility samples
…………………………………………………………………………………………………...165 
Appendix 14: Temporary changes to the Protocol implemented/to be implemented as a result of 
COVID-19 pandemic……………………………………………………………………………………166 
4 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACTH 
Adrenocorticotropic hormone 
AEs 
Adverse Events 
ALT (SGPT) 
Alanine-aminotransferase 
ANOVA 
Analysis of Variance 
ANCOVA 
Analysis of Covariance 
AST (SGOT) 
Aspartic-aminotransferase 
AT 
Ataxia Telangiectasia 
ATM 
Ataxia Telangiectasia Mutated 
A-T NEST
Ataxia-Telangiectasia Neurological Examination Scale Toolkit 
ATP 
Adenosine triphosphate 
AUC 
Area under the plasma drug concentration vs. time curve 
BARS 
Brief Ataxia Rating Scale 
BMD 
Bone mineral density 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
CD4+ lymphocytes 
Cluster differential 4 positive lymphocytes 
CGI-S / CGI-C 
Clinical Global Impression of Severity / Change 
CF 
Cystic fibrosis 
Cmax 
Maximum plasma drug concentration after dosing 
CNS 
Central Nervous System 
COPD 
Chronic obstructive pulmonary disease 
CPK 
Creatine phosphokinase 
51Cr 
Chromium-51 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
CYP3A4 
Cytochrome P450 3A4 
D 
Day 
2,3-DPG 
2,3-Diphosphoglyceric acid 
DSP 
Dexamethasone sodium phosphate 
ECG 
Electrocardiogram 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 27 of 121 
EDS 
EryDex System 
EDS-EP 
EryDex System end product 
EIA 
Enzyme immunoassay 
EP 
Evaluable Population 
EQ-5D-3L 
EuroQol 5D Three-level version 
EQ-5D-5L 
EuroQol 5D Five-level version 
ESI-MS 
Electrospray mass spectrometry 
FAS 
Full Analysis Set 
FSI 
First Subject In 
FWER 
Family-wise error rate 
G6PD 
Glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
SGOT (AST) 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT (ALT) 
Serum Glutamic-Pyruvic Transaminase 
HbA1c 
Blood glycosylated haemoglobin 
Hct 
Hematocrit 
HDL 
High density lipoprotein 
Hb 
Hemoglobin 
HbA1c 
Blood glycosylated hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPLC 
High Performance Liquid Chromatography 
hr 
Hour 
IBD 
Inflammatory bowel disease 
ICARS 
International Cooperative Ataxia Rating Scale 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICSH 
International Committee for Standardization in Hematology 
IEC 
Independent Ethics Committee 
IMP 
Investigation Medicinal Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intention-to-Treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
IU 
International Unit 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LOCF 
Last observation carried forward 
LSI 
Last Subject In 
LSLV 
Last Subject Last Visit 
M 
Month 
MAO 
Monoamine oxidase 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 28 of 121 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
µCi 
Microcuries 
mCi 
Millicuries 
min 
Minute 
mmHg 
Millimeters of mercury (blood pressure) 
MMRM 
Mixed Model Repeated Measures 
mICARS 
Modified version of the International Cooperative Ataxia Rating 
Scale excluding oculomotor items (17-19) and items 8-12 
NSAID 
Non-steroidal anti-inflammatory drug 
OC 
Observed cases 
OTC 
Over-the-counter 
pBAR 
Probabilistic baseline randomization 
PK 
Pharmacokinetic(s) 
RBCs 
Red Blood Cells 
RCL 
Red Cell Loader 
RDO 
Retrieved Dropout 
RDW 
Red blood cell distribution width 
RMANOVA 
Repeated Measures Analysis of Variance 
RT 
Room Temperature 
SAEs 
Serious Adverse Events 
SARA 
Scale for Assessment of Rating of Ataxia 
SD 
Standard Deviation 
SNRI 
Serotonin-norepinephrine reuptake inhibitor 
SOPs 
Standard Operating Procedures 
SP 
Safety Population 
SSRI 
Selective serotonin reuptake inhibitor 
t1/2 
Half-life 
T50 
Time to disappearance of 50% of the labelled red blood cells from 
the circulation 
99mTc 
Technetium-99m 
TCA 
Tricyclic antidepressant 
TEAEs 
Treatment Emergent Adverse Events 
tmax 
Time to maximum plasma concentration after dosing 
ULN 
Upper limit of normal 
WBC 
White Blood Cells 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
5 
TITLE OF STUDY 
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 
6 
PROTOCOL NUMBER 
This study is being conducted under Protocol No. IEDAT-02-2015. 
7 
BACKGROUND AND STUDY RATIONALE 
Background Information 
Overview of the 
 System (EDS) 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-Clinical Trials with EDS 
Pharmacokinetics is the only characteristic of the drug product (dexamethasone sodium phosphate; DSP) 
pharmacology that differs from that obtained with the ordinary routes of administration (oral, intravenous, 
intramuscular, etc.) due to the novel method of administration by ex vivo encapsulation of the drug into 
human autologous red blood cells which are then infused.  The pharmacokinetics of the drug product in 
humans was evaluated in clinical trials.  It is not possible to study the pharmacokinetics in animal models 
Page 29 of 121
CCI
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 30 of 121
because the dephosphorylation rate of the pro-drug, DSP, to the diffusible active drug, dexamethasone, in 
human RBCs is very different from RBC dephosphorylation rates in other species (Zocchi et al, 1991).   
Summary of Human Clinical Trials with EDS 
A total of 209 subjects have received at least one dose of EDS-EP. Of these, 115 participated in Investigator-
initiated and 89 in Sponsor-initiated studies. A total of 1827 EDS-EP infusions have been administered; 
366 of these infusions were performed in the 89 patients enrolled in Sponsor-initiated studies. Twenty-two 
patients with AT were administered 344 EDS-EP infusions in a phase II study (IEDAT-01-2010) and in 
subsequent compassionate use.   
Table 1 below lists the trials performed to date, the indication, the number of subjects, the doses 
administered, the treatment duration, and key safety findings. 
Table 1. Summary of Clinical Studies Conducted to Date Using EDS-EP 
EryDel 
Study # 
Indication 
# of 
unique 
subjects 
Range of 
doses (mg 
DSP) 
Infusions 
Key safety findings 
References 
# 
Frequency 
Investigator-initiated Studies 
01 
Chronic 
obstructive 
pulmonary 
disease 
(COPD) 
10 
0.78-8.78 
2 
Q 15 days 
None reported in publication 
Rossi et al. 
2001 
02 
Cystic 
Fibrosis 
17 
1.2-14.5 
3-24
Q 21 days 
or monthly 
None reported in publication 
Rossi et al. 
2004 
02 
Extension 
Cystic 
Fibrosis 
17 
1.2-14.5 
24 
Q 21 days 
or monthly 
None reported in publication 
Extension 
study: 
Lucidi et al. 
2006 
03 
IBD 
(Ulcerative 
Colitis & 
Crohn’s 
Disease) 
10 
1.1-10.9 
3 
Monthly 
Fever (n=1 [10%]) 
Annese et al. 
2005 
04 
Crohn’s 
Disease 
1 
1.0-21.8 
36 
Monthly 
None reported in publication 
Castro et al. 
2006 
05 
Crohn’s 
Disease 
18 
2.4-14.7 
24 
Monthly 
Dropouts: n=2 (11%; non–
compliance with protocol)  
Castro et al. 
2007 
06 
Ulcerative 
Colitis 
20 
5.0-24.0 
2 
Every 14 
days 
None reported in publication 
Bossa et al. 
2008 
07 
Cystic 
Fibrosis 
5 
1.0-21.8 
34 
monthly 
None reported 
Data on file: 
EryDel SpA 
08 
COPD 
15 
1.0-21.8 
36 
every 28 ± 
5 days 
None reported 
Data on file: 
EryDel SpA 
09 
Ulcerative 
colitis 
19 
9.9±4.1* 
6 
monthly 
None reported in publication 
Bossa et al. 
2013 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 31 of 121
EryDel 
Study # 
Indication 
# of 
unique 
subjects 
Range of 
doses (mg 
DSP) 
Infusions 
Key safety findings 
References 
# 
Frequency 
Sponsor-initiated Studies 
10 
IBD 
(Ulcerative 
Colitis & 
Crohn’s 
Disease) 
Total: 33 
EryDex: 
21 
Placebo: 
12 
1.0-21.8 
3 
or 
6 
15 days, 
30 days 
Premature terminations: 
- Total: 10/33 (30.3%)
- EryDex: 6/21 (28.6%)
- Placebo: 4/12 (33.3%)
Adverse Dropouts: None
Lack of efficacy: 6 (EryDex – 4
[19.0%]; Placebo – 2 [16.7%])’
Lost to Follow-up: EryDex – 3
(14.3%); Placebo - 0
Poor compliance: EryDex – 1
(4.8%); Placebo - 0
SAE: Placebo – 1 (8.3%) – acute
pancreatitis (hospitalization) 
Any AE: EryDex - 11 (53.4%); 
Placebo - 8 (66.7%) 
Most frequent AEs: GI Disorders 
(EryDex – 28.6%; Placebo- 50%); 
Metabolism & Nutrition 
Disorders (EryDex –23.8%; 
Placebo - 0%) 
Cro.Co.Dex 
Clinical Study 
Report 
(Data on file: 
EryDel SpA) 
11 
Crohn’s 
Disease 
EryDex: 
28; 
Placebo: 
23 
1.0-21.8; 
5±2.8* 
12 
Monthly 
Premature terminations:  
- Total: 44/51 (86.3%)
- EryDex: 23/28 (82.1%)
- Placebo: 21/23 (91.3%)
Adverse Dropouts –3
Intestinal occlusion – 2 (EryDex),
abdominal hernia complications -
1 (Placebo)
Lack of efficacy – 22 (EryDex –
13 [56.5%]; Placebo – 16
[76.2%])
Premature termination of trial by
Sponsor – 7
Protocol violation – 1
Administrative withdrawal - 2
Death: Placebo - 1(Traffic
accident after end of study).
SAEs: 10
- EryDex – 6: Crohn’s relapse(2),
GI haemorrhage, intestinal
obstruction, sub-ileus, spinal
fracture;
- Placebo – 4: sub-ileus(3),
septicaemia staph
CRODEX-01 
Clinical Study 
Report 
(Data on file: 
EryDel SpA) 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
EryDel 
Study # 
Indication 
# of 
unique 
subjects 
Range of 
doses (mg 
DSP) 
Infusions 
Key safety findings 
References 
# 
Frequency 
12 
(IEDAT
-ERY01
-2010)
Ataxia-
Telangiec-
tasia 
EryDex: 
22 
0.7 – 18.6 
6 
Monthly 
Premature terminations: 4 (18%) 
- Withdrawal of consent (1);
- AE (lab abnormality - 2);
- Protocol violation (1)
SAEs: 2 (9%); pneumonia and
bronchiectasis; both considered
not related to study drug;
Most frequent AEs (>10% ):
Otitis (3), Cough (3),
Fever (3), Flu syndrome (3)
IEDAT-
ERY01-2010 
Clinical Study 
Report 
(Data on file: 
EryDel SpA) 
13 
(IED-
PK01-
2013) 
Healthy 
volunteers 
18 
(9/group) 
Group 1: 
3.28-5.73; 
4.2±0.27** 
Group 2: 
14.44-
21.28; 
16.9±0.9** 
1 
once 
Premature terminations: 2(11.1%) 
- Withdrawal of consent (1);
- Lost to follow-up (1).
SAEs: none.
AEs requiring treatment:
abdominal discomfort (1), GI pain
(1), gingival pain (1).
IED-PK01-
2013 Clinical 
Study Report 
(Data on file: 
EryDel SpA) 
14 
(Ery51
Cr-01-
2014) 
Healthy 
volunteers 
10 
(5/group) 
Group 1: 
12.0-16.2; 
14.6±2.0** 
Group 2: 
Sham 
1 
once 
Premature terminations: none 
SAEs: none 
Most frequent AEs: 
- Headache (Group 1: 2 of 5;
Group 2: 3 of 5) 
Other: No clinically meaningful 
changes in  routine laboratory 
tests, hemolysis panel, ECG, vital 
signs or physical exam 
Ery51Cr-01-
2014 Clinical 
Study Report 
(Data on file: 
EryDel SpA) 
Abbreviations: COPD, chronic obstructive pulmonary disease; IBD, inflammatory bowel disease; 
*mean ± standard deviation; **mean ± standard error of the mean
A total of 1827 EDS-EP infusions of EDS-EP have been administered to the subjects in these studies, and 
no toxicity related to RBCs processed for dexamethasone dosing has been observed. These include 51 
pediatric patients (< 18 years) suffering from cystic fibrosis (n=11), Crohn’s disease (n=19) or AT (n=22, 
one patient was 19 years of age at inclusion); some of these patients have been exposed to EDS for up 36 
months. There was no consistent pattern of dexamethasone-related adverse findings reported in these 
pediatric populations.  
Additional detailed information on pre-clinical and clinical studies evaluating the EDS can be found in the 
current version of the Investigator’s Brochure. 
7.1.3.1 
Clinical Study IEDAT-ERY01-2010: Pilot Proof of Concept Phase II Trial in Patients with Ataxia 
Telangiectasia [Chessa et al, 2014] 
Title: Evaluation of Effects of Intra-Erythrocyte Dexamethasone Sodium Phosphate on Neurological 
Symptoms in Ataxia-Telangiectasia Patients  
Study Design and Patient Population 
This was a single-arm, open-label, 6-month, Phase II study to assess the effect of the EryDex System end 
product (EDS-EP; dexamethasone sodium phosphate [DSP] encapsulated in autologous erythrocytes by the 
EDS process) on neurological symptoms of patients with Ataxia Telangiectasia (AT) enrolled in two centers 
in Italy. Males and females, > 3 years of age, with neurological signs of AT (un-coordination of the head 
Page 32 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
and eyes in lateral gaze deflection, gait ataxia associated with an inappropriately narrow base), an 
autonomous gait (or helped by support), and a genetic diagnosis of AT (at least one ATM mutation) and/or 
ATM protein deficiency by Western blot, were included. Patients with low CD4+ lymphocytes counts, 
current/previous neoplastic disease, history of severe impairment of the immunological system, chronic 
conditions representing a contraindication to the use of steroid drugs, or any other significant disease that 
could have put the patient at risk were excluded. Females of childbearing potential that were pregnant, 
breastfeeding or not using adequate contraception were also excluded. Eligible patients could not have 
participated in a trial with another investigational agent within 30 days of the start of the Screening Period, 
and must have discontinued prior steroid medication at least 30 days before the first dose of EDS-EP.  
Objectives 
The primary objective of the trial was to evaluate the effect of EDS-EP in improving neurological symptoms 
of AT patients over a 6-month treatment period, assessed by means of the ICARS (Trouillas et al., 1997). 
The ICARS is a 100-point semi-quantitative scale offering a compartmentalized quantification of the 
following 4 sub-scores: Posture and gait disturbances, kinetic functions, speech disorders, and oculomotor 
disorders. The ICARS rating was performed by a trained neurologist at baseline (before the first dose) and 
at 1, 3 and 6 months after the first EDS-EP administration; analysis of the change from baseline at each visit 
was performed on the ITT population using Repeated Measures Analysis of Variance (RMANOVA). 
Secondary objectives of the trial were to evaluate the safety profile of EDS-EP through the assessment of 
TEAEs, including steroid-dependent adverse reactions, SAEs, standard laboratory parameters, physical 
examination, vital signs, ECGs and concomitant medications and procedures.  Additionally, the effects of 
EDS-EP were assessed on the patients’ global health status (IGA), ocular motility, and adaptive behaviour 
(VABS). The effect of EDS-EP on special laboratory parameters, i.e. total cholesterol, HDL, LDL, blood 
glycosylated hemoglobin (HbA1c), CD4+ lymphocytes counts, α-fetoprotein, urinary cortisol and plasma 
cortisol, was also measured. 
Methods 
Patients providing informed consent (along with consent of their parents or legal guardian, as required) 
entered a 30-day screening period, during which any prior corticosteroid treatment was withdrawn. 
Medical history and demographic information was collected, and physical and neurological 
examinations, vital signs, ECG and standard laboratory tests were performed. Patients meeting all 
selection criteria were enrolled in the treatment period and had the physical examination, vital signs 
and laboratory tests repeated and all efficacy evaluations performed at baseline (Day 0) prior to receiving 
the first of 6 monthly infusions of EDS-EP. The amount of DSP added to the 50 mL of the subject’s blood 
in the encapsulation procedure was kept constant for all patients, i.e. 500 mg/20 mL DSP solution, 
and was expected to deliver approximately 10-15 mg of DSP by using the previous EDS version 3.1.2 over 
the one-month period between doses.  
A physical examination, vital signs and routine laboratory tests were performed at each monthly visit. 
The primary efficacy measure (ICARS) was assessed at one month, and at the 3-month visit, all efficacy 
assessments were done, along with the special laboratory tests (before drug infusion). A final evaluation 
was performed at 6 months after the initial infusion (one month after the last dose), during which all 
efficacy and safety assessments were performed. The occurrence of any AEs and the use of concomitant 
medication were recorded from the time of signing of the consent form until the end of the study. 
Blood samples for the PK analysis were collected from selected patients prior to dosing (0 hr), and at 4 
hours and 15 and 30 days post-dose for the first and fourth infusions. 
Page 33 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Disposition 
A total of 26 patients with AT were screened and 22 were enrolled in the study, representing the ITT 
population.  Four subjects discontinued prematurely; one withdrew consent, another patient was dropped 
due to a protocol violation (CD+4 lymphocytes below cut-off at baseline), and 2 patients experienced 
laboratory abnormalities (decrease in CD4+ lymphocytes count) that led to their withdrawal.   
Demographics and Disease Characteristics 
The mean (SD) age of the AT patients was 11.2 (3.5) years, with 11 (50%) patients being males. All patients 
were Caucasian with a mean weight of 29.1 (9.5) kg and BMI of 15.6 (2.6). The average age of diagnosis 
of AT was 60.0 (35.2) months, with a mean age of symptom onset of 25.9 (17.5) months. The mean baseline 
scores for the ICARS and VABS were 50.6 (12.8) and 5.5 (2.0), respectively. Mean baseline scores on the 
sub-scales of the ICARS were as follows: posture/gait disturbance – 20.9 (7.1); kinetic function – 23.1 (6.2); 
speech disorders – 3.5 (1.4); and oculomotor disorders – 3.2 (1.0). Two patients were on inhalational 
steroids at screening, and these medications were discontinued.  
Efficacy Results 
Sixteen patients (72.7%) received all 6 infusions of EDS-EP, as planned. Results for the primary efficacy 
measure (change from total baseline ICARS score) for the ITT population (n=22) indicated an overall 
statistically significant (p=0.02, RMANOVA) improvement with EDS-EP treatment. Significant 
improvement was observed after 3 and 6 months of treatment with EDS-EP for the kinetic sub-score of the 
ICARS, the clinician rated the Investigator Global Assessment (IGA), adaptive behavior (as assessed by the 
VABS) and ocular motility.  
Secondary analyses. The mean DSP dose/infusion was 7.5±1.8 mg. There was however, substantial 
variability in the patient-specific DSP encapsulation in erythrocytes, with mean doses of DSP measured in 
the EDS-EP for each subject ranging from 0.7±0.1 to 18.6±1.9 mg (patients received 6 doses). Additional 
analyses were performed to determine if there was a relationship between DSP dose and efficacy response. 
In these analyses, patients were categorized as “loaders” if their mean DSP dose was 5 mg or higher. Loaders 
(64%) as compared to non-loaders (27%) showed a clinically significant improvement on the ICARS 
(defined as > 10% improvement versus baseline) at 6 months. Loaders had a mean percent decrease 
(improvement relative to baseline) of -14.4% for the ICARS total score, compared to -4.7% for non-loaders. 
Safety Results 
The safety population included all 22 patients. Overall, 15 (68.2%) of patients experienced at total of 29 
TEAEs, most of which were rated as mild (~60% of subjects) and not related to the study medication (> 
90% of patients), with the exception of 1 patient with a mild hypercholesterolemia. Two SAEs were reported 
during the study, including one case of severe pneumonia and a second patient with bronchopneumonia, 
and bronchiectasis and bleeding; both patients required hospitalisation. Both cases were considered 
unrelated to study medication and resolved with treatment. 
Two patients had a > 20% decrease in CD4+ lymphocytes count during the study period which resulted in 
premature discontinuation, and were considered related to study medication. 
There were no clinically meaningful changes in mean values for routine laboratory parameters with EDS-
EP treatment, except for serum iron, which showed a > 20% mean decrease from baseline value, with 8 
patients having newly occurring abnormal (low) values at the final visit (one reported as a TEAE). For the 
special laboratory parameters, no clinically meaningful changes were observed, except for urinary cortisol, 
which showed an approximately 30% decrease from baseline to the final visit (statistically significant, 
Page 34 of 121

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
p=0.016). Although this could indicate an effect of EDS-EP on the hypothalamo-pituitary-adrenal axis, a 
comparison of blood and urinary cortisol levels versus dose did not indicate any relationship. No clinically 
significant changes with EDS-EP treatment were observed for vital signs, ECGs, or physical examination 
findings. 
Conclusions 
In this open-label study in AT patients > 3 years of age, EDS-EP treatment for 6 months led to a statistically 
significant improvement in the primary efficacy measure, the ICARS, which assesses key symptoms of the 
disease. Additional statistically significant benefits of EDS treatment were noted in the Kinetic Function 
sub-scale of the ICARS, IGA, adaptive behavior (VABS), and ocular motility (ad hoc scale). EDS-EP was 
generally well tolerated in this subject population, with only two patients discontinuing prematurely due to 
adverse events. Two patients experienced serious adverse events related to pulmonary infections; most AEs 
were mild in intensity and considered unrelated to study medication. 
Laboratory findings indicated a low serum iron levels in approximately one third of patients and a mean 
reduction in urinary cortisol, which did not appear to be related to the dose administered. 
The level of DSP loading indicated variability in RBC encapsulation across patients. Almost half of the 
patients had mean DSP dose of less than 5 mg, whereas a DSP dose between 10-15 mg was targeted. The 
variability was caused by sub-optimal encapsulation conditions associated with the use of EDS process 
version 3.1.2 used in this study. Future studies will use the EDS process version 3.2.0 that has demonstrated 
increased loading and reduced variability in encapsulation. 
Pilot observation that higher DSP load appears to be associated with improved response of the ICARS has 
led the Sponsor to target higher DSP doses in future efficacy studies. 
7.1.3.2 
Clinical Study IED-PK01-2013 
Title: Pharmacokinetic Study to Measure Plasma Concentrations of Dexamethasone following EryDex 
(Dexamethasone Sodium Phosphate Encapsulated in Autologous Erythrocytes) Infusion in Healthy 
Volunteers 
Study Design, Subject Population and Methodology 
This Phase 1, open-label, single-center (US), uncontrolled study was performed to characterize the 
pharmacokinetic (PK) properties of two planned doses (Group 1: ~ 2.5 to 5 mg; Group 2: ~ 15 to 20 mg) of 
EDS end product (DSP encapsulated in erythrocytes), when administered as a single infusion to 18 (9 in 
each group) healthy male and non-fecund female volunteers, using a new version of the EDS process 
(version 3.2.0) to load the subject’s erythrocytes with DSP. The study also evaluated the safety and 
tolerability of the 2 different dose ranges based on treatment-emergent adverse events (TEAEs), serious 
AEs (SAEs), laboratory parameters, vital signs, ECGs and physical/ neurological examination findings, 
with the safety of the lower dose (Group 1) being assessed before proceeding to the higher dose (Group 2). 
Subjects were followed for 42 days after EDS end product infusion, with blood samples being taken just 
prior to dosing (0 min) and at 15 and 30 minutes, at 1, 2, 4, 8, 12 and 24 hours, and at 3, 7, 14, 21, 28, 35 
and 42 days post-infusion for measurement of plasma dexamethasone, using a validated HPLC-ESI-MS 
method, and determination of PK parameters. A follow-up evaluation was performed 84 days post-infusion. 
Disposition, Demographics and Doses Administered 
Forty-five subjects were screened, and 18 eligible subjects were enrolled (9/group) and received EDS end 
product. Six subjects in each group were male, and other demographic characteristics were similar 
between 
Page 35 of 121
 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 36 of 168 
groups. Of the 18 subjects treated with study drug, 2 (11.1%) subjects discontinued from the study prior to 
study completion: one withdrew consent (Group 1) and the other was lost to follow-up (Group 2).  
The mean (±SEM) actual DSP doses were 4.2±0.27 (range: 3.28–5.73) and 16.9±0.90 (range: 14.44–21.28) 
mg DSP for Groups 1 and 2, respectively. In Group 1 the actual DSP dose administered was within the 
target range of 2.5 to 5 mg in 7 of 9 subjects (2 subjects had loaded doses above 5 mg), while in Group 2, 
the target range of 15 to 20 mg was achieved by 4 of the 9 subjects (3 subjects had loaded doses below 15 
mg, and 2 had doses above 20 mg). 
Pharmacokinetic Results 
One subject in Group 2 missed more than 20% of the PK blood samples; therefore, 9 subjects in Group 1 
and 8 subjects in Group 2 were included in the Per Protocol dataset used for the PK analyses.  Most of the 
dexamethasone was rapidly released from the RBCs with a maximum peak occurring approximately 1 hr 
after the end of the IV infusion, independently of the dose administered. The Cmax for dexamethasone was 
approximately 26 ng/mL and 135 ng/mL for Group 1 and Group 2 EDS end product, respectively. 
Dexamethasone release from the erythrocytes could be detected until 14 and 35 days after the single IV 
infusion of EDS end product in Groups 1 and 2, respectively.  
A dose-relationship was observed for dexamethasone elimination, with a longer terminal elimination half-
life for Group 2 (T½el ~ 4.5 day) when compared to Group 1 (T½el ~0.85 day). This difference in the 
aforementioned terminal half-life estimates could be due to a difference in detectable dexamethasone levels 
in Group 2 and 1, respectively. The Cmax and AUC of dexamethasone measured for the actual dosing range 
of 3.3 mg to 21.3 mg DSP encapsulated in RBCs were in proportion marginally higher than the levels 
expected based on the dose. 
Safety Results 
Adverse events. There were no SAEs, or discontinuations due to AEs in either group. Five of 9 (55.6%) 
subjects in Group 1 reported a total of 5 TEAEs, all of mild intensity. In Group 2, 5 subjects (55.6%) 
reported a total of 6 TEAEs, 4 of mild and 3 of moderate intensity. Two subjects had TEAEs that required 
drug treatment, one with abdominal discomfort (treated with an antacid) and the other with gastrointestinal 
pain (treated with anti-gas agent) and gingival pain (treated with analgesics). All of the TEAEs resolved 
without any sequelae. No Group 1 subjects received a concomitant medication during the study and only 
two Group 2 subjects received one or more concomitant medications for their TEAEs (abdominal 
discomfort, gingival pain, and gastrointestinal pain). 
Standard laboratory tests. A number of small but statistically significant transient changes in hematological 
(absolute eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, RBC count, MCH, neutrophils, 
platelet, and WBC count) and biochemical (AST, creatine phosphokinase, CO2, creatinine, glucose, 
cholesterol, potassium, sodium, LDH, HDL and BUN) parameters associated with DSP administration were 
observed. Sporadic abnormal values (high/low) were noted for some of the laboratory hematology and 
biochemistry parameters at Day 2 and/or the final visit (Day 42); however, none of these were considered 
to be clinically significant. No meaningful changes from baseline were observed in any urinalysis parameter 
throughout the study. Both increases and decreases compared to baseline were observed for laboratory 
analytes in Groups 1 and 2, without any consistent pattern of change.   
Other laboratory tests. Serum cortisol levels were significantly reduced up to the 48-hour time point in 
Group 1, while in Group 2 a significant decrease in serum cortisol levels was observed through the 7-day 
time point and at Day 42, but not at Day 14. Urinary cortisol showed no significant reduction at any time 
point. 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-
specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, Version 
8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
All 9 patients in each of the treatment groups had normal RBC osmotic resistance values at NaCl 
concentrations from 0.55% up to 0.85% on Day 1 before the EDS process. The majority of the patients 
had normal RBC osmotic resistance values at NaCl concentrations between 0.30% and 0.50%; 
however, 4 patients (2 in Group I and 2 in Group II) showed a pattern of decreased lysis while one subject 
had a pattern of borderline increase. Results for RBC osmotic resistance for the sample taken from the 
infusion bag, following the EDS process, confirmed a pattern of decreased lysis at the 0.40%-0.50% 
concentration range in 3 (1 in Group I and 2 in Group II) out of 4 patients that had this pattern before the 
procedure. All other patients exhibited RBC osmotic fragility within the normal range.  
Free hemoglobin values were above normal (high) on Day 1 (prior to infusion) in 4 of 9 patients in Group 
1 and in 6 of 9 patients in Group 2. The mean value for free hemoglobin before infusion in the 9 patients 
in Group 1 was 6.79 mg/dL (median 5.30 mg/dL) with a maximum subject value of 12.60 mg/dL, and 
the mean value for the 9 patients in Group 2 was 23.62 mg/dL (median 16.20 mg/dL) with a maximum 
subject value of 76.00 mg/dL. Free hemoglobin was detected sporadically also after infusion during this 
trial.  
Analysis of plasma samples (taken for PK determination) indicated the presence of free hemoglobin in 
samples at baseline prior to the EDS end product infusion. The presence of free plasma hemoglobin may 
have resulted from the blood drawing technique used to collect the samples (e.g., use of IV catheter with a 
22-gauge needle). Analysis of urine samples for hemoglobin, bilirubin, urobilinogen, urine clarity and 
color did not detect any pattern suggestive of hemoglobinuria or associated findings in any subject.
Other safety parameters. Abnormalities in vital signs that were reported as TEAEs included a mild 
increase in diastolic blood pressure (DBP) on the day of study drug infusion, two reports of mild 
‘orthostatic tachycardia’ on the day of dosing, and mildly rapid heartbeat/palpitations; all resolved 
without sequelae. Small statistically significant mean changes (p <0.05) were observed for systolic blood 
pressure, diastolic blood pressure and pulse rate, primarily at early time-points (Days 2 and 3), in both 
groups, but did not indicate any pattern of adverse change.  No statistically significant mean changes 
from Baseline were observed at any time point for supine respiratory rate, body temperature measures or 
body weight. 
The overall interpretation of the ECG did not indicate any adverse cardiac effects of EDS-EP treatment, as 
no newly occurring abnormalities were observed post-baseline.  In addition, no statistically significant 
changes in any ECG parameter were noted at Day 42.  One physical examination finding was reported 
(Day 42) as a TEAE (mild severity right eye upper lid inflammation that was not considered to be 
clinically significant by the Investigator), and one subject had a new abnormality in reflexes 
reported on the neurological examination (Day 42).
7.1.3.3 
Clinical Study Ery51Cr-01-2014 
Title: Determination of the In Vivo Recovery and Survival of EryDex (Dexamethasone Sodium Phosphate 
Encapsulated in Autologous Erythrocytes) in Non-patient Volunteer Subjects 
Study Design and Methodology 
This was a randomized, single-blind, single-center, concurrently controlled, exploratory, Phase I study to 
determine the in vivo kinetics (24-hour post-infusion recovery and T50 survival) of EDS-processed 
autologous RBCs in non-patient volunteers. RBCs were radiolabeled with Chromium-51 (51Cr) for the in 
vivo kinetic study. In addition, the in vitro characteristics of the RBCs processed using the EDS were 
determined using a standard panel of RBC assays [pH at 37C, hemolysis, ATP, 2,3-DPG, extracellular 
potassium, extracellular glucose, extracellular lactate, packed cell volume, RBC morphology, complete 
blood count (CBC)] and a hemolysis panel was assessed immediately prior to the infusion, and 1 h and 24 
h after completion of infusion.  Safety assessments included monitoring for adverse events (AEs), routine 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
laboratory tests (hematology, biochemistry, urinalysis), vital signs, physical examinations, ECG 
evaluations, serum pregnancy testing for fecund women, and documentation of concomitant medications.  
Eligible subjects who provided informed consent underwent a screening period of up to 30 days prior to 
receiving a single IV infusion of EDS followed by a 49-day follow-up period. A series of blood samples 
were collected over the first 24 hours from each subject for the measurement of 24-hour recovery of radio-
labelled RBCs; additional samples were taken at 48, and 72 hours and 7 days post-infusion, and weekly 
thereafter through 49 days post-infusion.  
A total of 10 non-patient volunteer subjects meeting all selection criteria were enrolled and randomly 
assigned (1:1) to one of the 2 treatment groups (n=5 each): 
•
Group 1 - Active Drug Arm: 5 mL of dexamethasone sodium phosphate (DSP) solution (25
mg/mL) mixed with 11 mL of water for injection is added to the concentrated RBCs.
•
Group 2 - Sham Arm: 5 mL of Hypotonic Solution 2 (sham of the 5 mL of Drug) plus 11 mL of
Water for injection is added to the concentrated RBCs.
All subjects received the study treatment and completed the 49-day follow-up period.  
Results  
The study has been completed in the field, and the final results are summarized below. 
RBC Recovery and Survival 
The results for the mean RBC recovery for Group 1 (77.9%) indicate that DSP-loaded EDS-processed cells 
met the FDA criteria for 24-hour RBC recovery ≥ 75% (Dumont and AuBuchon, 2008). The mean life span 
(MLS) of EDS-processed RBCs in Group 1 was 84.3 days with a mean T50 (α/2) of 42.1 days, while these 
values were 88.9 days and 44.4 days, respectively, in Group 2. These data suggest that there is no adverse 
impact on the survival of EDS-processed cells based on a comparison with published results for RBCs used 
for transfusion. 
In vitro characteristics of EDS-processed RBCs 
Results suggest that RBCs maintain normal ATP-dependent metabolic and biochemical functions after 
completion of the EDS process. The alterations induced by the EDS process in the characteristics of the 
RBCs, e.g. MCV, total hemoglobin, hematocrit, MCHC, MCH, platelets and WBC count, do not impact 
their recovery and survival in the circulation. The quantity of EDS-processed RBCs (roughly 10 mL) that 
are infused with the EDS-EP constitutes less than 1% of the total RBCs in circulation; therefore, changes 
in these cells do not have an impact on the vital functions of the blood. The only purpose of this small 
fraction of EDS-processed RBCs is to transport DSP (and not to carry oxygen, as is the function of RBCs 
for transfusion) and release it into the circulation over 30 days. 
Summary of Safety Data 
No consistent pattern of changes of a magnitude that led to values that were abnormal, or were deemed 
clinically notable, was detected in subjects receiving EDS-processed erythrocytes containing DSP or saline 
for measures evaluating a pre-specified hemolysis panel of tests, or other routine laboratory hematology, 
biochemistry, and urinalysis parameters. Similarly, there was no evidence of a systematic effect on vital 
signs, weight, or ECGs, and no pattern of adverse events was detected with the trial treatments. There were 
no discontinuations due to AEs, serious adverse events (SAE), or AEs rated severe or unexpected.  
Page 38 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
 
 
 
 
 
 
 
  
Study Rationale 
Study IEDAT-02-2015 is an international, multi-center, one-year, randomized, double-blind, placebo-
controlled, Phase III study to assess the effect of two non-overlapping dose ranges of EDS-EP on 
neurological symptoms of patients with AT. The primary efficacy endpoint will be at the 6-month 
assessment.  Patients completing the initial 6-month treatment period will be eligible to continue treatment 
in a 6-month, double-blind, placebo-controlled extension performed to evaluate long-term safety and 
provide preliminary evidence of a long-term effect on symptoms of AT.  
Rationale for Using the EDS in Treating AT Patients 
AT is considered a rare disease by the Office of Rare Diseases of the National Institutes of Health (US), as 
well as by Orphanet, the consortium of European partners. There is no marketed drug approved to treat AT, 
and there is no treatment available that slows down or stops the progression of AT patients to early 
debilitating disability and mortality. Symptomatic, preventive, and supportive management of the key 
disabilities and symptoms of the disease has provided limited benefit. Immune deficiencies are managed by 
administration of immunoglobulins, and infections are managed by both preventive and symptomatic use 
of antibiotics. Developmental deficiencies are managed by physical therapies, education, or targeted 
treatments (Hoche et al, 2012). 
Neurological degeneration is the major contributor to the severe outcome of the disease. The progression 
of the neurologic problems is currently unstoppable. Anti-parkinson and antiepileptic drugs provide limited 
benefit in the management of extrapyramidal symptoms. The serendipitous discovery of the benefit of short-
term betamethasone in a patient with AT (Buoni et al, 2006), and further pilot, uncontrolled, short–term 
treatment trials in small numbers of patients have suggested that betamethasone at doses of 0.03 mg/kg, but 
not 0.01 mg/kg, given for a short period has beneficial effects on the neurological impairment of AT patients 
(Russo et al, 2009; Broccoletti et al, 2008). Treatment discontinuation in these studies was accompanied by 
the reappearance of symptoms, suggesting that long-term administration may be required to preserve the 
benefit.  
These early findings with administration of betamethasone prompted the search for steroids that could be 
given at low plasma concentrations for an extended period of time without the associated steroid-like 
effects. The EDS, consisting of dexamethasone sodium phosphate (DSP) encapsulated in autologous 
erythrocytes, allows the administration of dexamethasone at low plasma concentrations that are associated 
with approximately 80-85% occupation of the glucocorticoid receptor (GR), similar to the GR occupancy 
that occurs with the betamethasone plasma concentrations reported by Broccoletti et al, 2011. The EDS 
provides the benefit of low and constant plasma delivery of dexamethasone without the associated steroid 
side effects, despite long-term use in the pediatric population (Rossi et al, 2001; Lucidi et al, 2006; Annese 
et al, 2005; Bossa et al, 2008; Castro et al, 2007).  
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
The mechanism of action of glucocorticoids in producing the benefits observed in A-T patients was 
postulated to occur through regulation of expression of corticosteroid-responsive genes, suppression of 
inflammatory cytokines, or its effect as an antioxidant (Russo L. et al., 2009). Recently, an effect of 
dexamethasone on ATM (Ataxia Telangiectasia Mutated) gene splicing in an AT lymphoblastoid cell line, 
leading to production of a new active ATM protein variant, has been demonstrated (Menotta M. et al., 
2012). This may explain in part the beneficial effect of treatment with glucocorticoid analogues in AT 
patients. The results show, for the first time in mammalian cells, a short direct repeat-mediated non-
canonical splicing event induced by dexamethasone that leads to the skipping of mutations upstream of 
nucleotide residue 8450 of ATM Coding DNA Sequence (CDS). 
A pilot, open-label, 6-month study was performed with EDS-EP in AT patients (Chessa et al, 2014). In this 
study, statistically significant (p=0.02; RMANOVA) improvement (reduction) in the ICARS score from 
baseline to endpoint (~4 points; ITT population; n=22) was observed. The decision to initiate the current 
double-blind, placebo-controlled study in AT patients was based on the results from this pilot study, as well 
as the other evidence of the benefit of steroids in treating the disease, as described above.   
Rationale for the Patient Population 
The selection criteria for the proposed confirmatory trial have been based on the cardinal symptoms of 
ataxia telangiectasia (AT), the limitations posed by the natural history of the disease, the identification of 
neurological symptoms that may respond to therapy, prior experience gained through a Phase II European 
study, and feedback from AT experts in Europe (Universities of Rome and Brescia), Israel (Sheba Medical 
Center, Tel Aviv), and the US (Johns Hopkins University, Baltimore, MD). A brief description of the 
important features of AT is provided prior to discussing the selection criteria. 
Ataxia telangiectasia (AT) is a rare inherited autosomal recessive, multisystem disorder, characterized by 
the following: progressive neurologic disease, including cerebellar ataxia and oculomotor apraxia; 
cutaneous and ocular telangiectasia (90%); increased alpha-feto-protein levels (95%); reduced or absent 
IgA levels (70%) and ATM protein (98%); increased susceptibility to chronic nasal and pulmonary 
infections (70%); delayed organ maturation; and increased susceptibility to X-rays and malignancies 
(Hoche et al, 2012). In countries where marriage between cousins is uncommon, such as in the U.S., the 
incidence of AT is about 1 in 40,000 live births. However, among ethnic groups where cousin-cousin 
marriages are common, the incidence increases significantly. The carrier frequency is approximately 1 in 
100 persons (https://www.ataxia.org/pdf/Ataxia%20Telangiectasia.pdf). The estimated prevalence in 
Europe is 1 in 100,000 population (Orphanet. 2014). Ataxia telangiectasia is due to mutations in the ATM 
gene located on human chromosome 11 (11q22.3). These defects in the ATM gene reduce or eliminate the 
function of the ATM protein that controls cell division and is involved in double-strand DNA repair (Lee 
and McKinnon, 2000; Boehrs et al, 2007), thus leading to repeated infections and malignancies.  
The onset of symptoms becomes evident in early childhood when children demonstrate unsteadiness while 
walking, or swaying when standing still or sitting. Most children with AT have stable neurologic symptoms 
for the first 4 to 5 years of life, but begin to show increasing problems in early school years. Oculomotor 
apraxia, slurred speech, and difficulties in swallowing appear in late pre-school and early school age 
children. AT patients are unable to control their muscles by the time they are 10 to 12 years of age, and this 
may lead to problems with fine motor functions (writing, coloring, and using utensils to eat), and slurring 
of speech (dysarthria) that usually stop progressing after the age of about 12 to 15 years. Most AT patients 
are restricted to wheelchair use for ambulation around this age. Involuntary movements such as tremors, 
myoclonic jerks, dystonia, chorea, athetosis, etc., are variable in the age of onset and rate of progression. 
(Boder, 1985; Perlman et al, 2003; Chun and Gatti, 2004) The immune system becomes progressively 
weaker, and recurrent respiratory infections and blood cancers are noted in late-stage patients. There is 
high 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
variability in life-expectancy; however, most patients die around the age of 25 years, largely due to chronic 
lung disease or malignancies. (Poupard, 2003; Crawford et al, 2006) 
The key selection criteria for the current study in AT patients are based on selecting patients demonstrating 
the cardinal features of the disease, but devoid of findings that may expose them to high risk of morbidity 
and/or mortality. The study will include males and females, 6 years of age and older, with neurological 
signs of AT (in-coordination of the head and eyes in lateral gaze deflection, gait ataxia associated with an 
inappropriately narrow base) who have a proven molecular diagnosis of AT (at least one ATM mutation) 
and/or ATM protein deficiency by Western blot. Patients must have an autonomous gait or be helped by a 
support (i.e. local ICARS score for Item 1 – Walking Capacities between 0 and 4, included).  Additionally, 
patients must have a body weight > 15 kg, and CD4+ lymphocytes count of >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). .
The lower age-limit has been increased to 6 years (the completed Phase 2 study used 3 years) to ensure that 
patients can provide assent. The lower age limit of 6 years was also chosen to ensure the patients have a 
confirmed diagnosis of AT based on neurological findings and are able to comply with the requirements of 
the study, e.g. multiple blood samples. The neurological signs listed as the requirement allow a clinical 
diagnosis of AT. A diagnosis of AT will be confirmed based on genetic tests; however, these test results do 
not need to be available at baseline prior to randomizing a patient. The principal efficacy measure, the 
ICARS, assesses neurological signs including gait. Patients who are in wheelchairs cannot be assessed for 
the effect on gait, a significant component of the treatable symptoms of AT.  
Children with AT may have a lower body weight compared to age-matched controls; therefore, the 
minimum weight requirement was lowered to 15 kg. CD4+ lymphocyte counts have been included to assess 
the immune status of these patients as the ATM gene compromises their ability to combat infections. CD4+ 
lymphocyte cut-off limits have been proposed stratified by age as recommended by AT experts. Patients 
whose counts are consistently below 150/mm3 (for patients > 6 years), or below 200/mm3 (for patients > 6 
years and in presence of oral infections, like oral candidiasis, documented at the screening or recurrent as 
per medical history/adverse events documentation) or below 400/mm3 (for patients 6 years of age) during 
treatment will have their treatment interrupted.  
The exclusion criteria for the study are designed to exclude patients who would be at increased risk for an 
adverse outcome related to treatment with EDS-EP or their participation in the trial due to their medical 
history/current status or use of concomitant medication. Dexamethasone has teratogenic potential in 
rodents; therefore, females of childbearing potential will be included only in case they are practicing 
adequate contraception as described at section 9.2.2. Pregnant women will be excluded. Dexamethasone is 
excreted in breast milk; therefore, patients who are breast-feeding are also excluded. Patients with AT are 
at increased risk of neoplastic and immunological diseases due to the decreased ability of the ATM gene to 
repair DNA; therefore, patients with these conditions are excluded. Patients who are currently on steroids 
or have taken them within the last month, are excluded, as their effects may confound the assessment of the 
efficacy and safety of EDS-EP. 
Rationale for the Study Design 
Double-blind Design 
The double-blind design is being used to minimize the systematic bias in ratings of efficacy that may result 
from the rater, patient or caregiver knowing the treatment that the patient is receiving. The double-blind 
design also minimizes bias in assessing the potential relationship of safety findings to the study 
treatments.  
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Use of a Placebo Control 
The study will evaluate two doses of EDS-EP, compared to placebo, in the treatment of patients with AT.  
Currently, there is no approved treatment for AT; therefore, no active control has been included in the study.  
Patients with AT have a progressive disease course with fluctuating symptoms; therefore, the use of a 
placebo control group is needed to define the course of the illness in ‘untreated’ patients receiving the usual 
standard of care. The placebo control will allow testing of the null hypothesis and provide a statistically 
valid assessment of the effects of EDS-EP treatment.  
The initial double-blind, placebo-controlled treatment period will last for 6 months, with patients having a 
1 in 3 chance of being randomized to placebo. After the initial 6-month treatment period, one third of the 
patients in the Placebo group will be randomized (1:1) to receive treatment with one of the two EDS-EP 
doses (Group 1: ~5-10 mg DSP/infusion; Group 2: ~14-22 mg DSP/infusion).  At Month 9, one third of the 
placebo group will be randomly switched to EDS-EP, as above, while the remaining patients will continue 
to receive double-blind treatment with placebo for the remainder of the extension period. The randomization 
of the placebo group in a 1:1:1 fashion to be switched to EDS-EP at 6 or 9 months or remain on placebo 
throughout the extension treatment period will be done at baseline to avoid bias. This procedure will 
minimize the number of patients remaining on placebo for one year, while still providing placebo data for 
up to one year for comparison with EDS-EP group in the evaluation of long-term safety and efficacy.  All 
placebo-treated patients will be eligible to start open-label treatment with EDS-EP at the one-year time-
point, provided they have completed the visits at 6, 9 and 12 months (or more), meet entry criteria and 
provide informed consent/assent for the open-label, extension study (Study IEDAT-03-2018). In case a 
patient is willing to be enrolled in the open-label study IEDAT-03-2018, but the study has not yet received 
IRB/EC approval at the time the patient reaches Visit 15/Month 12, the patient may undergo unscheduled 
monthly assessments/infusions (according to the assigned blinded treatment) starting from the time Visit 
15/Month 12 should be performed, and continuing until the site has been initiated for the open-label study 
IEDAT-03-2018 and he/she has been evaluated for eligibility for the study. This design allows all placebo-
treated patients the opportunity to be treated with the active drug, while still maintaining a small number of 
patients on placebo for up to 12 months to facilitate collection of placebo-controlled data for analysis of 
long-term efficacy and safety.  The optional open-label extension study will allow patients who are doing 
well to continue treatment with EDS as long as their physician determines they are benefitting from it and 
not experiencing any adverse effects that would necessitate discontinuation of treatment. 
Minimization Procedure to Equalize Randomization by Gender, Age, and Region 
Ataxia telangiectasia is a progressive illness, with symptoms worsening over time (Crawford et al, 2000). 
Therefore, to decrease potential heterogeneity among treatment groups in baseline symptomatology related 
to differences between groups in the number of younger and older patients, as well as by gender (symptoms 
of the disease and disease course may differ between males and females) and geographical region, 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.  
Primary Efficacy Endpoint at 6 Months 
The primary efficacy endpoint (‘Modified’ ICARS total score change from baseline) will be assessed at 
Visit 9 (Month 6 or at early discontinuation), at the end of the initial double-blind, placebo-controlled 
treatment period.  At this point in the study, the patient would have received 6 monthly infusion of EDS-
EP (~5-10 or ~14-22 mg DSP/infusion) or placebo.  In a previous open-label pilot study in AT patients, 
statistically significant improvement from baseline in the ICARS score was noted at the 6-month time-
point 
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Clinical Study Protocol IEDAT-02-2015 
EDS in Ataxia Telangiectasia Patie
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
following 6 monthly infusions of EDS.  It is anticipated that similar results will be observed following 6 
months of treatment in this double-blind, placebo-controlled trial. The 6-month endpoint was selected as it 
represents an adequate amount of time to assess an effect on a neurodegenerative disorder (e.g. Alzheimer’s 
disease; Parkinson’s disease).   
Open-label Treatment 
The option to continue open-label treatment with EDS in a separate study (Study IEDAT-03-2018) will be 
available to all patients who complete 12 months (or more) of double-blind treatment, and have assessments 
at 6, 9 and 12 months (Visits 9, 12 and 15), including those patients originally randomized to placebo.  All 
patients will receive the high dose range of EDS-EP (~14-22 mg DSP/infusion).  The Investigator will 
assess the patients at the 12-month time-point (Visit 15), to ensure that there are no safety concerns that 
would preclude the patient from continuing treatment with EDS-EP. Infusions will be performed on a 
monthly basis during the open-label extension treatment phase, and assessments of safety and efficacy will 
be done at regular intervals. In case a patient is willing to be enrolled in the open-label study IEDAT-03-
2018, but the study has not yet received IRB/EC approval at the time the patient reaches Visit 15/Month 12, 
the patient may undergo unscheduled monthly assessments/infusions (according to the assigned blinded 
treatment) starting from the time Visit 15/Month 12 should be performed, and continuing until the site has 
been initiated for the open-label study IEDAT-03-2018 and he/she has been evaluated for eligibility for the 
study. 
Rationale for EDS Doses 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
 
 
 
  
 
 
 
 
   
Rationale for Efficacy Measures 
The efficacy measures for this trial were selected based on feedback from Regulatory Authorities. The 
efficacy measures to be used in the study are described below.  
International Cooperative Ataxia Rating Scale (ICARS) 
The ICARS will be used to measure efficacy in the study. The internal consistency, criterion-related 
validity, and internal construct validity of the ICARS have been established in patients with focal cerebellar 
lesions (Schoch B et al, 2007). The inter-rater reliability, test-retest reliability and internal consistency have 
also been validated in patients with spinocerebellar ataxia (Weyer et al, 2007, Schmitz-Hubsch et al , 
2006a). The ICARS total score satisfied all psychometric criteria in a validation study in patients with 
Friedrich’s Ataxia (Cano et al, 2005; Metz et al 2013) The ICARS has been used as an outcome measure in 
interventional studies in patients with ataxia, but there are no clinical data to suggest the magnitude of 
change on the ICARS that would correspond to a clinically relevant improvement, due to the absence of 
any drug producing such a benefit. The ICARS has been used in several studies in patients with Friedreich’s 
Ataxia over the age of 8 years, in phase 3 potentially pivotal trials (Lynch et al, 2010), as well as in open-
label long-term studies (Meier et al, 2012).  
The ICARS was used also in two interventional studies in children with AT.  Zanolli et al, 2012 showed a 
statistically significant decrease in the ICARS total score in a placebo-controlled crossover study in 13 
children with AT treated with oral betamethasone (Zannolli et al, 2012). Nissenkorn et al, using ICARS as 
a secondary endpoint, showed improvement in the static and kinetic subscales in a short-term open-label 
study in 17 children (from 4 years of age) treated with amantadine (Nissenkorn et al, 2013).  
Incoordination of eye movements, nystagmus and loss in saccadic eye movement control is observed early 
in the AT disease process (Hoche et al, 2012). The ICARS items relating to ocular motility do not provide 
a comprehensive assessment of this domain.  Also, no scale has been validated for the measurement of 
ocular motility in AT patients. The investigator will be asked to assess the ocular motility item based on the 
site’s clinical paradigm and the instructions for rating the ICARS.  
As AT is a severe, relentlessly progressive disorder that leads to loss of independent movement in most 
patients by the age of 10 to16 years, any statistically significant difference from placebo over a 6-month 
period should be considered as a treatment success.  
Most of the developmental and validation studies of the ICARS were performed in patients who were 10 
years of age or older. An international study has been completed (ClinicalTrials.gov: NCT01942850) to 
extend its validity to patients in the age-range of 5 to10 years. Data collected from this validation study in 
selected centers [Data on file, EryDel S.p.A] indicated that the distribution of scores for the ICARS for 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
Page 46 of 168 
patients with AT under 10 years of age was similar to the scores for these patients on other validated scales 
such as the SARA (Schmitz-Hubsch et al, 2006b) and the BARS (Schmahmann et al, 2009). Data collected 
from the validation study in selected centers confirmed that the severity of AT increased with age in patients 
under the age of 10 years, as demonstrated by a significant correlation of the total scores on the ICARS, 
SARA, and the BARS, but not for patients above 10 years.  Overall, the distribution of scores for the ICARS 
for 5 to 10 year-old patients with AT was similar to the scores for other validated scales such as the SARA, 
BARS, CGI-S and CGI unstructured.  
The variability associated with having multiple centers across different countries and languages, and 
multiple raters for the ICARS within each center, will be minimized by the use of central remote raters who 
will provide ratings of the ICARS based on video recordings of the patients’ ICARS assessments performed 
by the site raters. These videos will be provided to the remote rater blinded to the treatment condition and 
in random order, without specifying the visit of the study. These remote ratings will be used in the analysis 
of the primary efficacy endpoint.  
Although the ICARS will be rated in its entirety, the primary analyses will be limited to the ‘Modified’ 
ICARS; this version excludes Items 8-12 related to kinetic function and Items 17-19 related to oculomotor 
functions that are required for visual control, as these items are not directly predictive of change in 
functioning.  
CGI-C and CGI-S 
The Clinical Global Impression (CGI) consists of two 7-point, clinician-rated, Likert-type scales assessing 
change from baseline (CGI-C) and severity of illness (CGI-S) (Guy, 1976). In the current study, an overall 
assessment of the change in the patient’s neurological symptoms of AT, compared to the status at baseline, 
will be performed at each visit and used as the key secondary efficacy measure. To ensure independence of 
this rating from the rating of the ICARS (the primary efficacy measure), a different rater will perform the 
CGI-C.   
In addition, the severity of illness at baseline and at each subsequent timepoint will be assessed using the 
CGI-S. No version of the CGI-S exists which has been specifically adapted for use in AT patients; therefore, 
a 5-point structured version was developed which takes into account the severity of the following symptoms 
of AT: ataxia (walking), dysarthria, dysmetria, extrapyramidal symptoms (chorea, myoclonus, dystonia, 
and tremor), and eye movements.  Ratings of none, mild, moderate, severe, and very severe are selected 
based on the level of symptomatology. A pilot validation study has been performed in AT patients using 
the CGI-S scale, and the results indicate that the CGI–S adequately discriminated patients with mild, 
moderate, or severe disease [Data on file, EryDel S.p.A.]. The distribution of patients to different scores on 
the CGI-S of AT was similar using the ICARS, BARS, and SARA in 6 to 9 year-olds. The CGI-S for 
patients ≥10 years of age was greater than in 6 to 9 year-old patients; however, the distribution of scores on 
the ICARS, BARS, and SARA was similar across severity categories. 
Vineland Adaptive Behaviors Scale (VABS) 
Functional intelligence generally is defined as one's ability to behave adaptively in daily life. Specifically, 
it includes the person's ability to express and comprehend language, behave appropriately in interpersonal 
situations, understand and use social behaviors, protect himself/herself, and care for himself/herself, in 
terms of personal hygiene and domestic independence. Although several scales and observation systems for 
measuring adaptive behavior have been developed since the 1940s, when the construct of adaptive behavior 
was formally introduced, one of the most widely accepted scales is the Vineland Adaptive Behavior Rating 
Scales (VABS; Sparrow and Cicchetti, 1985; Sparrow et al, 2005).   

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
The VABS is used primarily with children and adolescents from birth to age 18 years, but may be used for 
adults suspected of having a mental handicap based on obtained IQ. The scale measures adaptive behavior 
in four major domains, Communication, Daily Living Skills, Socialization, and Motor Skills. These 
domains include several subdomains, as follows:  
•
Communication: Receptive, Expressive, Written
•
Daily Living Skills: Domestic, Personal, Community
•
Socialization: Interpersonal Relationships, Play & Leisure, Coping Skills
•
Motor Skills: Gross, Fine
In the current study, this scale will be used to assess the strengths and weaknesses of the AT patients in each 
of these specific areas of adaptive behavior which may be impacted by the disease.   
QoL Scale (EQ-5D-5L) 
Improvements in quality of life (QoL) are an important goal for treatment of patients with AT.  Therefore, 
the EQ-5D-5L scale assessing QoL has been included as a secondary efficacy measure. The EQ-5D is a 
standardized instrument for assessing health-related QoL in a variety of health conditions (Rabin and de 
Charro, 2001). The EQ-5D-5L is a newer version of the scale, which includes five levels of severity for 
each of the five EQ-5D dimensions (Herdman et al, 2011), and has been validated in a diverse patient 
population in 6 coutries, including 8 patient groups with chronic conditions and a student cohort (Janssen 
et al, 2013). For children and adolescents, the EQ-5D-5L administrators will be trained to help the younger 
population in the study complete the scale.  Assessment of the EQ-5D-5L will be performed by the patient, 
or the patient’s parent/caregiver, at regular intervals throughout the study. 
A-T NEST
The A-T NEST represents a refinement of the A-T scale published by Crawford et al. (2000)17 that was 
developed to quantitatively describe the diverse range of abnormalities seen in patients with A-T and record 
their rate of progression. The development of the A-T scale was based on data collected from 52 patients 
with confirmed A-T attending the Johns Hopkins Hospital, who were between the ages of 1 to 19 years. 
Based on agreements on the ratings of video-taped examinations between 2 highly experienced raters, and 
the use of a weighted kappa score, principal component analysis, 9 items were selected; 2 items were 
dropped due to poor inter-rater agreements, and replaced by 3 other items. The final 10 items capture the 
essential neurologic features of the disorder.  
The A-T NEST index offers advantages over other scales used to assess A-T as it was developed specifically 
for this disorder and thus, captures the broad range of deficits experienced by these patients. The index may 
be able to capture progression of the disorder faithfully. The A-T NEST scale has been used internationally 
over the last decade by A-T clinical experts, as part of the Ataxia Telangiectasia Children’s Project (ATCP), 
who have made further changes and recommendations for its use internationally.  
The inter-rater reliability, test-retest reliability and internal consistency have not been validated 
concurrently in large number of patients with A-T from multiple countries with a wide variety of raters. The 
ability of the A-T NEST to assess treatment-induced change has also not been determined, and there are no 
clinical data to suggest the magnitude of change on the A-T NEST that would constitute a clinically relevant 
change. 
The use of the A-T NEST in this Study would allow collection of data for the validation of psychometric 
properties of the scale, from experienced international raters. It would also allow determination of its intra 
Page 47 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 48 of 121 
and inter-rater reliability, based on the data from the CGI-S of A-T and the ICARS, and concordance of A-
T NEST scores with these validated scales. Lastly, the study would help assess if the A-T NEST possesses 
treatment sensitivity.  

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 49 of 121 
8 
STUDY OBJECTIVES 
Initial Treatment Period (6 months) 
Primary Efficacy Objective: 
•
Efficacy: To evaluate the effect of two dose ranges (~5-10 and ~14-22 mg DSP/infusion) of EryDex
System end product [EDS-EP; the EDS is a combination product that is used to load dexamethasone
sodium phosphate (DSP) into autologous erythrocytes, creating the EDS end product, which is infused
into the patient], compared to placebo, on central nervous system (CNS) symptoms measured by the
‘Modified’ International Cooperative Ataxia Rating Scale (ICARS) in patients with ataxia
telangiectasia (AT).
Key Secondary Efficacy Objective: 
•
To evaluate the effect of EDS-EP, compared to placebo, in this population on the Clinical Global
Impression of Change from baseline (CGI-C).
Safety Objective: 
•
To evaluate the safety and tolerability of EDS-EP, compared to placebo, in AT patients, based on the
occurrence of Treatment-Emergent Adverse Events (TEAEs), including Serious AEs and
discontinuations due to AEs, and changes in vital signs, laboratory parameters, ECGs and
physical/neurological examination findings.
Secondary Efficacy Objectives: 
•
To evaluate the effect of EDS-EP, compared to placebo, in this population on the following efficacy
measures:
o
Clinical Global Impression of Severity (CGI-S) of neurological symptoms of AT;
o
Adaptive behavior measured by the Vineland Adaptive Behavior Scales (VABS).
Tertiary Objectives: 
•
To evaluate the effect of EDS-EP on health-related QoL using the EQ-5D-5L scale;
•
To assess the pharmacokinetic and pharmacodynamic relationships between dexamethasone
administered through EDS-EP and safety, tolerability, and demographic variables.
•
To evaluate the pharmacokinetic (PK) profile of dexamethasone administered through EDS-EP at two
dose 
levels 
based 
on 
pooled 
data 
from 
all 
patients 
in 
each 
treatment 
group.
A determination of individual PK parameters will be performed for patients with an adequate number
of PK blood samples after the initial infusion.
Exploratory Objective: 
•
To collect data on the use of the A-T NEST concurrent with the ICARS, CGI-S and CGI-C, as well as
its use in languages other than English, and compare it with the data from the scales referenced to assess
the psychometric properties of the A-T NEST.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 50 of 121 
Extension Treatment Period (6 months) 
Primary Objective: 
•
To evaluate the efficacy of two dose ranges (~5-10 and ~14-22 mg DSP/infusion) of EDS-EP, compared
to placebo,  in treating CNS symptoms in AT patients during long-term treatment (up to 12 months), as
measured by the ‘Modified’ ICARS.
Secondary Objectives: 
•
To evaluate the long-term (up to 12 months) safety and tolerability of EDS-EP in AT patients;
•
To compare the effects of the two dose ranges of EDS-EP on the clinician’s global impression (CGI-C
and CGI-S), adaptive behavior (VABS), and QoL (EQ-5D-5L scale).
9 
INVESTIGATIONAL PLAN 
Study Design 
This is an international (North America, Europe, Africa, Asia, and Australia), multi-center, one-year, 
randomized, double-blind, placebo-controlled, Phase III study, designed to assess the effect of two non-
overlapping dose ranges of EDS-EP (dexamethasone sodium phosphate in autologous erythrocytes), 
administered by IV infusion once per month, on neurological symptoms of patients with ataxia 
telangiectasia (AT). 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. 
Listings of the study procedures to be performed at each visit are provided in Section 11.0. 
Study Population 
 
Inclusion Criteria  
To be eligible, the patient must meet all of the following criteria: 
1.
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. Such signs of AT illustrate the body systems in which changes shall be confirmed
but the listed changes are examples and other changes in those systems may be observed and
documented to confirm the diagnosis of AT.
2.
Patient is in autonomous gait or is helped by periodic use of a support (i.e. local ICARS score for Item
1 – Walking Capacities between 0 and 4, included).
3.
Patient will be investigated for the proven genetic diagnosis of AT (prior documentation or by central
laboratory test report).
4.
Patient is at least 6 years of age, of either sex.
5.
Body weight > 15 kg.
6.
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.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 51 of 121 
 
Exclusion Criteria  
To be eligible, the patient must not meet any of the following criteria: 
General 
1.
Females that are
a.
pregnant, or are breast-feeding (for EU countries only);
b.
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. 
2.
A disability that may prevent the patient from completing all study requirements.
3.
Current participation in another clinical study.
Medical History and Current Status 
4.
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).
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.
Patients with diabetes that has been stabilized (i.e. no hypoglycemic or hyperglycemic episodes in the
past 3 months) will be eligible.
10. 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.
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 will be 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 EDS.
18. Requires any concomitant medication prohibited by the protocol, as specified in Section 11.8.
19. Has taken a drug or treatment known to cause major organ system toxicity during the past year.
20. Use of any drug that is a strong inducer/inhibitor of CYP3A4 within 4 weeks before baseline.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Documentation of Randomization 
This is a randomized, double-blind, placebo-controlled, one-year study in which a minimum of 180 patients 
meeting all of the inclusion/exclusion criteria were anticipated to be randomized equally (1:1:1; 60 patients 
per group; due to the Covid-19 outbreak, the enrollment was closed with 175 randomized patients.) to 
receive one of the two dose ranges of EDS-EP or placebo, as follows:  
•
Group 1 – EDS-EP low dose range of ~5-10 mg DSP/infusion;
•
Group 2 – EDS-EP high dose range of ~14-22 mg DSP/infusion;
•
Group 3 – Placebo EDS infusion.
Randomization will be done through a centralized Interactive Voice/Web Response System (IVRS/IWRS). 
In the 6-month Initial Treatment Period, each patient will receive 6 infusions of EDS-EP (~5-10 or ~14-22 
mg DSP/infusion) or placebo, given at monthly intervals. After 6 months of treatment, patients in the EDS-
EP groups (Groups 1 and 2) who enter the Extension Treatment Period will continue on the same 
randomized treatment and will receive an additional 6 monthly infusions of EDS-EP. However, patients in 
the placebo group (Group 3) will be randomly assigned at baseline to be switched to one of the two dose 
ranges of EDS-EP in a 1:1 ratio in an incremental fashion, with one third of patients being switched at 6 
months, another third at 9 months, and the remaining patients at 12 months, provided they continue 
treatment in the open-label study (IEDAT-03-2018).  
At the time of screening, the patient will receive a unique 7-digit subject alphanumeric code consisting of 
3 digits (two letters and 1 number) representing the center and 4 digits numbers representing the order in 
which the subject was screened.  For example, subject number IT1-0003 would correspond to the third 
subject screened at Center IT1. This subject alphanumeric code, will be used for the subject throughout the 
remainder of his/her participation in the trial, and will not be re-assigned to any other subject.  
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria at Baseline will be 
eligible for being assigned to treatment. Assignment to treatment within each of the 3 groups will be done 
on Day 1, just prior to the time of dosing. At the time of randomization, the subject will be assigned a unique 
randomization number by the IVRS/IWRS, which will be linked to the subject’s treatment assignment. This 
number will be entered in the eCRF at Baseline, but will not be used as a subject indentifier.   
Premature Discontinuation 
Patients who discontinue from the study prematurely must have their reason for discontinuation entered in 
the Case Report Forms (CRFs). Patients who discontinue from the study after having received a dose of 
study medication will not be replaced.  
All patients who discontinue prematurely prior to Month 6 (final visit of Initial Treatment Period) will be 
asked to return for all final (Month 6; Visit 9) efficacy and safety evaluations. Similarly, patients who 
discontinue prematurely during the Extension Treatment Period will be requested to return for all final 
(Month 12; Visit 15) assessments.  
Screening for adrenal insufficiency will be performed in all patients, regardless of weight, via early morning 
(before 8:00 AM) plasma cortisol testing following discontinuation of the study drug, according to the 
procedures described in Appendix 12.  The timing of the sample collection with regard to the prior EDS-
EP infusion will be left up to the clinical judgment of the Investigator.  
Page 52 of 121

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 53 of 121 
Record of Study Participants and Screening Failures 
The investigator will be required to maintain a confidential record of all study participants, including all 
patients who were screened for the study, but were not randomized to treatment. The confidential record 
must include sufficient information so that it would be possible to contact the study patient. Information on 
patients who have signed ICFs, but have failed screening, should be entered on the Screen Failure CRF. 
The primary reason for screen failure will be recorded using the following categories: 
•
Did not meet entry criteria
•
Major protocol deviation
•
Pre-treatment Event/Adverse Event
•
Lost to follow-up
•
Voluntary withdrawal (specify reason)
•
Study termination
•
Other (specify reason).
Subject numbers assigned to patients who fail screening will not be reused. 
10 STUDY MEDICATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Sponsor’s name and contact information, center identification, storage conditions (5 ± 3 °C), lot number 
and expiry date (Appendix 6). 
 
 
 
Dose and Administration 
 
 
 
   
 
 
 
 
 
  
•
Group 1 (~5-10 mg/infusion): 
•
Group 2 (~14-22 mg/infusion): 
•
Group 3 (Placebo): 
A description of the EDS and details of the procedure for the encapsulation process are provided in 
Appendix 5. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Page 55 of 121
 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
   
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
Blinding and Randomization 
This is a randomized, double-blind study; therefore, the Sponsor, Investigator, site staff (other than the 
unblinded pharmacist/technical operator) and patient will not be aware of the treatment assignments. A 
minimum of 180 patients were anticipated to be randomly assigned equally to one of the 3 treatment 
groups 
Page 56 of 121
 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
(1:1:1; 60 patients/ group; due to the Covid-19 outbreak, the enrollment was closed with 175 randomized 
patients) by the Investigator using an IVRS/IWRS. 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.   
The customized IVRS will have the capability to process up to twenty-four (24) concurrent phone calls, 
while maintaining acceptable levels of performance and data integrity. The IVRS/IWRS will be able to 
capture, store, and process data for all subjects in this project. All data inputs by the user will be checked 
for validity by the IVRS/IWRS whenever such entries are performed. The user will be notified of any invalid 
entries or transaction errors that could prevent the user from continuing with the transaction. The 
IVRS/IWRS will store data in an Oracle relational database. The IVRS/IWRS can be customized to provide 
additional messages at specific visits. If the users encounter system problems or lock the IVRS/IWRS access 
during a call, they will be presented with the option to transfer to a customer service representative at the 
IVRS/IWRS Help Desk. The minimization algorithm will be customized for the protocol and fully tested 
within the IVRS/IWRS.  
The Investigator may break the blind on an individual patient by using the IVRS/IWRS.  This should be 
done only in a medical emergency in which the patient’s treatment assignment needs to be known in order 
to properly treat the patient. The reason for breaking the blind must be provided.  
Accountability 
During the course of the study, the unblinded study pharmacist or site personnel designated by the 
Investigator to manage the study medication must record the study drug disposition and keep the 
accountability forms updated. The study drug accountability forms will be cross-checked with the 
Encapsulation Procedure Check-List (Appendix 7). A copy of the accountability forms must be kept in the 
study files at the site, and the other copy will be withdrawn by the CRO staff responsible for monitoring the 
unblinded study medication. The used and unused dexamethasone and placebo vials, as well as the 
Encapsulation Procedure Check-List, will be kept at the site for accounting and reconciliation by the CRA 
vs. the study documentation. Since the drug accountability records will be unblinded, the CRA responsible 
for monitoring these records will not be involved in monitoring any other aspect of the study. The used 
infusion bags containing any remaining erythrocytes (with DSP encapsulated) will be disposed of at the 
site, with appropriate documentation.  
Overdose 
Patients in the active group in this study will receive up to 6 infusions of EDS in the initial 6-month treatment 
period.  Each infusion should contain a maximum of approximately 22 mg DSP encapsulated in autologous 
RBCs.  However, based upon results of prior studies, some inter-individual variability in loaded dose is 
expected; therefore, administered doses of DSP greater than 30 mg will be considered an overdose. 
Treatment for an overdose should be the same as the clinical management for an overdose of 
dexamethasone.  
Occupational Safety 
There are no risks anticipated related to the study medication for the staff involved in administering EDS 
to the patients in this study. Standard procedures and precautions for handling needles and biological 
samples should be followed.   
Page 57 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-
specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, Version 
8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
11 EVALUATIONS AND PROCEDURES 
Written Informed Consent 
Written Informed Consent must be obtained from the patient and his/her parent/caregiver (if below the age 
of consent), or legal representative (if necessary), at screening prior to initiating any study procedures 
required by the protocol, according to the procedure described in Section 17.1. If consent is provided 
solely by the caregiver in accordance with local regulations, the patient must provide assent to participate 
in the study.  The details of the study should be discussed with the patient and parent/caregiver or 
legal representative (if necessary) prior to obtaining informed consent, and the Informed Consent Form 
(ICF) must be signed and dated by the patient, parent/caregiver/ legal representative (if necessary), and 
by the Investigator or his/her designee. A copy of the signed ICF will be provided to the patient, and the 
original will be retained with the source documents. The initial consent will cover one year of treatment; 
however, the patient will be asked to provide an additional consent/assent after completing the 6-
month initial treatment period, before continuing in the 6-month extension treatment period.   
Patients who complete the current study and elect to continue open-label treatment with EDS-EP in Study 
IEDAT-03-2018 will need to sign a separate consent form for that study.  In case a patient is willing to be 
enrolled in the open-label study IEDAT-03-2018, but the study has not yet received IRB/EC approval at 
the time the patient reaches Visit 15/Month 12, the patient may undergo unscheduled 
monthly assessments/infusions (according to the assigned blinded treatment) starting from the time Visit 
15/Month 12 should be performed, and continuing until the site has been initiated for the open-label study 
IEDAT-03-2018 and he/she has been evaluated for eligibility for the study. Before performing the 
additional infusions or any of the assessments associated with unscheduled visits, the patient or the 
parent/legal guardian, as well as the Investigator who conducted the consenting process, must sign the 
relevant ICF approved by Ethical Committee to allow these additional procedures to be performed.
Study Conduct 
This study is 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 
detailed listing of the assessments and procedures to be performed at each visit is provided in Section 11.4 
for the Initial Treatment Period and Section 11.5 for the Extension Treatment Period.  
As a results of the COVID-19 pandemic, temporary changes to the protocol have been impleted. These 
changes are described in Appendix 14. 
Screening Period/Baseline 
After providing consent/assent, as described in Section 11.1, each patient will undergo a 30-day Screening 
Period, during which any previous treatments with other corticosteroid compounds will be withdrawn 
(washout from previous treatment).  Demographic information will be collected for all patients, and 
additional information on the medical management and cost of illness will be collected in selected 
countries where such information can be reliably collected.  Each patient will undergo a series of 
screening evaluations, including medical history, physical and neurological examinations, measurement of 
vital signs, electrocardiogram 
(ECG), 
clinical 
laboratory 
tests 
[hematology, 
biochemistry, 
urinalysis, 
blood glycosylated hemoglobin (HbA1c), CD4+ lymphocytes count, –fetoprotein, C-
Reactive Protein (CRP), RBC antibodies (IgG, IgM, Qualitative Direct Coombs test), and serum and urine 
pregnancy test (women of childbearing potential)], and assessment of prior and concomitant 
medications. In addition, a blood 
Page 58 of 121 
 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
sample for mini-ATM detection will be collected. In selected centers, a 5-ml blood sample will be taken for 
assessing RBC osmotic resistance. A sample will be taken for the genetic assay for AT, if not previously 
reported, however, the results do not need to be available at baseline.  
The initial ratings of the ICARS and CGI-S will be performed at the screening visit. Throughout the study, 
the ICARS rating will be performed by qualified raters trained in the use of the scale and not involved in 
rating other scales. The ICARS rater will not have access to the results of other scales or to the safety data. 
In addition, the evaluation will be videotaped and rated by a central remote rater who will be blinded to the 
treatment assignment and the order in which the ratings were performed for each patient. The CGI rater will 
be blinded to the ICARS ratings and safety data, but will have access to ratings of other secondary efficacy 
measures when performing the assessment.  
If any abnormal laboratory test results, vital sign measurements, or ECG findings of clinical significance 
are noted at screening, these must be repeated during the 30-day screening period and the results made 
available prior to making the final decision on a patient’s eligibility for the study at Baseline. Adverse 
events, reported by the patient or observed by the investigator, and the use of concomitant medication will 
be recorded from the time of signing of informed consent through the end of the study.  
A sample will be collected before 8:00 AM for measurement of plasma cortisol during the screening period, 
prior to randomization at baseline. If the basal cortisol level is within the reference normal range, the patient 
can be enrolled in the study. If the 8:00 AM cortisol level is below 3-5 µg/dL (depending on assay) 
regardless of symptoms, or the patient exhibits signs or symptoms of adrenal insufficiency (see Appendix 
12) and has a cortisol <10 µg/dL, the patient will receive a high dose ACTH stimulation test, regardless of 
weight, within 24 hours. If the ACTH stimulation test is normal, the patient can be enrolled after the effects 
of the ACTH have dissipated (e.g., 30 days after ACTH administered).  If the patient fails the ACTH 
stimulation test they will be excluded from the study and referred to a pediatric endocrinologist, with a 
recommendation to prescribe stress dose steroids.
At Baseline (Day 0/1), vital signs and physical and neurological examinations will be repeated and the 
Columbia-Suicide Severity Rating Scale (C-SSRS) will be performed.  The inclusion/exclusion criteria will 
be reviewed and patients meeting all criteria will be randomized to one of the 3 treatment groups.  Two 
ratings will be done on the ICARS, one 24 hours before baseline (Day 0) and the other on Day 1 (pre-dose); 
video recording will be required for both assessments. In addition, the baseline ratings of the following 
efficacy measures will be performed prior to dosing: CGI-S (assess baseline severity of the patient for use 
in evaluating change at post-baseline visits), VABS, and EQ-5D-5L. The diverted blood sample (see Section 
11.6, at least 15 mL, will be drawn prior to dosing to measure baseline values for the foreseen laboratory 
tests.  The serum and urine pregnancy test will be repeated for women of childbearing potential. A baseline 
measurement of bone mineral density (BMD) will be performed.   
Initial Treatment Period (6 months) 
 
 
 
 
 
 
 
  
Page 59 of 121 
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
To maintain the blind, all properly prepared RBCs (EDS or Placebo) will be administered to the 
patients, without knowledge of the actual dose or treatment being administered.   
 
 
 
  
 
 
 
 
 
 
  
On Day 1, a blood sample will collected for measurement of free plasma hemoglobin, 1 hr post-infusion. 
On Days 2 and 15, a complete hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total and 
conjugated), CBC, LDH, urinalysis] will be performed.  
At Months 1, 2, 3, 4 and 5, a blood sample will be taken for dexamethasone PK before and 1 hr after the 
infusion (except for Month 1). Measurement of body weight and height in triplicate, as well as a C-SSRS 
assessment, will be performed at each of these visits. The diverted blood sample (see Section 11.6) will 
be collected for measurement of serum creatinine at Months 1, 2, 4 and 5, whereas creatinine will be part 
of the routine laboratory tests at Months 3 and 6. Upon completion of the EDS process, 2.5 mL of the 
treated blood will be collected for measurement of DSP concentration and a CBC. At Month 3, in 
selected centers, a 5-mL sample will be taken from the EryKit_01 bowl at the end of the process to 
assess RBC osmotic resistance.  
After completion of the IV infusion of the study treatment, a physical examination and vital signs will be 
performed (1-2 hr after infusion).  At Month 3 (Visit 6), a complete set of efficacy (ICARS, CGI-C, CGI-
S, VABS, and QoL) and safety (vital signs, ECG, routine laboratory tests, physical and 
neurological examinations) evaluations will be performed, and a hemolysis panel will be done pre- and 
post-infusion. In addition, the diverted blood samples will be collected for mini-ATM detection at Months 
2 and 6.  
The final evaluations for the Initial Treatment Period will take place at Visit 9 (Month 6 or at 
early termination) and will include all assessments of efficacy (ICARS, CGI-C, CGI-S, VABS, and 
EQ-5D-5L) and safety (vital signs [including weight and height in triplicate], ECG, routine laboratory 
tests, physical and neurological examinations, C-SSRS, BMD and assessments of AEs and concomitant 
medication use), as well as special laboratory tests [HbA1c, CD4+ lymphocytes count, –
fetoprotein, CRP, and RBC antibodies (IgG, IgM, Qualitative Direct Coombs test)]. A serum and urine 
pregnancy test will be performed for women of childbearing potential. The efficacy evaluations at 
Visit 9 will be used as Endpoint assessments for statistical purposes. The final blood sample 
(trough level) for the dexamethasone PK analysis will also be collected. The total volume of blood 
collected throughout the 6-month study for all PK samples would be approximately 42 mL.  
Extension Treatment Period (6 months) 
Patients completing the 6-month Initial Treatment Period and doing well on the study medication will be 
eligible for continuing treatment for an additional 6 months in the Extension Treatment Period. Informed 
Page 60 of 121 
 
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
consent/assent must be obtained in writing for the extension, as in the Initial Treatment Period. Patients 
meeting all entry criteria will be treated as follows: 
•
Patients originally randomized to one of the two dose ranges of EDS (Groups 1 or 2) will continue on
the same treatment;
•
Patients originally randomized to the Placebo group (Group 3) will be re-randomized (randomization
to be done at baseline) in equal proportions (1:1) to receive either the EDS-EP ~5-10 mg DSP/ infusion
or ~14-22 mg DSP/infusion (or the remaining dose of EDS-EP, if one of the doses has been eliminated
following the Interim Analysis), as follows:
o
Following 6 months of treatment, one third of the placebo patients will be switched to treatment
with EDS-EP, as described above;
o
After 9 months of treatment, one third of the placebo patients will be switched to treatment with
EDS-EP, as described above;
•
At 12 months, all remaining placebo patients who continue in the open-label phase will receive
treatment with EDS-EP, as described above.
Visit 9 (Month 6) evaluations from the Initial Treatment Period will serve as the Baseline assessments for 
the Extension Treatment Period.  Once these are completed, patients will have blood drawn for the EDS 
encapsulation procedure and will receive the infusion as before.  Vital signs and a physical 
examination will be performed after dosing.   
Subsequently in the Extension Treatment Period, EDS-EP infusions will be performed at Months 7, 8, 9, 
10 and 11 (Visits 10 – 14), after which vital signs (including body weight and height in triplicate) and 
a physical examination will be performed. The C-SSRS assessment will also be performed at each of 
these visits. A blood sample will be collected for measurement of serum creatinine at Months 7, 8, 10 
and 11, whereas creatinine will be part of the routine laboratory tests at Months 9 and 12. In addition, on 
Month 9 (Visit 12), all efficacy assessments (ICARS, CGI-C, CGI-S, VABS, and QoL) will be done 
prior to the infusion, and the neurological examination, routine laboratory tests and the ECG will be 
repeated.  Upon completion of the EDS process 2.5 mL of the processed blood will be collected for 
measurement of DSP concentration and a CBC.  
At Months 6 and 9, in selected centers, a 5-mL sample will be taken from the EryKit_01 bowl at the end 
of the process to assess RBC osmotic resistance. At Months 6 and 9, a hemolysis panel will be done pre- 
and post-infusion. 
The final evaluations for the Extension Treatment Period will take place at Visit 15 (Month 12 or at early 
termination) and will include all assessments of efficacy (ICARS, CGI-C, CGI-S, VABS, and QoL) 
and safety (vital signs [including weight and height in triplicate], ECG, routine laboratory tests, physical 
and neurological examinations, C-SSRS, BMD and assessments of AEs and concomitant medication 
use), as well as special laboratory tests [HbA1c, CD4+ lymphocytes count, –fetoprotein, CRP, and RBC 
antibodies (IgG, IgM, Qualitative Direct Coombs test)]. A final serum and urine pregnancy test will be 
performed for women of childbearing potential. 
In case a patient is willing to be enrolled in the open-label study IEDAT-03-2018, but the study has not 
yet received IRB/EC approval at the time the patient reaches Visit 15/Month 12, the patient may 
undergo unscheduled monthly assessments/infusions (according to the assigned blinded treatment) 
starting from the time Visit 15/Month 12 should be performed, and continuing until the site has been 
initiated for the open-label study IEDAT-03-2018 and he/she has been evaluated for eligibility for the 
study. 
Page 61 of 121
 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Patients completing 12 (or more) months of treatment in the combined Initial Treatment and Extension 
Treatment Periods and doing well on the study medication, will be eligible to continue treatment with EDS-
EP in a 12-month, open-label, extension study (Study IEDAT-03-2018). Informed consent must be obtained 
in writing for participation in this open-label extension study.  
Due to the length of time required for the encapsulation procedures (>2 hr), it is anticipated that only 1 or 
2 patients will be dosed on any one day.  
Safety Follow-up Visit 
For all patients who complete the one-year study and do not continue in open-label treatment, as well as 
those who discontinue treatment prematurely, a Safety Follow-up Visit (Visit 16) will be conducted 30 days 
after their final assessment or at least 60 days after their last infusion, whichever is longer. At this visit, the 
occurrence of any AEs or Serious AEs (SAEs) reported by the patient/caregiver or observed by the 
Investigator since the previous visit will be recorded.   
Evaluation and Infusion Schedule 
The 12 (or more) monthly infusions should be performed every 21-28 days. A window of ± 7 days will be 
permitted on the Day 15 visit and of + 10 days on each of the scheduled monthly post-baseline visits 
(Months 1 - 12). However, no EDS-EP infusion should be performed less than 21 days after the previous 
infusion. The window between an infusion and the subsequent one should be kept as regular as possible 
throughout the study, avoiding fluctuations in administration windows. The date of an infusion is not bound 
to the date of the initial treatment but to the date of the previous IMP administration. Infusions should not 
be skipped; therefore, if necessary, the infusion schedule can be modified to conform to the above 
guidelines.  
Schedule of Visits and Assessments 
An overview of the schedule of evaluations for the study is presented in the Study Flow Chart for the 
Screening period and 6-month Initial Treatment Period in Table 2A. The assessments that will be performed 
during the 6-month Extension Treatment Period are detailed in Table 2B.  
Page 62 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 28Apr2016; Version 3.2 (Amend. 3), 
25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 
7.1), Final 13 March 2018, Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 (Amend. 11), Final 24 
Jun 2020 
Page 63 of 121 
Table 2A. Study Flow-Chart: 6-Month Initial Treatment Period 
Visit (V) (z)  
Screening 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Study Day or Month (D/M) #  
D -30 to -1 
D0/1 
D2 
D15 
M1 
M2 
M3 
M4 
M5 
M6 (a,b) 
Procedure (§) 
Pre(c) 
Post(c) 
Pre(c) 
Post(c) 
Informed Consent Signature 
X 
Medical History/Demographics 
X 
Inclusion/Exclusion Criteria (v) 
X 
X 
EDS-EP Infusion (h) 
1 
2 
3 
4 
5 
6 
Culture-based sterility test (aa) 
X 
X 
X 
X 
X 
X 
Neurological Examination 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Scale 
X 
X 
Vital Signs (x) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X(d) 
X 
X 
Routine Laboratory Tests (e) 
X 
X(d) 
X 
X 
Serum creatinine 
X(w) 
X(w) 
X(w) 
X(w) 
Bone Mineral Density 
X 
X 
Serum($)/Urine(*) Pregnancy Test (o) 
X($) 
X($,*) 
X(*) 
X(*) 
X(*) 
X(*) 
X(*) 
X($) 
ICARS (with video recording) 
X(n) 
X(n) 
X 
X 
CGI-C 
X 
X 
CGI-S 
X 
X 
X 
X 
VABS 
X 
X 
X 
Quality of Life (EQ-5D-5L) 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
A-T NEST (in selected centers) 
X 
X 
X 
RBC osmotic resistance (t) 
X 
X 
X 
Special Laboratory Tests (m) 
X(f,g) 
X(f) 
X(f) 
Hemolysis Panel (s) 
X 
X 
X 
X 
X 
X 
Genetic AT diagnosis (q) 
X 
Mini-ATM detection 
X 
X 
X 
Dexamethasone PK sample 
X(i) 
X(i) 
X(j) 
X(k) 
X(l) 
X(l) 
X(l) 
X(l) 
X(l) 
X(l) 
X(l) 
EDS end product sample (u) 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Treatments 
Throughout the duration of the study 
Adverse Events 
Throughout the duration of the study 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 28Apr2016; Version 3.2 (Amend. 3), 
25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 
7.1), Final 13 March 2018, Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 (Amend. 11), Final 24 
Jun 2020 
Page 64 of 121 
Table 2B. Study Flow-Chart: 6-Month Extension Treatment Period 
Visit (z)  
V9 
V10 
V11 
V12 
V13 
V14 
Unscheduled 
Visit (£) 
V15 
V16 
Study Day or Month (D/M) # 
M6 (b) 
M7 
M8 
M9 
M10 
M11 
M12 (y) 
Safety 
Procedure (§) 
Pre(c) 
Post(c) 
Pre(c) 
Post(c) 
Follow-up (p) 
Informed Consent Signature 
X 
X 
Re-Randomization (r) 
X 
X 
EDS-EP Infusion (h) 
7 
8 
9 
10 
11 
12 
# 
Culture-based sterility test (aa) 
X 
X 
X 
X 
X 
X 
X 
Neurological Examination 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Scale 
X 
Vital Signs (x) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
Routine Laboratory Tests (e) 
X 
X 
Serum creatinine 
X(w) 
X(w) 
X(w) 
X(w) 
X 
Bone Mineral Density  
X 
Serum($)/Urine(*) Pregnancy Test (o) 
X(*) 
X(*) 
X(*) 
X(*) 
X(*) 
X(*) 
X(*) 
X($) 
ICARS (with video recording) 
X 
X 
CGI-C 
X 
X 
CGI-S 
X 
X 
VABS 
X 
X 
Quality of Life (EQ-5D-5L) 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
A-T NEST (in selected centers) 
X 
X 
X 
RBC osmotic resistance (t) 
X 
X 
Special Laboratory Tests (m) 
X(f) 
Hemolysis Panel (s) 
X 
X 
X 
X 
EDS end product sample (u) 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Treatments 
Throughout the duration of the study 
Adverse Events 
Throughout the duration of the study 
X 
a)
Efficacy evaluations on Month 6 (Visit 9) will be used as the Endpoint assessments for all efficacy measures.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 28Apr2016; Version 3.2 (Amend. 3), 
25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 
7.1), Final 13 March 2018, Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 (Amend. 11), Final 24 
Jun 2020 
Page 65 of 121 
b)
Month 6 (Visit 9; Endpoint) evaluations should be performed for all patients that complete the Initial Treatment Period, as well as patients that discontinue prematurely;
these evaluations will be used as the baseline assessments for the double-blind, Extension Treatment Period.
c)
Procedures to be done before (Pre) and after (Post) the EDS-EP infusion.
d)
These evaluations will be repeated only if abnormalities requiring follow-up were noted at the Screening evaluation; results from the repeat assessments must be available
at baseline to confirm eligibility before the patient can be randomized to treatment.
e)
Routine laboratory assessments to include complete hematology, biochemistry, and urinalysis.
f)
Special laboratory tests include HbA1c, CD4+ lymphocytes count, –fetoprotein (not repeated at baseline), CRP, and RBC antibodies (IgG, IgM, Qualitative Direct
Coombs test – not repeated at baseline).
g)
A sample will be collected before 8:00 AM for measurement of plasma cortisol during the screening period, prior to randomization at baseline. If the basal cortisol level
is within the reference normal range, the patient can be enrolled in the study. If the 8:00 AM cortisol level is below 3-5 µg/dL (depending on assay) regardless of
symptoms, or the patient exhibits signs or symptoms of adrenal insufficiency (see Appendix 12) and has a cortisol <10 µg/dL, the patient will receive a high dose ACTH
stimulation test, regardless of weight, within 24 hours. If the ACTH stimulation test is normal, the patient can be enrolled after the effects of the ACTH have dissipated
(e.g., 30 days after ACTH administered).  If the patient fails the ACTH stimulation test they will be excluded from the study and referred to a pediatric endocrinologist,
with a recommendation to prescribe stress dose steroids.
h)
Assigned study treatment: Group 1: EDS-EP dose range ~5-10 mg DSP/infusion; Group 2: EDS-EP dose range ~14-22 mg DSP/infusion; and Group 3: placebo.
i)
Samples to be collected before infusion (0 min), and 1 and 4 hr after the end of the infusion.
j)
Single sample to be collected 24 hr post-infusion (Day 2).
k)
Single blood sample to be taken in the morning.
l)
Blood samples to be collected prior to (trough) and 1 hour after (peak) the infusion, except in Months 1 (Visit 4) and Months 6 (Visit 9); only trough levels will be collected.
m)
Blood sample to be collected before 8:00 AM for measurement of plasma cortisol at the following times: (1) during the screening period (prior to randomization), (2) when
patients are symptomatic, and (3) when patients are at most risk for adrenal insufficiency and adrenal crisis, such as following discontinuation or interruptions of
dexamethasone dosing (i.e., loading failures and following discontinuation of the study drug).
n)
Video recording will not be required at the screening visit. The ICARS will be performed twice at Baseline, 24 hours apart (Days 0 and 1); the rating on Day 1 (pre-dose)
will be used as the baseline value for statistical analyses. ICARS video recording will be required on both Day 0 and Day 1 (before infusion).
o)
For women of childbearing potential only.  The test results must be negative at screening (serum) and baseline (urine) for the patient to be eligible for the study. Urine
pregnancy test will be performed before every infusion.
p)
A Safety Follow-up assessment will be performed 30 days after the final evaluation or at least 60 days after the final infusion, whichever is longer; at this visit, the
occurrence of any AEs or Serious AEs since the final evaluation will be reported.
q)
If the genetic test for AT has not been performed previously, the test will be done by the central laboratory.  For patients who require genetic testing to confirm the diagnosis,
test results do not need to be available before baseline.
r)
Patients originally randomized to placebo will be re-randomized to receive one of the two doses of EDS-EP, with one third of patients being switched at 6 months and
another third at 9 months.
s)
Hemolysis panel: free plasma hemoglobin, haptoglobin, bilirubin (total and conjugated), CBC (Day 2 and 15 only), LDH, and urinalysis (Day 2 and 15 only). On Day 1,
M3, M6 (b) and M9, only free plasma hemoglobin will be measured, 1 hr post-infusion.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 28Apr2016; Version 3.2 (Amend. 3), 
25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 
7.1), Final 13 March 2018, Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 (Amend. 11), Final 24 
Jun 2020 
Page 66 of 121 
t)
RBC osmotic resistance to be measured on a blood sample taken at screening and on a sample from the EryKit_01 bowl at the end of the process in selected centers only.
u)
Upon completion of the EDS process, the remaining sample in the satellite sample bag or, if this is not available, a sample collected from another EDS-EP sampling point,
will be used for determination of DSP content and CBC.
v)
Patients meeting all selection criteria at Baseline will be randomized (1:1:1) to one of the three treatment groups.
w)
Blood sample for serum creatinine measurement to be taken before infusion.
x)
Vital signs to include height and weight measurements in triplicate at screening, baseline and each monthly visit (pre-dose).
y)
Month 12 (Visit 15; Endpoint) evaluations should be performed for all patients that complete the Extension Treatment Period, as well as patients that discontinue
prematurely.
z)
The monthly infusions should be performed every 21-28 days. A window of ± 7 days will be permitted on the Day 15 visit and of + 10 days on each of the scheduled
monthly post-baseline visits (Months 1 - 12). However, no EDS-EP infusion should be performed less than 21 days after the previous infusion. The window between an
infusion and the subsequent one should be kept as regular as possible throughout the study, avoiding fluctuations in administration windows. The date of an infusion is not
bound to the date of the initial treatment but to the date of the previous IMP administration
aa) 1 mL blood collected, after blood diversion, for aerobic culture, before EDS process (see “Revised Study Procedures on Sterility Testing for Study IEDAT-02-2015 
(ATTeST)”; Appendix 13). Moreover, a sample of the EDS-EP (approximately 1 ml per inoculum for a total of 2 mL) will be collected from the satellite sample bag, to 
perform a culture-based sterility test. A 1-mL sterile sample of the EDS-EP will be stored under refrigeration as a "Retention Sample". 
(£)  In case a patient is willing to be enrolled in the open-label study IEDAT-03-2018, but the study has not yet received IRB/EC approval at the time the patient reaches Visit 
15/Month 12, the patient may undergo unscheduled monthly assessments/infusions (according to the assigned blinded treatment) starting from the time Visit 15/Month 12 
should be performed, and continuing until the site has been initiated for the open-label study IEDAT-03-2018 and he/she has been evaluated for eligibility for the study. 
An additional Informed Consent Form must be signed prior to the 1st unscheduled visit/infusion.  
(§) As a results of the COVID-19 pandemic, temporary additional safety assessments may be requested at some visits. These changes are described in Appendix 14.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 67 of 121 
Visit Schedule and Assessments – Initial Treatment Period 
Screening (Days -30 to -1) 
At Screening (Days -30 to -1) each patient will report to the clinic where the following procedures will be 
performed to establish eligibility for the study:  
a)
Obtaining written informed consent (before any study procedures)
b) Demography
c)
Medical history
d) Physical/neurological examination
e)
Vital signs – body weight and height in triplicate, calculation of BMI, temperature (orally or tympanic,
according to the specific medical practice of the Center), pulse, systolic and diastolic BP, and
respiratory rate
f)
Laboratory evaluations comprising the following tests:
i.
hematology - RBC, WBC, hemoglobin, hematocrit, platelets, neutrophils, eosinophils,
basophils, lymphocytes, monocytes, MCV, MCH, MCHC, and RDW
ii.
clinical chemistry – total protein, albumin, bilirubin, AST, ALT, BUN, creatinine, sodium,
potassium, chloride, bicarbonate, calcium, phosphorus, serum iron, LDH, alkaline
phosphatase, glucose, CPK, triglycerides, and cholesterol (total, HDL and LDL)
iii.
urinalysis (automated) – color, pH, specific gravity, glucose, ketones, nitrites, protein,
bilirubin, hemoglobin, urobilinogen and reflex microscopic RBC, WBC and casts (if indicated)
iv.
serum pregnancy test (women of childbearing potential)
g) Special laboratory tests: HbA1c, CD4+ lymphocytes count, –fetoprotein, CRP, and RBC antibodies
(IgG, IgM, Qualitative Direct Coombs test).
h) Blood sample (5 mL) for assessing RBC osmotic resistance (in selected centers)
i)
Mini-ATM detection – 2.5 mL of blood collected
j)
12-lead standard ECG
k) ICARS (video recording not required)
l)
CGI-S
m) Prior (previous 4 weeks) and concomitant medications
n) Adverse events (AEs) occurring after giving informed consent
o) Blood sample for AT genetic testing, if the test has not been performed previously.
For patients who require DNA sequencing and Western Blotting to confirm the genetic diagnosis of
AT, test results do not need to be available before baseline.
p) Plasma cortisol – sample to be collected before 8:00 AM and prior to randomization at baseline. If the
basal cortisol level is within the reference normal range, the patient can be enrolled in the study. If the
8:00 AM cortisol level is below 3-5 µg/dL (depending on assay) regardless of symptoms, or the patient
exhibits signs or symptoms of adrenal insufficiency (see Appendix 12) and has a cortisol <10 µg/dL,
the patient will receive a high dose ACTH stimulation test, regardless of weight, within 24 hours. If the

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 68 of 121 
ACTH stimulation test is normal, the patient can be enrolled after the effects of the ACTH have 
dissipated (e.g., 30 days after ACTH administered).  If the patient fails the ACTH stimulation test they 
will be excluded from the study and referred to a pediatric endocrinologist, with a recommendation to 
prescribe stress dose steroids. 
q) Patient eligibility and inclusion/exclusion criteria checklist (all test results must be available before
the Day 0 visit).
 Day 0/1 (Visit 1): Pre-Infusion (Baseline) 
Baseline assessments to be performed on Day 0 and Day 1 (pre-dose) are as follows:  
a)
Inclusion and exclusion criteria checklist; review of all selection criteria.
b) Vital signs - body weight and height in triplicate, calculation of BMI, temperature (orally or tympanic,
according to the specific medical practice of the Center), pulse, systolic and diastolic BP, and
respiratory rate. BP and pulse will be done 3 times (~10 min apart) starting at least 1 hour prior to
dosing;
c)
Physical/neurological examination
d) Laboratory evaluations, on the diverted blood sample (see Section 11.6), comprising the following
tests:
i.
hematology *
ii.
clinical chemistry *
iii.
urinalysis *
iv.
serum and urine pregnancy test (women of childbearing potential)
e)
Assessment of physical development, sexual maturation, and the effect of treatment with
dexamethasone on these aspects (Tanner scale)
f)
Special laboratory tests: HbA1c, CD4+ lymphocytes count, and CRP.
g) Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total and conjugated), LDH]
h) 12-lead standard ECG *
i)
ICARS – To be performed ~24 hours prior to dosing (Day 0; video recording required) and on Day 1
(baseline assessment prior to infusion; video recording required)
j)
CGI-S
k) VABS
l)
EQ-5D-5L
m) C-SSRS
n) Bone mineral density
o) 1 mL blood collected, after blood diversion (see Section 11.6), for aerobic culture
p) Autologous blood collection for EDS processing
q) Blood sample for plasma dexamethasone (pre-dose blank – 0 min)

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 69 of 121 
r)
t)
Upon completion of the EDS process 5 mL of the EDS-EP from the EryKit_01 bowl at the end of the
process will be collected to assess RBC osmotic resistance in selected centers.
u) Review of AEs – reported by the patient or observed by the Investigator
v) Review of concomitant medication
w) Infusion of EDS-EP autologous RBCs.
*These routine laboratory and ECG evaluations will be repeated only if abnormalities requiring follow-up
were noted on the Screening evaluations; results from these repeat assessments must be available at
baseline to confirm eligibility before the patient can be randomized to treatment.
Day 1 (Visit 1): Post-Infusion 
a)
Physical examination
b) Vital signs - temperature (orally or tympanic, according to the specific medical practice of the Center),
pulse, systolic and diastolic BP, and respiratory rate;
c)
Blood samples for plasma dexamethasone –1 and 4 hr after the end of the infusion.
d) Hemolysis panel [free plasma hemoglobin only, 1 hr post-infusion]
e)
Review of AEs – reported by the patient or observed by the Investigator
f)
Review of concomitant medication
Day 2 (Visit 2; 24 hours post-infusion) 
a)
A-T NEST
b) Blood sample for plasma dexamethasone collected 24 (± 2) hours post-infusion.
b) Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total and conjugated), CBC, LDH,
urinalysis]
c)
Review of AEs – reported by the patient or observed by the Investigator
d) Review of concomitant medication
Day 15 (Visit 3) 
a)
Blood sample for plasma dexamethasone – single sample to be collected in the morning
b) Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total and conjugated), CBC, LDH,
urinalysis]
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 70 of 121 
c)
Review of AEs – reported by the patient or observed by the Investigator
d) Review of concomitant medication
Day 30 (Month 1; Visit 4) 
a)
Physical examination
b) Vital signs – including body weight and height in triplicate,
c)
Laboratory evaluation on the diverted blood sample: serum creatinine
d) Urine pregnancy test will be performed before infusion (for women of childbearing potential)
e)
C-SSRS
f)
A-T NEST
g) 1 mL blood collected, after blood diversion, for aerobic culture
h) Autologous blood collection for EDS processing
i)
Blood sample for plasma dexamethasone (trough) infusion.
j)
l)
Review of AEs – reported by the patient or observed by the Investigator
m) Review of concomitant medication
n) Infusion of EDS-EP autologous RBCs.
Month 2 (Visit 5) 
a)
Physical examination
b) Vital signs – including body weight and height in triplicate,
c)
Laboratory evaluation on the diverted blood sample: serum creatinine
d) Urine pregnancy test will be performed before infusion (for women of childbearing potential)
e)
C-SSRS
f)
Mini-ATM detection on the diverted blood sample
g) 1 mL blood collected, after blood diversion, for aerobic culture
h) Autologous blood collection for EDS processing
i)
Blood sample for plasma dexamethasone prior to (trough) and 1 hr after (peak) the end of infusion
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 71 of 121
j)
l)
Review of AEs – reported by the patient or observed by the Investigator.
m) Review of concomitant medication
n) Infusion of EDS-EP autologous RBCs.
Month 3 (Visit 6) 
Pre-infusion 
a)
Physical/neurological examination
b) Vital signs – including body weight and height in triplicate,
c)
12-lead standard ECG
d) Laboratory evaluations on the diverted blood sample, comprising the following tests:
i.
hematology
ii.
clinical chemistry
iii.
urinalysis
e)
Urine pregnancy test will be performed before infusion (for women of childbearing potential)
f)
C-SSRS
g) ICARS (with video recording)
h) CGI-C
i)
CGI-S
j)
VABS
k) EQ-5D-5L
l)
Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total and conjugated), LDH]
m) 1 mL blood collected, after blood diversion, for aerobic culture
n) Autologous blood collection for EDS processing
o) Blood sample for plasma dexamethasone prior to (trough) and 1 hr after (peak) the end of infusion
p) Upon completion of the EDS process, fill the satellite sample bag with approximately 6 mL of EDS-
EP by gravity (approximately 2 mL if no other samples but the ones for sterility culture test will be
collected).
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 72 of 121 
q)
s)
Review of AEs – reported by the patient or observed by the Investigator.
t)
Review of concomitant medication
u) Infusion of EDS-EP autologous RBCs.
Post-infusion 
v) Physical examination
w) Vital signs
x) Hemolysis panel [free plasma hemoglobin only, 1 hr post-infusion]
Month 4 (Visit 7) 
a)
Physical examination
b) Vital signs – including body weight and height in triplicate,
c)
Laboratory evaluation on the diverted blood sample: serum creatinine
d) Urine pregnancy test will be performed before infusion (for women of childbearing potential)
e)
C-SSRS
f)
A-T NEST
g) 1 mL blood collected, after blood diversion, for aerobic culture
h) Autologous blood collection for EDS processing
i)
Blood sample for plasma dexamethasone prior to (trough) and 1 hr after (peak) the end of infusion
j)
l)
Review of AEs – reported by the patient or observed by the Investigator
m) Review of concomitant medication
CCI
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 73 of 121 
n) Infusion of EDS-EP autologous RBCs.
 Month 5 (Visit 8) 
a)
Physical examination
b) Vital signs – including body weight and height in triplicate,
c)
Laboratory evaluation on the diverted blood sample: serum creatinine
d) Urine pregnancy test will be performed before infusion (for women of childbearing potential)
f)
C-SSRS
g) 1 mL blood collected, after blood diversion, for aerobic culture
h) Autologous blood collection for EDS processing
i)
Blood sample for plasma dexamethasone prior to (trough) and 1 hr after (peak) infusion
j)
l)
Review of AEs – reported by the patient or observed by the Investigator
m) Review of concomitant medication
n) Infusion of EDS-EP autologous RBCs.
 Month 6 (Visit 9; Endpoint Evaluation for Efficacy) 
The following procedures will be performed at the final visit on Month 6, or if the patient discontinues 
from the study prematurely: 
a)
Physical/neurological examination
b) Vital signs – body weight and height in triplicate, temperature (orally or tympanic, according to the
specific medical practice of the Center), pulse, systolic and diastolic BP, and respiratory rate
c)
Blood sample for plasma dexamethasone – single sample to be taken in the morning (just before the
infusion for patients continuing in the 6-month Extension Treatment Period)
d) 12-lead standard ECG
e)
Laboratory evaluations on the diverted blood sample, for patients continuing in the 6-month
Extension Treatment Period, comprising the following tests:
i.
hematology
ii.
clinical chemistry
iii.
urinalysis
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 74 of 121 
iv.
serum pregnancy test (women of childbearing potential)
f)
Assessment of physical development, sexual maturation , and the effect of treatment with
dexamethasone on these aspects (Tanner scale)
g) Special laboratory tests on the diverted blood sample for patients continuing in the 6-month Extension
Treatment Period: HbA1c, CD4+ lymphocytes count, –fetoprotein, CRP, and RBC antibodies (IgG,
IgM, Qualitative Direct Coombs test)
h) Mini-ATM detection on the diverted blood sample for patients continuing in the 6-month Extension
Treatment Period
i)
ICARS (with video recording)
j)
CGI-C
k) CGI-S
l)
VABS
m) EQ-5D-5L
n) C-SSRS
o) Bone mineral density
p) Review of AEs – reported by the patient or observed by the Investigator
q) Review of concomitant medication
Visit Schedule and Assessments – Extension Treatment Period 
Month 6 (Visit 9) 
Final evaluations for the 6-month Initial Treatment Period will serve as baseline evaluations for patients 
continuing in the 6-month Extension Treatment Period.  
a)
Obtain written informed consent for the extension period
b) Randomized switch of one-third of placebo patients to EDS-EP treatment
c)
1 mL blood collected, after blood diversion, for aerobic culture
d) Autologous blood collection for EDS processing
e)
Upon completion of the EDS process, fill the satellite sample bag with approximately 6 mL of EDS-
EP by gravity (approximately 2 mL if no other samples but the ones for sterility culture test will be
collected).
f)
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 75 of 121 
h) Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total and conjugated), LDH]
i)
Urine pregnancy test will be performed before infusion (for women of childbearing potential)
j)
Review of AEs – reported by the patient or observed by the Investigator
k) Review of concomitant medication
l)
Infusion of EDS-EP autologous RBCs.
Post-infusion 
m) Physical examination
n) Vital signs
o) Hemolysis panel [free plasma hemoglobin only, 1 hr post-infusion]
Months 7, 8, 10 and 11 (Visits 10, 11, 13 and 14) 
a)
Physical examination
b) Vital signs – including body weight and height in triplicate,
c)
Laboratory evaluation on the diverted blood sample: serum creatinine
d) Urine pregnancy test will be performed before every infusion (for women of childbearing potential)
e)
C-SSRS
f)
A-T NEST (at Months 7 and 10 [Visits 10 and 13] only)
g) 1 mL blood collected, after blood diversion, for aerobic culture
h) Autologous blood collection for EDS processing
i)
k) Review of AEs – reported by the patient or observed by the Investigator
l)
Review of concomitant medication
m) Infusion of EDS-EP autologous RBCs.
Month 9 (Visit 12) 
Pre-infusion 
a)
Randomized switch of another one-third of placebo patients to EDS-EP treatment
b) Physical/neurological examination
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 77 of 121 
Unscheduled Visit(s) 
In case a patient is willing to be enrolled in the open-label study IEDAT-03-2018, but the study has not yet 
received IRB/EC approval at the time the patient reaches Visit 15/Month 12, the patient may undergo 
unscheduled monthly assessments/infusions (according to the assigned blinded treatment) starting from the 
time Visit 15/Month 12 should be performed, and continuing until the site has been initiated for the open-
label study IEDAT-03-2018 and he/she has been evaluated for eligibility for the study.   
a)
Obtain written informed consent (prior to the first additional infusion only)
b) Physical examination
c)
Vital signs – including body weight and height in triplicate,
d) Laboratory evaluation on the diverted blood sample: serum creatinine
e)
Urine pregnancy test will be performed before every infusion (for women of childbearing potential)
f)
C-SSRS
g) 1 mL blood collected, after blood diversion, for aerobic culture
h) Autologous blood collection for EDS processing
i)
k) Review of AEs – reported by the patient or observed by the Investigator
l)
Review of concomitant medication
m) Infusion of EDS-EP autologous RBCs.
Month 12 (Visit 15; Final Visit) 
a)
Physical/neurological examination
b) Vital signs – including body weight and height in triplicate,
c)
12-lead standard ECG
d) Laboratory evaluations on the diverted blood sample, comprising the following tests:
i.
hematology
ii.
clinical chemistry
iii.
urinalysis
iv.
serum pregnancy test (women of childbearing potential)
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 78 of 121 
e)
Assessment of physical development, sexual maturation, and the effect of treatment with
dexamethasone on these aspects (Tanner scale)
f)
Special laboratory tests on the diverted blood sample: HbA1c, CD4+ lymphocytes count,
-fetoprotein, CRP, and RBC antibodies (IgG, IgM, Qualitative Direct Coombs test)
g) ICARS (with video recording)
h) CGI-C
i)
CGI-S
j)
VABS
k) EQ-5D-5L
l)
C-SSRS
m) Bone mineral density
n) Review of AEs – reported by the patient or observed by the Investigator.
o) Review of concomitant medication
Safety Follow-up Visit (Visit 16) 
All patients who discontinue prematurely, as well as those who complete the 12-month treatment period 
but do not continue treatment in the open-label extension study, will be required to return for a Safety 
Follow-up Visit (Visit 16) 30 days after their final assessment or at least 60 days after their last infusion, 
whichever is longer. At this visit, A-T NEST will be administered and the occurrence of any AEs or Serious 
AEs (SAEs) reported by the patient/caregiver or observed by the Investigator since the previous visit will 
be recorded.  
Visit Windows 
A window of ± 7 days will be permitted on the Day 15 visit and of + 10 days on each of the scheduled 
monthly post-baseline visits (Months 1 - 12). However, no EDS-EP infusion should be performed less than 
21 days after the previous infusion. The window between an infusion and the subsequent one should be 
kept as regular as possible throughout the study, avoiding fluctuations in administration windows 
 Laboratory Sample Collection  
Revised study procedures to ensure sterility of the EDS-EP 
New aseptic procedures have been implemented to ensure sterility during blood collection for the EDS 
process, the various steps of the EDS process, sample collection for routine laboratory tests, sample 
collection from the EDS-EP for sterility testing, and administration of the EDS-EP to the patient.  Details 
of these procedures are described in a separate document entitled “Revised Study Procedures on Sterility 
Testing for Study IEDAT-02-2015 (ATTeST)”, which will be provided to each site (see Appendix 13).  
These new procedures include the following measures that must be performed to ensure sterility:  
•
Blood sampling under sterile conditions.
•
Careful hand washing and use of fresh (non-sterile) gloves for each patient, disinfected frequently
using a bactericidal rub.
•
Frequent and repeated use of a bactericidal solution, including the mandatory use of 2%
chlorhexidine in 70% isopropyl alcohol for disinfection of the skin at the venipuncture site, or

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 79 of 168 
during handling of the venous catheter (if used), and for disinfecting ports, connectors and working 
surfaces/environments.  
•
  
Blood sampling 
Venous blood samples will be drawn for routine safety evaluations (hematology and clinical chemistry). 
The maximum volume of blood drawn for laboratory analyses on any one day will be approximately 68 ml: 
•
1.0 mL for hematology tests [Screening, Day 0 (optional) and Months 3, 6, 9 and 12]
•
5.0 mL for clinical chemistry [Screening, Day 0 (optional) and Months 6 and 12]
•
3.5 mL for clinical chemistry [Day 0 (optional) and Months 3 and 9]
•
1.0 mL for CD4+ lymphocytes tests (Screening, Day 0, Month 6 (pre-dose), and Month 12); samples
for alpha fetoprotein, C-reactive protein, and Hb1Ac to be taken at same timepoints from blood
collected for clinical chemistry or hematology.
•
1.0 mL for RBC antibody testing (Screening, and Months 6 and 12)
•
Sample for serum pregnancy test (Screening, Day 0 and Months 6 and 12) to be taken from blood
collected for clinical chemistry.
•
Hemolysis panel (pre and post infusion):
o
1.0 mL for free hemoglobin (Day 0, Day 1 - 1 hr post-infusion, Months 3, 6, 9 pre- and post-
dose, and Days 2, and 15);
o
3.5 mL for haptoglobin (Days 0, 2 and 15, and Months 3, 6 and 9 pre-dose);
o
Bilirubin, LDH will be measured from the clinical chemistry or haptoglobin samples;
o
1.0 mL for CBC (Days 2 and 15); CBC at Day 0 and Months 3, 6 and 9, will be measured from
the hematology samples.
•
2.5 mL for Mini-ATM detection (Screening and Months 2 and 6).
•
1.0 mL for separate serum creatinine measurement (Months 1, 2, 4, 5, 7, 8, 10 and 11)
•
2.0 mL for plasma cortisol measurement (Screening, and when adrenal insufficiency is suspected
[Appendix 12]);
•
6.0 mL for the high dose ACTH stimulation test (to be peformed in response to signs or symptoms of
adrenal insufficiency [Appendix 12]) – samples to be taken prior to ACTH administration (0 min) and
30 and 60 min post-dose.
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 80 of 121 
Results of plasma cortisol measurements and the ACTH stimulation test will be made available only to 
the Principal Investigator, and will not be available to raters performing the primary and secondary 
efficacy asssessments.  
•
3.0 mL for PK samples [Day 1 (0 hr), Day 2 (24 hr), Day 15, and Months 2, 3, 4, and 5 (pre- and post-
dose), and Month 1 and 6 (pre-dose)].
•
1.0 mL for PK samples [Day 1 (1 and 4 hr post-dose)].
In addition, on the day of the infusion ~50 mL of blood will be drawn for use in the EDS Process and 
assessments on EDS-processed RBCs.   
The total amount of blood to be drawn on any single day or within any 8-week period conforms to the 
guidelines specified for pediatric patients by the World Health Organization (Howie, 2011).  
Urine collection 
Urine needed for the urinalysis will be collected at Screening, Day 0 (optional), Days 2 and 15 (as part of 
hemolysis panel) and Months 3, 6, 9 and 12, according to local laboratory guidelines.  
Pregnancy test 
All female patients of childbearing potential will have a blood sample drawn at Screening, Baseline (Day 
0), Month 6 and Month 12 (final visit) for a serum pregnancy test. “Non-childbearing potential” is defined 
as follows:  
•
surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), or
•
patient is pre-pubertal, with confirmation that menstruation has not started.
Results of the serum pregnancy test must be negative at Screening for the patient to be included in the study. 
A urine pregnancy test will be performed montly before every infusion. Results of the urine pregnancy test 
must be negative at Baseline (Day 0) for the patient to be randomized. 
All blood and urine samples for safety (hematology/ clinical chemistry/ urinalysis) and special laboratory 
evaluations will be analyzed by an external (central) laboratory.  
Measurement of Dexamethasone Sodium Phosphate and Other Analytes in Infusion Bag 
Sample  
Once the EDS encapsulation procedure has been completed, a sample of the contents of the infusion bag 
will be collected for analysis of the dexamethasone sodium phosphate (DSP) concentration, so that the 
actual dose administered to each patient can be determined.  The procedure to be followed for this sample 
is as follows: 
1.
After the EDS encapsulation procedure is completed, the erythrocyte suspension in the collection
bag will be gently mixed and aseptically sampled for the following assays;
2.
Two different 500-µL aliquot of the erythrocyte suspension will be transferred to two cryo-tube
with a screw cap, which will be stored immediately at < -20°C in a monitored freezer until analysis
(samples require immediate freezing to avoid modification of DSP content). The tubes will be
labeled with the following information:
a.
Study No.
b.
Sample from Infusion Bag

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
c.
Center No.
d.
Subject No.
e.
Nominal timepoint of sample collection
3.
The tubes will be kept frozen at < -20°C pending shipment for analysis. Samples will be shipped
to the laboratory [INC/inVentiv Health Clinique, 2500 Einstein Street, Québec, QC, GIP 0A2,
Canada] in batches.  The site will organize these shipments when all samples have been collected
for more than one patient.  The laboratory will analyze the DSP concentration in a sample from one
tube using a validated LC/MA/MS method (see Appendix 8). The second sample will be kept
frozen as a control.
4.
INC/inVentiv Health Clinique will provide the results for dexamethasone sodium phosphate
concentration, which will be transferred to the database.
Concomitant Medications 
All patients to be included in the study must not have received oral or parenteral steroid therapy within 4 
weeks prior to the administration of EDS. However, treatment with inhaled or intranasal steroids for asthma 
or allergies, as well as the use of topical steroids, will be permitted. In addition, patients with a history of 
use or currently using any of the following medications will be excluded from participation, according to 
the guidelines specified:  
•
Narcotic analgesics – use within 4 weeks prior to baseline;
•
Antipsychotics - unless used at a low, stable dose starting at least 4 weeks prior to baseline, in
which case they will be permitted;
•
Drugs that are strong inducers (e.g. carbamazepine, St. John’s wort) or inhibitors (e.g.
clarithromycin, grapefruit juice) of CYP3A4 within 4 weeks prior to baseline;
Drugs that are inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) may alter the plasma
levels of dexamethasone, which is metabolized by this enzyme.  Therefore, in the current study, any
drug that is a strong inducer or inhibitor of CYP3A4 will be prohibited from use during the trial.
Patients who are taking these drugs upon entry into the screening period should have the
medication discontinued, if possible, or be switched to another similar medication that does not
have this property.  A link to a website with a list of drugs that are strong inducers or inhibitors of
CYP3A4 will be provided to the Investigator as a reference.
•
Amphotericin-B within 4 weeks prior to screening – combination with corticosteroids or
corticotropin (ACTH) may induce hypopotassemia;
•
Any immunization, vaccination or skin test, especially using a live, attenuated vaccine, within
4 weeks prior to screening. The use of a vaccine that contains killed viruses is left to the clinical
judgement of the Principal Investigator, and the standard of care at the site.
Patients on stable doses of other drugs, such as antihypertensives, benzodiazepines, antihistamines 
(histamine receptor blockers), birth control, proton-pump inhibitors, vitamins/multi-vitamins, anti-diabetics 
agents and lipid-lowering agents (e.g. statins), will be eligible for the study. The use of other concomitant 
medications with CNS effects should be discussed with and approved by the Medical Monitor at the CRO 
before prescribing to the patient during the study. Use of immunoglobulins either administered by IV or IM 
route is permitted; the Investigator should determine the optimal timing of the dose with respect to the EDS 
infusion.   
Page 81 of 121

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 82 of 121 
During the entire period of the study, starting with the signing of the ICF, any new treatment that is initiated 
must be reported in the CRF using the pharmacological name (not the trade name, with the exception of 
medicines in fixed combination), specifying daily dose, route, duration of treatment, reason for use. After 
screening, patients should be instructed to contact the Investigator before starting any OTC or prescription 
medication on their own or as prescribed by their physician. The Medical Monitor at the CRO should be 
informed of any new medication that may be a prohibited medication and is started during the study, and 
will make a decision whether or not it is acceptable for the patient to continue in the trial.  

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 83 of 168 
12 EFFICACY EVALUATIONS 
ICARS 
Description of the ICARS 
The primary efficacy endpoint in the AT study will be the mean change from baseline to endpoint (Month 
6 or early discontinuation) in the total score on the ‘Modified’ International Cooperative Ataxia Rating 
Scale (ICARS). 
The ICARS (Trouillas et al, 1997), the most frequently used clinician-(neurologist) rated measure in 
patients with ataxias, was developed by a Committee of the World Federation of Neurology to help 
standardize common manifestations of syndromes that lead to cerebellar dysfunction. The ICARS is a 100-
point, semi-quantitative scale offering a compartmentalized quantification of the following 4 sub-scores: 
Posture and Gait Disturbances (34 points), Kinetic Functions (52 points), Speech Disorders (8 points), and 
Oculomotor Disorders (6 points).  
The complete ICARS will be rated in the current study; however, for the primary efficacy endpoint, the 
‘Modified’ ICARS will used.  The ‘Modified’ ICARS excludes all of the Oculomotor Disorders items 
(items 17-19) and items 8-12 in the Kinetic Functions domain, as these items do not directly contribute to 
functioning.  
Validity of ICARS in AT Patient Population 
The internal consistency, criterion-related validity, and internal construct validity of the ICARS have been 
established in patients with focal cerebellar lesions (Schoch B et al, 2007). The inter-rater reliability, test-
retest reliability and internal consistency have also been validated in patients with spinocerebellar ataxia 
(Weyer et al, 2007, Schmitz-Hubsch et al , 2006a). The ICARS total score satisfied all psychometric criteria 
in a validation study in patients with Friedrich’s Ataxia (Cano et al, 2005; Metz et al 2013) The ICARS has 
been used as an outcome measure in interventional studies in patients with ataxia, but there are no clinical 
data to suggest the magnitude of change on the ICARS that would correspond to a clinically relevant 
improvement, due to the absence of any drug producing such a benefit. The ICARS has been used in several 
studies in patients with Friedreich’s Ataxia over the age of 8 years, in phase III potentially pivotal trials 
(Lynch et al, 2010), as well as in open-label long-term studies (Meier et al, 2012).  
The ICARS was used also in two interventional studies in children with AT. Zanolli et al, 2012 showed a 
statistically significant decrease in the ICARS total score in a placebo-controlled crossover study in 13 
children with AT treated with oral betamethasone (Zannolli et al, 2012). Nissenkorn et al, using ICARS as 
a secondary endpoint, showed improvement in the static and kinetic subscales in a short-term open-label 
study in 17 children (from 4 years of age) treated with amantadine (Nissenkorn et al, 2013). As AT is a 
severe, relentlessly progressive disorder that leads to loss of independent movement in most patients by the 
age of 10 to 16 years, any statistically significant difference from placebo over a 6-month period should be 
considered as a treatment success.  
Most of the developmental and validation studies of the ICARS were performed in patients who were 10 
years of age or older; an international study has been completed (ClinicalTrials.gov: NCT01942850) to 
extend its validity to patients in the age-range of 5 to10 years. Data collected from the validation study in 
selected centers [Data on file, EryDel S.p.A] indicated that the distribution of scores for the ICARS for 
patients with AT under 10 years of age was similar to the scores for these patients on other validated scales 
such as the SARA (Schmitz-Hubsch et al, 2006b) and the BARS (Schmahmann et al, 2009). Data collected 
from the validation study in selected centers confirmed that the severity of AT increased with age in patients 
under the age of 10 years, as demonstrated by a significant correlation of the total scores on the ICARS, 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
SARA, and the BARS, but not for patients above 10 years.  Overall, the distribution of scores for the ICARS 
for 5 to 10 year-old patients with AT was similar to the scores for other validated scales such as the SARA, 
BARS, CGI-S (structured and unstructured versions).  
Standardization of Ratings and Use of Central Remote Rater 
To maximize the consistency of the data obtained from the ICARS, the same neurologist, qualified, trained, 
and certified in the use of the ICARS and with expertise in the field of AT disorders, will evaluate the same 
patient at approximately the same time throughout the study. ICARS ratings should be completed without 
consulting scores from the previous visit. In addition, each ICARS administration will be video recorded 
according to a standardized procedure. The video recordings from each patient will be sent to central remote 
raters, where they will be blindly evaluated in random order. The ICARS ratings from the central remote 
raters will be used for the primary efficacy endpoint analysis.   
The ICARS will be performed at screening and repeated twice at Baseline, on Day 0 and on Day 1 prior to 
administration of study medication.  Both the Day 0 and Day 1 assessments will be videotaped and scored 
by the local rater.  The Day 1 assessment video will be rated by the central rater and used as a baseline 
covariate in the analysis.  In the event that the Day 1 assessment could not be performed, or is not available, 
the Day 0 assessment will be rated by the central rater and will be used as the baseline.   
Clinical Global Impression (CGI-C and CGI-S) 
The CGI (Guy, 1976) is the general name for two scales, the CGI - Change scale (CGI-C) and CGI- Severity 
scale (CGI-S).  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. In the current study, the change from the patient’s baseline condition will be assessed at all post-
baseline visits, and the mean rating of change at Endpoint (Month 6 or early discontinuation) will be the 
key secondary efficacy measure The rater performing the CGI-C will be different from the rater performing 
the ICARS rating, and will assess the patient without access to the ICARS ratings or safety data.  A 
guideline for performing the rating of change using the CGI-C is provided below.
For the CGI-C rating, clinicians will be required to conduct a full clinical interview and examination of the 
patient, if necessary with the caregiver present. The interview and examination should assess 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 CGI-C rating should be based 
on a holistic assessment of the patient, and should not be anchored to specific change or cut-off scores of 
performance-based measures.  It is not necessary for the rater to use specific scales or be guided by their 
scores for severity; however, the rater may review findings on other measures that are assessed in the trial, 
e.g. VABS, quality of life scale (EQ-5D-5L), to guide their assessments. The raters may also use additional 
scales or measures to assess specific domains; however, it is important that the raters use the same methods 
at baseline and at all subsequent visits.
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). 
However, no version of the CGI-S exists which has been specifically adapted for use in AT patients; 
therefore, a 5-point version was developed that takes into account the severity of the following symptoms 
of AT: 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) are selected based on the level of symptomatology.  Two independent versions of the CGI-S scale were 
developed, a structured scale, based on the 5 disease-related anchors and an unstructured scale based on the 
clinical judgment of an experienced physician. Both the structured and unstructured versions were field-
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
tested.  The final structured CGI-S score is based on the severity of the symptoms in each domain, as 
indicated below: 
•
A rating of 0 (not ill/asymptomatic) can be made only if there are no symptoms, or a rating of mild
on only one symptom domain;
•
A rating of 1 (mild) can be made only if there are not more than 2 domains rated greater than mild;
•
A rating of 2 (moderate) can be made only if there are not more than 2 domains rated greater than
moderate;
•
A rating of 3 (severe) can be made only if there are not more than 2 domains rated greater than
severe;
•
A rating of 4 (very severe) can be made only if there are at least 2 domains rated as severe and at
least 2 rated as very severe.
A pilot validation study has been performed in AT patients using the CGI-S scale, and the results indicate 
that the CGI-S adequately discriminated patients with mild, moderate, or severe disease [Data on file, 
EryDel S.p.A.]. The distribution of patients to different scores on the CGI-S of AT was similar using the 
ICARS, BARS, and SARA in 6 to 9 year olds. The CGI-S for patients 10 years of age or older was greater 
than in 6 to 9 year old patients; however, the distribution of scores on the ICARS, BARS, and SARA was 
similar across severity categories.  
Vineland Adaptive Behaviors Scale (VABS) 
The VABS has been included as a secondary efficacy measure to assess adaptive behavior (Sparrow and 
Cicchetti, 1985; Sparrow et al, 2005). The expanded version of the VABS consists of 540 items, 261 of 
which were taken from the short form, which will be used in this study.  The VABS is administered using 
a semi-structured interview by a qualified interviewer with a parent or caregiver who takes care of the 
patient. Adaptive behavior is measured according to four scales, each subdivided into eleven subscales. 
Each subscale is further divided into clusters (2 to 8 items) listed in evolutionary order; each cluster is 
sorted to a target item. A score is assigned to each item based on whether the patient performs that activity 
"usually", "sometimes" or "never"; answers of "no chance" or "I do not know" are also provided. Therefore, 
the complete form indicates the strengths and weaknesses of the patient in specific areas of adaptive 
behavior, allowing the psychologist or educator to select the program best suited to the patient, explain the 
activities to emphasize in the program, monitor progress during its use and assess the final outcome.  
Scales and Subscales. The VABS is divided into four scales and eleven subscales: 1) Communication: 
Receptive, Expressive, Written; 2) Daily Living Skills: Personal, Domestic, Community; 3) Socialization: 
Interpersonal Relationships, Play & Leisure Time, Coping Skills; 4) Motor Skills: Gross, Fine.  An optional 
fifth subscale, the Maladaptive Behavior Index, will not be assessed in this study.   
Generally, to maximize data consistency, the same rater (psychologist or person experienced in use of the 
scale) should evaluate the same patient on the same assessments at approximately the same time of day, 
whenever possible. The assessments must be performed without consulting the results of the prior visit.  
Quality of Life Scale 
A patient/caregiver-rated assessment of quality of life (QoL) will be performed using the EQ-5D-5L scale. 
The EQ-5D is a standardized instrument for assessing health-related QoL, which provides a simple 
descriptive profile and a single index value for health status in a variety of health conditions (Rabin and de 
Charro, 2001). The scale was originally designed for use in adult populations, 18 years of age and older. 
The EQ-5D includes single item measures of five health dimensions: mobility, self-care, usual activities, 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
pain/discomfort, and anxiety/depression. Each item has three possible response options that allow the 
subject to rate (no problems/some or moderate problems/extreme problems) their current state with respect 
to each of the 5 domains. In addition, EQ-5D includes a global rating of current health using a visual 
analogue scale (VAS) ranging from 0 (worst imaginable) to 100 (best imaginable). The EQ-5D is 
cognitively simple, and provides a score that can be compared across different conditions 
(http://www.euroqol.org/).  
The EQ-5D-5L that will be used in this study is a newer version of the scale, which includes five levels of 
severity (i.e., no problems, slight problems, moderate problems, severe problems, and extreme problems) 
for each of the five EQ-5D dimensions (Herdman et al, 2011); rather than the three levels included in the 
previous version (EQ-5D-3L). The EQ-5D-5L has been validated in a diverse patient population in 6 
coutries, including 8 patient groups with chronic conditions (e.g. cardiovascular disease, respiratory disease, 
depression, diabetes, liver disease, personality disorders, arthritis, stroke) and a student cohort (Janssen et 
al, 2013).  
For children and adolescents, the EQ-5D-5L administrators will be trained to help the younger population 
in the study complete the scale. The EQ-5D-5L administrator will explain in detail the scale to the younger 
patients and will confirm that they understand how the scale should be completed. They will explain what 
each domain measures in a child friendly manner and will confirm that the respondent understands how to 
complete the scale. With regards to the usual activities domain, the administrator will explain that this 
domain measures if a subject has difficulties going to school, or with hobbies, sports, playing and doing 
things with family or friends. The administrator will be present during the completion and will be available 
to help the child if he/she does not understand a question or he/she has questions related to scale completion. 
If the patient is unable to complete the scale, it will be completed by the patient’s parent/cargiver.  
Rater Requirements and Training 
Properly qualified raters will need to be identified at each site to perform the ratings on the efficacy 
measures. The ICARS rater must remain blinded to other assessments and will not have access to the safety 
data. The CGI rater will not have access to the ICARS ratings or safety data, but may refer to other scales 
in scoring the CGI.  Training and certification on the ICARS and CGI will take place at the Investigator’s 
meeting and additional training and an intra-rater reliability (test-retest) assessment will be performed 
during the study.  
Order of Test Performance 
The ICARS should be the first scale administered.  The sequence of performance for the other efficacy 
assessments is not fixed across the study; however, the order in which these tests are performed for an 
individual patient should be kept constant throughout the trial.   
Exploratory Efficacy Measure 
A-T NEST
Measurement of ataxia is difficult, as assessment of the magnitude of movement error – or “lack of order”, 
the etymologic definition of “ataxia” – necessarily includes many complexities and confounders. Numerous 
ordinal scales have been developed to account for “lack of order” in various human conditions, and 
validated to widely varying stringency in different disease populations. The International Cooperative 
Ataxia Rating Scale (ICARS) was targeted to the 1997 understanding of features of cerebellar ataxia in 
1997, and later validated in patients with Friedreich Ataxia (Cano et al, 2005), and focal cerebellar lesions 
(Schoch et al, 2007)   before being used as the primary outcome measure for a therapeutic trial of subjects 
with ataxia telangiectasia (Broccoletti et al, 2008). Another scale for ataxia, the Scale for the Assessment 
Page 86 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 87 of 121 
and Rating of Ataxia (SARA), was developed and validated for assessment of spinocerebellar ataxia 
(Schmitz-Hubsch et al, 2006) and later refined and compared to other scales for spinocerebellar ataxia 
subtypes (Monte et al, 2017).   
A critical problem for measurement of the neurologic disability experienced by those children and adults 
with ataxia telangiectasia, however, is its broad range of abnormalities. Each of these are statistically 
independent contributors to an overall score, with many features more characteristic of classic models of 
known extrapyramidal dysfunction than cerebellar degeneration  (Crawford et al, 2000). The original 
description of ataxia telangiectasia was titled as a disorder characterized by athetosis (Syllaba et al, 1926), 
with the “ataxia” label applied only after cerebellar pathology was identified (Boder et al, 1957). A scale 
encompassing the broadest range of the ataxia telangiectasia phenotype was developed and validated by 
multiple observers in a single institution in 2000 (Crawford et all, 2000). The A-T NEST scale, consisting 
of independent and combined elements assessing the range of the disorder, evolved out of that scale by 
consensus of international A-T clinical experts convened by the Ataxia Telangiectasia Children’s Project 
(ATCP) over the last decade. Study IEDAT-02-2015 offers an opportunity to validate the A-T NEST scale 
with its well-defined training materials in a multicenter setting, comparing intra- and inter-rater reliability 
and individual subject stability from one assessment to the next. As such, it offers the ideal platform for 
development of a more sensitive and more meaningful outcome measure for future studies of the disorder. 
The A-T NEST scale and detailed instructions will be provided to the sites selected for this exploratory 
analysis. 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
13 SAFETY EVALUATIONS 
The assessment of safety and tolerability will be based on the following: 
a)
Vital signs
b) Standard laboratory tests (clinical chemistry, hematology, and urinalysis)
c)
12-lead standard ECG
d) Physical and neurological examinations
e)
Special laboratory parameters
f)
C-SSRS
g) BMD
h) Tanner staging
i)
Subjective reporting of any AE by the patient
j)
Objective observation of any AE by the Investigator
k) The investigator will be asked to comment on any clinically significant abnormal test results.
The frequency of investigations that involve blood draws have been modified to ensure that the volume of 
blood taken from patients conforms to the guidelines specified for pediatric patients by the World Health 
Organization (Howie, 2011).  
Physical and Neurological Examinations 
Physical and neurological examinations will be performed as specified on the Schedule of Visits and 
Assessments. If clinically significant abnormal findings are noted at Screening, the examination should be 
repeated prior to Baseline. The physical examination will include an examination of general appearance, 
skin, neck (including thyroid), eyes and ears, nose, mouth, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities and nervous system.  Genital, urinary tract and rectal examinations are not required.  The 
findings will be entered on the Physical Examination section of the CRF. 
Vital Signs 
Vital signs assessments will be performed as specified on the Schedule of Visits and Assessments and will 
include body weight, temperature (orally or tympanic, according to the specific medical practice of the 
Center), pulse, systolic and diastolic blood pressure, and respiratory rate. Height will be measured by a 
stadiometer in triplicate at Screening and every subsequent visit, and used along with body weight (also 
measured in triplicate) to calculate Body Mass Index (BMI). Pulse and blood pressure will be measured 
after the patient has been in the supine position for at least 5 minutes. At Day 0/1, prior to dosing, 
measurements of blood pressure and pulse (supine) will be repeated 3 times, at least 10 minutes apart, and 
the values will be averaged to obtain the baseline values.   
If a change of clinical relevance from pre-dose to post-dose is observed, the vital signs assessment should 
be repeated as often as needed, at the discretion of the Investigator. Guidelines for clinically notable vital 
signs values are provided in Appendix 4. Findings should be documented on the Vital Signs section of the 
Case Report Form.   
Page 88 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Electrocardiogram (ECG) 
All patients will have a standard 12-lead ECG performed as specified on the Schedule of Visits and 
Assessments. At Screening the ECG will be done in triplicate, at least 10 min apart, and the values will be 
averaged to obtain the baseline values. If clinically significant abnormal findings are noted at Screening 
and do not normalize on the repeat evaluation at Baseline (in triplicate), the patient will not be enrolled.  
The review and interpretation of the 12-lead ECGs will be performed by a centralized ECG service, to 
ensure consistency across site. These results will be used for determination of a patient’s eligibility for 
enrolment in the trial, as well as post-dose safety monitoring. An initial review of the ECG will be 
performed by a cardiologist or qualified physician at the investigational site. The report from the centralized 
ECG service must be reviewed by the Investigator, initialed and dated, and copies inserted in the patient’s 
records and attached to the CRF. If clinically significant abnormalities are found, the patient’s ECG should 
be repeated at regular intervals until it returns to normal.   
Each ECG tracing must have the following information entered on it: 
•
Study number,
•
Site number,
•
Subject’s number and initials,
•
Date and time ECG obtained.
If clinically significant abnormalities are found, the patient’s ECG should be repeated at regular intervals 
until it returns to normal. The cardiologist or qualified physician reviewing the ECGs should use the 
following guidelines in determining the clinical significance of any abnormal findings:  
•
PR interval: < 100 msec or > 210 msec
•
QRS interval: < 50 msec or > 120 msec
•
QTc interval: > 450 msec
•
Heart rate: < 50 bpm (sinus bradycardia) or > 120 bpm (sinus tachycardia)
•
Morphology: presence of T-wave inversion, abnormal R-waves, pathological Q-waves, or
significant ST elevation or depression.
The ECG database created by the centralized service will be used in all analyses. Details of the procedures 
related to the centralized ECG service will be provided in a separate manual.  
Standard Laboratory Evaluations and Screening Tests 
Blood and urine samples for measurement of standard laboratory parameters will be as specified on the 
Schedule of Visits and Assessments. If clinically significant abnormal findings are noted at Screening and 
do not normalize on the repeat evaluation at Baseline, the patient will not be enrolled. 
Evaluations of the hematology, clinical chemistry and urinalysis analytes listed in Table 3 will be performed 
at each of the visits listed above. In addition, a serum pregnancy test will be performed for women of 
childbearing potential at Screening, Baseline (Day 0), Month 6 and Month 12 (or at early discontinuation). 
For women of childbearing potential also a monthly urine pregnancy test will be performed before every 
infusion throughout the study. For details on aseptic procedure for blood withdrawal and on blood diversion 
see “Revised Study Procedures on Sterility Testing for Study IEDAT-02-2015 (ATTeST)” (Appendix 
13). 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Table 3. Summary of laboratory analytes 
LABORATORY ANALYTES 
Hematology or CBC 
Clinical Chemistry 
Urinalysis (automated) 
Hematocrit 
Sodium 
Alkaline phosphatase 
Color 
Hemoglobin 
Potassium 
LDH 
pH 
RBC count 
Chloride 
CPK 
Specific gravity 
WBC count 
Calcium 
Triglycerides  
Protein 
Differential WBC count 
Phosphorus 
Total cholesterol 
Glucose 
•
Neutrophils
Serum iron 
HDL cholesterol  
Ketones 
•
Lymphocytes
Bicarbonate 
LDL cholesterol  
RBC, WBC, casts * 
•
Monocytes
Glucose 
Nitrites 
•
Eosinophils
BUN 
Bilirubin 
•
Basophils
Creatinine 
Hemoglobin 
Platelets 
Total bilirubin 
Urobilinogen  
MCV 
Albumin 
* Reflex microscopic
analysis to be performed
only if other analytes are
abnormal on automated
testing
MCH 
Total protein 
MCHC 
AST (SGOT) 
RDW 
ALT (SGPT) 
Special Diagnostic Tests: 
Serum pregnancy test (to be performed at Screening, Baseline (Day 0), Month 6 and Month 12 for 
women of childbearing potential). For women of childbearing potential also a monthly urine 
pregnancy test will be performed before every infusion throughout the study. 
The Investigator must review screening laboratory values, as well as any repeat assessments, prior to the 
first administration of the study agent, to ensure that the patient meets the protocol’s inclusion/exclusion 
criteria. The Investigator must review laboratory values from each subsequent evaluation within 24 hours 
of receipt of the laboratory report. After the review is completed, the Investigator must sign and date each 
laboratory report.  
A central laboratory will be used for analyzing all samples from routine laboratory tests. The central 
laboratory will provide normal reference ranges for the laboratory tests on the laboratory results report. A 
value is considered normal when it falls on or within the upper and lower limits of the reference range for 
the laboratory. A value is considered abnormal when it exceeds the upper or lower limit of the reference 
range. The central laboratory will provide the normal reference ranges for each parameter, and will verify 
that the result is not due to pre-analytical problems (e.g., sample taken improperly, sample stored 
incorrectly, sample labeled incorrectly) or to analytical problems (e.g., machine not accurately calibrated, 
technical problems with equipment or reagents, or deterioration of analyte). If there are any conflicts 
between reference ranges in Appendix 4 and the reference ranges for the central laboratory, the central 
laboratory reference ranges will have precedence in the determination of AEs.  
The Investigator must evaluate any change of clinical relevance from pre-dose to post-dose in a laboratory 
test as to whether it meets the definition of an adverse event, and repeat, if needed, any clinically significant 
abnormal laboratory test. Any laboratory abnormalities meeting the definition of an adverse event should 
be recorded on the Adverse Events CRF. 
Page 90 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 91 of 121 
Refer to Section 14.0, “Reporting Safety Information” for further directions. 
Special Laboratory Evaluations 
Measurement of selected “special” laboratory parameters has been included in the study to evaluate 
potential effects of dexamethasone (EDS-EP) treatment (for details on aseptic procedure for blood 
withdrawal and on blood diversion see “Revised Study Procedures on Sterility Testing for Study IEDAT-
02-2015 (ATTeST)”; Appendix 13). The following special laboratory parameters will be assessed in the
study:
•
Blood glycosylated hemoglobin (HbA1c, %), CD4+ lymphocytes, α-fetoprotein (not repeated at
baseline), C-reactive protein (CRP), and RBC antibodies (IgG, IgM, Qualitative Direct Coombs test)
(not repeated at baseline)– to be performed at Screening and Baseline (Day 0) and on Months 6 and 12
(or at early discontinuation).
•
Screening for adrenal insufficiency will be performed in all patients, regardless of weight, via early
morning (before 8:00 AM) plasma cortisol testing at the following times: (1) during the screening
period (prior to randomization), (2) when patients are symptomatic, and (3) when patients are at most
risk for adrenal insufficiency and adrenal crisis, such as following discontinuation or interruptions of
dexamethasone dosing (i.e., loading failures and following discontinuation of the study drug). If the
8:00 AM cortisol level is below 3-5 µg/dL (depending on assay) regardless of symptoms, or the
patient exhibits signs or symptoms of adrenal insufficiency (Appendix 12) and has a cortisol <10
µg/dL, the patient will receive a high dose ACTH stimulation test, regardless of weight, within 24
hours. If the ACTH stimulation test is normal, the patient can be enrolled, or can continue dosing with
EDS-EP, after the effects of the ACTH have dissipated (e.g., 30 days after ACTH administered).  If
the patient fails the ACTH stimulation test they will be excluded or discontinued from the study and
referred to a pediatric endocrinologist, with a recommendation to prescribe stress dose steroids.
•
High dose ACTH stimulation test – In the event that patients show signs or symptoms of adrenal
insufficiency (Appendix 12) during the study, especially following interruption of the study drug
(including loading failures), they will be tested for adrenal insufficiency using a high dose ACTH
stimulation test (250 µg given i.v. or i.m.), regardless of weight.  If ACTH testing confirms adrenal
insufficiency, the patient will be referred for evaluation and treatment. Blood samples (2.0 mL) for
measurement of plasma cortisol will be collected prior to ACTH administration (0 min), and at 30 and
60 min post-dose. A rise in plasma cortisol level to greater than 18 µg/dL within 60 min demonstrates
a normal result.  A rise in cortisol to less than 18 µg/dL within 60 min demonstrates an abnormal
response.
Results of plasma cortisol measurements and the ACTH stimulation test will be made available only to
the Principal Investigator, and will not be available to raters performing the primary and secondary
efficacy asssessments.
•
Hemolysis panel [free plasma hemoglobin, haptoglobin, bilirubin (total and conjugate), CBC, LDH and
urinalysis] – to be performed on Day 1 (pre-dose), Days 2 and 15 (CBC and urinalysis on Days 2 and
15 only). On Day 1 and Months 3, 6, and 9 (post-infusion) free plasma hemoglobin only is to be
performed;
•
Mini-ATM detection will be performed at Screening and at Months 2 and 6.
Background
Short-term treatment with glucocorticoid analogues improves neurological symptoms characteristic of
AT; however, the mechanism of action has not been elucidated. Short direct repeat-mediated non-

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
canonical splicing events were induced by low-dose dexamethasone in human AT cell lines, which led 
to the skipping of mutations upstream of nucleotide 8450 of the ATM coding sequence (Menotta et al., 
2012). The resulting transcript provided an alternative open reading frame that translated into a new 
ATM protein variant with the complete functional kinase domain, the mini-ATM variant. This mini-
ATM variant was also identified in lymphocytes from AT patients receiving the EDS-EP treatment. 
Hence, dexamethasone may partly restore ATM activity in AT cells through a new molecular 
mechanism that overcomes most of the mutations so far described within this gene. Therefore, in the 
current study, blood samples (3 mL) to determine the mini-ATM will be taken at Screening, Month 2 
and Month 6. 
Process description for quantification of mini-ATM expression in the blood of AT patients 
Tempus™ Blood RNA Tubes will be provided to each center. Three mL of blood will be drawn directly 
into the Tempus™ Blood RNA Tubes; filling up the tube to the black mark on the tube label indicates 
the collection of approximately 3 mL. Immediately after the Tempus tube is filled, the blood will be 
stabilized by shaking the tube gently for 10 seconds to ensure that the Stabilizing Reagent makes 
uniform contact with the sample. The collected samples will be transferred to the reference laboratory 
using the same couriers used to ship routine laboratory samples to the central laboratory, in data-logger 
equipped containers. Validated molecular diagnostic kits and extraction procedures will be used in the 
selected reference laboratory for the test procedure. 
Sterility Testing of EDS-EP 
 
 
 
 
  
 
 
 
 
 
  
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS (Posner et al, 2007; Posner et al, 2011) is a standardized suicidal rating system that has 
provided data for the pediatric suicidal risk analysis of antidepressants conducted by the Food and Drug 
Administration (FDA). The pediatric version of the scale will be used for patients who are less than 12 
years of age at the screening visit (and will be used throughout the study, even if a patient turns 12 during 
the course of the study). At Screening, an assessment of suicidality will be performed using the 
“Baseline/Screening” version of the C-SSRS.  At the baseline visit, upon admission to the clinical unit, the 
“Baseline” version of the C-SSRS will be performed.  Follow-up assessments will be performed using the 
“Since Last Visit” version of the C-SSRS.  Subjects with suicidal ideation will be excluded from 
participating in the trial. 
Page 92 of 121 
CCI

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 93 of 121 
Bone Mineral Density (BMD) 
Measurements of BMD will be performed for all patients at Baseline and repeated at 6 and 12 months to 
assess potential steroid-related changes.  Bone mass will be measured in the spine and total body (less the 
head), following the guidelines provided in the 2013 International Society for Clinical Densitometry 
Official Pediatric Position (Gordon et al, 2014).  The suggested method for assessing BMD in the study is 
dual energy x-ray absorptiometry (DXA). The analysis will be performed with Z-scores following the above 
guidelines. The same method of assessment will be used for each patient throughout the study. 
Tanner Staging 
Assessment of physical development, sexual maturation, and the effect of treatment with dexamethasone 
on these aspects will be evaluated using the Tanner scale (Marshall and Tanner 1969, 1970) at Baseline, 
and 6 and 12 months. The scale defines physical measurements of development in children, adolescents 
and adults based on external primary and secondary sex characteristics, such as the size of the breast, 
genitals, testicular volume and development of pubic hair. Due to natural variation, individuals pass through 
the Tanner stages at different rates, depending in particular on the timing of puberty. Tanner staging of the 
breasts in pre-menarchal females and of the scrotum in males who have not completed puberty, will be 
performed. Post-menarchal females and males who have completed puberty will be excluded from this 
growth analysis.  

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 94 of 121 
14 REPORTING SAFETY INFORMATION 
Adverse Events 
Assessment of Adverse Events (AEs) will be performed throughout the study, from the time of signing of 
the ICF at the start of the Screening period through the final study visit (Month 12 or early discontinuation). 
All Adverse Events will be recorded in the CRF.  In addition, all subjects will be followed up through 30 
days after the final visit (Month 12 or early discontinuation) or at least 60 days after the final infusion, 
whichever is longer, for the occurrence of any AEs or SAEs.   
 Glossary 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the 
therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal product 
related to any dose should be considered adverse drug reactions. The phrase “response to a medicinal 
product” means that a causal relationship between a medicinal product and an adverse event is at last a 
reasonable possibility, i.e., the relationship cannot be ruled out. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or not related 
to the medicinal (investigational) product. 
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) 
Any untoward medical occurrence that at any dose: 
•
Results in death,
•
Is life-threatening, i.e., an event which, in the view of the Investigator, places the subject at
immediate risk of death from the event as it occurred (it does not include an event which
hypothetically might have caused death if it were more severe)
•
Requires inpatient hospitalization or prolongation of existing hospitalization,
•
Results in persistent or significant disability/incapacity,
•
Is a congenital anomaly/birth defect (if exposure to product just before conception or during
pregnancy resulted in an adverse outcome in the child), or
•
Is an important medical event that may jeopardize the subject or may require medical intervention
to prevent one of the outcomes listed above.
Symptoms or medically significant laboratory or instrumental (e.g., electrocardiographic) abnormalities of 
a pre-existing disease, such as cancer or other disease, should not be considered an adverse event.  However, 
the occurrence of new symptoms, or laboratory or instrumental abnormalities, as well as worsening of pre-
existing symptoms, are considered adverse events.  

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 95 of 121 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is an adverse event, the nature or severity of which is not consistent 
with the applicable product information (e.g., Investigator’s Brochure for an unapproved investigational 
product or Package Insert/Summary of Product Characteristics for an approved product).  
Non-Serious Adverse Event 
A non-serious adverse event is any adverse event that does not meet the criteria listed above for a serious 
adverse event. 
 Data Collection 
For each event, record the following information on the Adverse Event section of the Case Report Form: 
• Classification of the Event: Classify the event as either serious or non-serious
• Description of Signs or Symptoms: Whenever possible, record a specific diagnosis for the event.  If a
diagnosis cannot be made, then record each sign or symptom separately, e.g., record nausea and
vomiting as two events.  If multiple episodes of an event occur, separated by an appropriate time interval
to justify considering the subsequent episodes as a repeat occurrence, record each episode separately on
the Case Report Form.
• Onset Date and Time: Record the date and time the event started.  If a change from baseline/previous
evaluation in a laboratory test is reported as an adverse event, record the start date as the date of
collection of the first lab sample that shows the change.
• Stop Date and Time: Record the date and time the event resolved.  If a change from baseline/previous
evaluation in a laboratory test is reported as an adverse event, record the stop date as the date of
collection of the first sample that shows a return to the previous level.
• Intensity:
1.
Mild: Event not resulting in disability/incapacity, which resolves without treatment.
2.
Moderate: Event not resulting in disability/incapacity, which requires treatment.
3.
Severe: Event resulting in temporary and mild disability/incapacity, which requires
treatment.
• Relationship to the Study Agent: Every effort should be made to determine the cause of each adverse
event.  The correlation between the study agent and the adverse event should be classified as follows:
1.
Probable
a) The event follows a reasonable temporal sequence from administration of the
study agent;
b) The event follows a known response pattern to the study agent;
c) The event cannot be reasonably explained by:
•
the known characteristics of subject’s clinical state, or
•
by other therapy administered, or
•
by the diagnostic/interventional procedure;
d) There is evidence of partial or complete disappearance of the event after
withdrawal of the product (positive de-challenge)

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 96 of 121 
2.
Possible
a) The event follows a reasonable temporal sequence from administration of the
study agent;
b) Causation of the event by the study agent cannot be excluded;
c) The event follows a known response pattern to the study agent but the event could
have been produced by:
•
the subject’s clinical state, or
•
other therapy administered, or
•
a diagnostic/interventional procedure.
3.
Unlikely
a) The adverse event follows a reasonable temporal sequence from administration
of the study agent;
b) Other reasons are more likely to be the cause of the adverse event, based on the
present knowledge of the
•
disease under treatment, or
•
other therapy administered, or
•
study drug;
c) A causal relationship between the adverse event and the study drug cannot be
ruled out with certainty.
4.
Not Related  The event is either a pre-dose event or is definitely due to causes separate from the
administration of the study agent, i.e., 
•
documented pre-existing condition
•
technical and/or manual procedural problems
•
concomitant medication
•
subject’s clinical state.
• Action Taken, in relation to treatment of the AE:
0.
None
1.
Drug treatment required (a medication was prescribed or changed; record on the
Concomitant Medication section of the Case Report Form)
2.
Non-drug treatment required (a non-drug treatment was prescribed or changed,
record under “Comments” in the Adverse Event section of the Case Report Form)
3.
Hospitalization or prolonged hospitalization (fill out an SAE report)
4.
Diagnostic or clinical test(s) conducted (attach a copy of the results to the Case
Report Form)
5.
Subject discontinued from the study

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 97 of 121 
• Action taken with study treatment
0. Dose not changed
1. Drug interrupted
2. Drug withdrawn
3. Not applicable
• Subject Outcome:
1.
Recovered without sequelae
2.
Recovered with sequelae (describe the sequelae under “Comments” in the Adverse
Event section of the Case Report Form)
3.
Not Recovered, event on-going (follow the subject until a definite outcome can be
determined.  When follow-up data are collected, report follow-up information under
“Comments” in the Adverse Event section of the Case Report Form; if event is serious,
fill in a follow-up Serious Adverse Event Report)
4.
Died (list primary cause of death under “Event Description” of the Adverse Event
section of the Case Report Form; if available, attach a copy of the autopsy report to the
Case Report Form and send a copy to the Sponsor)
• Comments:
Provide other pertinent clinical information and observations under “Comments” in the Adverse
Event section of the Case Report Form.  For example, record predisposing or contributing
conditions, such as previous history, concomitant diseases or medications, and/or procedural
risks.
Subject Follow-up 
Every attempt should be made to follow the subject until the adverse event has resolved or until the 
Investigator determines the subject has returned to an acceptable state of health. 
Reporting Serious Adverse Events (SAEs) 
The Investigator must report all serious adverse events within 24 hours, irrespective of the relationship 
to study medication, to the CRO, by fax or by e-mail (as back-up option), completing the appropriate 
reporting form.  The CRO will then forward this information to EryDel within one business day of receipt.  
The names of the CRO contact will be communicated to the investigators by the CRO prior to the start of 
subject enrollment.  
The minimum information required for an initial report of a Serious AE is as follows: 
•
Sender of report (name, address of Investigator, site number),
•
Subject identification (screening number),
•
Protocol number,
•
Reportable event.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
All SAE reports and any case of overdose leading to an AE or SAE must be faxed using the appropriate 
reporting form to the following number within 24 hours:  
 
  
 
 
 
 
In case of fax failure, all sites can use the following email address as back-up option: 
 
In case of death, a comprehensive narrative report of the case should be prepared by the Investigator and 
sent to the CRO by mail together with the Serious AE Form, retaining a copy on-site. If an autopsy is 
performed, a copy of the autopsy report should be actively sought by the Investigator and sent to the CRO 
as soon as available. A copy of the autopsy report will be retained on-site. 
A follow-up Serious Adverse Event Report will be completed by the Investigator if important follow-up 
information (i.e., diagnosis, outcome, causality assessment, results of specific investigations) are made 
available after submission of the initial form. The follow-up form will be sent to the CRO as described 
above.  
If the Investigator becomes aware of any deaths or Serious Adverse Events after the end of the 60-day 
follow-up window established in the protocol following investigational product administration, they will 
be reported to the CRO as described above. 
Safety Reporting to Investigators, IRBs/IECs, and Regulatory Authorities 
The Sponsor or their designee will be responsible for reporting all SAEs to regulatory authorities, 
investigators, and Independent Ethics Committees / Institutional Review Boards (IRBs/IECs), as 
applicable, in accordance with national regulations for the United States.  For all active investigators located 
in the United States, the Sponsor or their designee will prepare an expedited report for all SAEs that are 
unexpected and potentially related to the study drug, and copies will be distributed according to all 
applicable laws and regulations.  The investigational site also will forward a copy of all expedited reports 
to their IRB/IEC.  
Reporting Overdose 
If the investigational site staff administering the study medication reports that a subject was given more 
than the specified dose of study medication, this will be considered an overdose and must be reported 
immediately to the Investigator. Any instance of overdose, whether symptomatic or not, must be 
communicated to the CRO within 24 hours and be fully documented as a Serious Adverse Event.  Details 
of any signs or symptoms and their management should be recorded including details of any antidote(s) 
administered. 
Pregnancy 
This study will exclude pregnant and breast-feeding patients, and females of childbearing potential, unless 
they are practicing adequate contraception, as determined by their Health Care Provider.  As a further 
precaution, a serum pregnancy test will be performed at Screening and Baseline (Day 0), and repeated at 
Page 98 of 121 
PPD
PPD

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Months 6 and 12 (or at early discontinuation) for all young women who have had a menstrual period within 
the past year. Results of the pregnancy tests at Screening and Baseline must be negative for the patient to 
be randomized to treatment.   
If a patient becomes pregnant during the study, she will be discontinued from the study immediately. 
Patients and their parents/caregivers should be instructed to notify the Investigator if it is determined that, 
after completion of the study they have become pregnant, either during the treatment phase of the study or 
within 30 days of completing the study. Whenever possible a pregnancy should be followed to term, any 
premature terminations reported, and the status of the mother and child should be reported to the CRO or 
EryDel after delivery. 
Based on the estimated half-life of dexamethasone given with the EDS, i.e. less than 4 days, a period of one 
month of continued contraception should follow after study conclusion or early termination due to any 
reason. 
Breaking the Study Blind by the Investigator 
In case of emergency, the Investigator may break the blind for an individual patient, if the knowledge of 
the administered compound is deemed necessary for the safety of the patient.  Breaking of the blind will be 
performed by the Investigator by calling/logging into the IVRS/IWRS system.   
If the study blind is broken, the Investigator must immediately notify the CRO and provide the subject’s 
number. The reason for breaking the blind should be noted on the Adverse Event (or Serious Adverse Event) 
section of the Case Report Form. EryDel will inform the Independent Safety Monitoring Board of the 
unblinding. 
Independent Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will be established by EryDel to review the safety 
of all patients enrolled in this trial, on an ongoing basis. No EryDel employee or investigator involved in 
the EDS clinical studies will be a voting member of this board. The DSMB will regularly review the safety 
data as it accrues. 
The Board will be regularly notified of the occurrence of any fatal or life threatening events immediately 
(within 7 calendar days) and any other serious adverse events within 15 calendar days. The Board will also 
receive updates on any adverse dropouts on a regular basis (once per month).  The Board will have access 
to the blinded safety data including serious AEs and adverse dropouts, as well as clinically significant 
abnormal laboratory tests, vital signs and ECGs at periodic intervals. The Board may request an unblinding 
of the treatment groups if there is a safety concern.  
The DSMB will review all of the safety data on an ongoing basis, with special emphasis on the incidence 
and severity of steroid related events, new infections, and serious AEs and deaths, in addition to the standard 
safety parameters. After reviewing the emerging safety profile for EDS-EP, the Board will make a 
recommendation to EryDel to (a) amend the ongoing study (e.g., increase safety monitoring, modify 
dosing), (b) terminate the EDS program (e.g., the EDS-EP safety profile is unacceptable), (c) continue the 
clinical program as designed. The current study protocol will not be amended or changed (this includes the 
study design and entry criteria) unless mandated by the emerging (unblinded) safety profile of EDS-EP.  
Details of the DSMB charter (separate document) will be submitted to regulatory authorities, and will be 
available to IECs/IRBs upon request. 
Page 99 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
15 SUBJECT COMPLETION AND DISCONTINUATION 
Definitions 
A patient will be considered to have ‘completed’ the Initial Treatment Period of the study when he/she 
returns for the final evaluations on Month 6. ‘Discontinuation’ will refer to any subject who does not 
complete the full 6 months (±30 days) of this initial post-baseline treatment period of the study. Patients 
who continue in the Extension Treatment Period will be considered to have ‘completed’ this period of the 
study when he/she returns for the final evaluations on Month 12. ‘Discontinuation’ will refer to any subject 
who does not complete the full 12 months (±30 days) of this extension. 
Procedures for Handling Withdrawals 
In the absence of a medical contraindication or significant protocol violation, every effort should be made 
by the Investigator to keep the patient in the study; however, should the patient be withdrawn prior to Month 
6 during the Initial Treatment Period or Month 12 during the Extension Treatment Period. All efforts should 
be made to complete all final evaluations and report the observations as thoroughly as possible at the time 
of the patient’s withdrawal, with an explanation of why the subject is withdrawing from the study. 
The criteria for discharging a patient from the study prior to the final study examination are listed below.  
The Investigator must indicate the primary reason (only one can be reported) for discontinuation, as well 
as the date when the decision was made; these will be specified on the ‘End of Study’ form. 
A patient may be withdrawn from study participation if: 
•
Any hypersensitivity or allergic reaction, clearly linked to the study medication, has occurred;
•
the patient experiences an AE sufficiently severe, in the opinion of the investigator, that it
contraindicates the patient continuing in the study;
If the patient experiences a systemic illness considered unrelated to the study medication, it still must
be reported as an AE.
•
the patient/caregiver withdraws consent (e.g. subject refuses to have any more blood samples taken
for the EDS process; in this instance a specific reason must be recorded by the investigator);
•
a major protocol deviation that jeopardizes the continued well-being of the patient or poses an risk to
the patient’s health;
If the patient is able to abstain in the future from activities/behaviors that constituted a major
protocol violation, the patient should be allowed to continue.
•
the patient is lost to follow-up, i.e., the subject did not return to the clinic, and attempts to contact the
subject were unsuccessful.  Attempts to contact the subject must be documented;
•
the Sponsor, IEC/IRB), or regulatory agency terminates the study.
Dropouts will not be replaced.  
The Investigator may terminate a patient’s study participation at any time during the study if a patient meets 
the study termination criteria described above. In addition, a patient or his/her parent/guardian may 
discontinue the patient’s participation without giving a reason at any time during the study. Should a 
patient’s participation be discontinued, the primary reason for termination must be recorded. For patients 
who discontinue prior to Month 6/12, an attempt should be made to perform all final (Month 6/12) 
assessments on the patient, and to follow up on any safety issues until resolution. Patients who discontinue 
prematurely, but return for scheduled efficacy evaluations will become part of the RDO analysis 
population. 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 101 of 121 
Patients who complete 12 months of treatment will be eligible for entry into the open-label study (Study 
IEDAT-03-2018), provided there are no issues that would preclude their continuing in the trial.  
Patients who discontinue prematurely, as well as those patients completing the Initial Treatment Period 
(Month 6) and not continuing in the Extension Treatment Period, and those completing Month 12 of the 
study and not entering the optional open-label study (Study IEDAT-03-2018), should be followed up for 
60 days after their final infusion regarding the occurrence of any Serious Adverse Events.  

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 102 of 121 
16 STATISTICAL METHODS 
 Analysis of Efficacy  
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the change from baseline to the follow-up assessments at Days 90 
and 180, in the total score on the ‘Modified’ International Cooperative Ataxia Rating Scale (ICARS).  
Key Secondary Efficacy Endpoint 
The key secondary efficacy end point is the CGI-C rating of change from baseline at the follow-up 
assessments at Days 90 and 180.  
Other Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed in the study: 
•
The change of CGI-S score from baseline to follow-up based on repeated measures at Days 90 and
180
•
The change of VABS score from baseline to follow-up based on repeated measures at Days 90 and
180
Tertiary Efficacy Endpoints  
The following tertiary efficacy endpoint will be assessed in the study: 
•
The change of QOL scores (EQ-5D-5L scale) from baseline to follow-up based on repeated
measures at Days 90 and 180.
This measure will be considered exploratory. 
Statistical Methods 
All data collected on the A-T NEST from the selected centers on Day 2 and subsequent visits will be 
delivered to John Hopkins Statistical group for evaluation of the data, and performance of any analyses 
needed to determine/ confirm the psychometric properties of the scale.  
Sample Size 
Based on the very low prevalence of AT, as well as the high disability, morbidity and mortality, the number 
of subjects available for prospective trials is extremely limited.  Furthermore, only aggregate Phase II study 
results are available (IEDAT-ERY01-2010 Clinical Study Report).  Hence, in the absence of a file with the 
raw item score for each subject, the treatment effect and variability of the ‘Modified’ ICARS is unknown.  
Therefore the parameters needed to identify an appropriate sample size for this study were estimated using 
the aggregate Phase II results.  
Sample size calculations are based on the analysis of the primary efficacy variable (i.e., ‘Modified’ ICARS) 
under the following assumptions.  
•
For aggregate ICARS, a treatment difference of 3.7 - 4.2 for the ~14-22 mg dose versus placebo
with respect to ICARS measurements is expected, with a standard deviation of 5.0 - 7.4 (IEDAT-
ERY01-2010 Clinical Study Report).

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
•
For ‘Modified’ ICARS, the treatment difference is expected to be less than the aggregate ICARS,
therefore, instead of examining a treatment difference between 3.7 and 4.2, the range between 3.0
and 3.7 was examined.  The decrease in treatment difference is expected given that most of the
questions in the Kinetic Function domain are not included in the ‘Modified’ ICARS and Chessa et
al (2014) reported this domain as demonstrating the greatest overall improvement.
•
For ‘Modified’ ICARS, the standard deviation is expected to be more than the aggregate ICARS,
therefore, instead of examining a standard deviation between 5.0 and 7.4, the range between 5.0
and 8.0 was examined.  This increase is expected given that removing questions from health
assessment instruments can decrease precision and increase standard deviations (Awad, 2008;
McHorney et al, 1992; McHorney, 1997).
•
The primary efficacy variable will be tested, comparing ~14-22 mg dose versus placebo at the 0.05
two-sided significance level. Testing of the ~5-10 mg dose versus placebo will only proceed if the
~14-22 mg dose is significant. Consequently, no adjustment for multiplicity is needed for testing
the two dose levels.
Table 4 below provides power estimates for the range of potential treatment differences and standard 
deviations.  Estimates must be based on ranges, since point value estimates for ‘Modified’ ICARS are not 
available. 
Table 4. Power given treatment difference and standard deviation 
estimates for a sample size of 54 
Treatment Difference 
Standard Deviation 
Power 
3.0 
5.0 
99.3% 
6.0 
95.7% 
7.0 
88.3% 
8.0 
78.7% 
3.2 
5.0 
99.7% 
6.0 
97.5% 
7.0 
91.9% 
8.0 
83.6% 
3.4 
5.0 
99.9% 
6.0 
98.6% 
7.0 
94.6% 
8.0 
87.8% 
3.6 
5.0 
>99.9%
6.0 
99.3% 
7.0 
96.6% 
8.0 
91.1% 
3.7 
5.0 
>99.9%
6.0 
99.5% 
7.0 
97.3% 
8.0 
92.5% 
As seen in Table 4, a sample size of 54 provides sufficient power for a study design with two repeated 
measures to assess the primary efficacy endpoint of change from baseline in ‘Modified’ ICARS between 
two groups with a two-sided 0.05 significance level, when the treatment difference ranges between 3.0 and 
3.7, and the standard deviation ranges between 5.0 and 7.0 (PASS®, Module “Tests for Two Means in a 
Repeated Measures Design”). 
Page 103 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
The final sample size will be adjusted for 10% loss to follow-up, for a final sample size of about 60 per 
group. It is anticipated that the screen failure rate will be approximately 25%; therefore, at least 240 patients 
would need to be screened to enroll 180 eligible patients. Due to the Covid-19 outbreak, the enrollment was 
closed with 175 randomized patients as of the 30th of March 2020. Statistical guidance determined that 175 
patients (versus the goal of 180 patients) would not materially change the power of the study. 
 Populations for Analysis 
The following analysis sets will be used: 
1) Intention-to-treat population (ITT): All randomized patients.
2) Full Analysis Set (FAS) (Also referred to as MITT): All 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.
3) Per Protocol Population (PP): all patients enrolled into the study who received at least one dose of
randomized treatment, fulfilled all Inclusion/Exclusion criteria, did not have any major protocol violations,
and completed the Initial Treatment Period of the study as planned (ie, returned for a final evaluation).
Patients who discontinue prematurely for reasons other than protocol violations, but return for their final
evaluation, would still be part of the PP population, e.g. patients who discontinue due to AEs should be
included.
4) Safety Population (SP): all patients who received at least one dose of randomized treatment.
Background and Demographic Characteristics 
The background and demographic characteristics will consist of age, sex, height, body weight, BMI, past 
and current medical conditions, and history of disease. Continuous variables will be summarized by mean, 
standard deviation, median, and range (minimum, maximum), and discrete variables will be summarized 
using frequencies and percentages.  
Study Medication 
The number of patients receiving each dosing condition (~5-10 or ~14-22 mg DSP/infusion or placebo) 
will be reported, and the average dose of EDS-EP (RBC-encapsulated DSP) in patients administered the 
active treatment (Groups 1 and 2, Safety population), based on measurements of samples taken from the 
infusion bags prior to dosing, will be summarized by mean, standard deviation, median, and range 
(minimum, maximum). 
Concomitant Medications and Therapy 
A listing of concomitant medications administered from the time of dosing of the study medication through 
completion of the final evaluation (Month 6/12 or early discontinuation) will be provided by treatment 
group.  Concomitant medication taken during the Screening period will be listed separately.  
Safety Evaluations 
All patients in the Safety Population will be included in the safety analyses. All adverse events will be listed 
and summarized by body system and preferred term.  The incidence of AEs (%) and their intensity and 
relatedness to the study drug, as assessed by the Investigator, will be reported.  Serious adverse events 
(SAEs) and events which are newly occurring or worsening after administration of the study medication 
will be summarized. In addition, adverse events that result in death or discontinuation (ADO) of the study 
medication will be listed separately. 
Page 104 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 105 of 121
Other safety parameters such as vital signs, standard laboratory parameters, ECGs, physical/neurological 
examination findings, and special laboratory parameters will be listed and summarized accordingly. 
Abnormal and clinically notable values will be identified and listed for each parameter, as appropriate. 
Where feasible, mean changes from baseline will be examined using a paired t-test.  
16.2.6.1 Interim Safety Analysis 
An independent Data Safety Monitoring Board (DSMB) will be established by EryDel to review the safety 
of all patients enrolled in this trial, on an ongoing basis. No EryDel employee or investigator involved in 
the EDS-EP clinical studies will be a member of this board. The DSMB will periodically review the safety 
data accrued. 
The DSMB will meet regularly to assess the safety from the emerging data. The first DSMB meeting will 
occur prior to the start of the trial, and the DSMB will decide when the first data review safety DSMB 
meeting will occur. They will also propose a tentative schedule for subsequent meetings that they may alter 
based on emerging safety data. The time between successive meetings should not be more than three 
months. 
After reviewing the emerging safety profile for EDS-EP, the DSMB will make a recommendation to EryDel 
to (a) amend the ongoing EDS-EP study, (b) terminate the EDS-EP, or (c) continue the clinical program as 
designed. The current study will not be amended or changed (this includes the study design and entry 
criteria) unless mandated by the emerging (unblinded) safety profile of EDS-EP.  
A separate DSMB Statistical Analysis Plan will be developed for specifying the analyses, tables, listings 
and figures to be prepared for DSMB meetings.  
The DSMB will be regularly notified of the occurrence of any fatal or life threatening events immediately 
(within 7 calendar days) and any other serious adverse events within 15 calendar days. The DSMB will also 
receive updates on any adverse dropouts on a regular basis (once per month).  The DSMB will have access 
to the blinded safety data including serious AEs and adverse dropouts, as well as clinically significant 
abnormal laboratory tests, vital signs and ECGs at periodic intervals. The DSMB may request an unblinding 
of the treatment groups if there is a safety concern.  
Details of the DSMB charter (separate document) will be submitted to regulatory authorities, and will be 
available to Ethics Committees/IRBs upon request.  
 Efficacy Analyses 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the change from baseline to the follow-up assessment at Days 90 and 
180 in the total score on the ‘Modified’ International Cooperative Ataxia Rating Scale (ICARS). 
The null (H0) and alternative (H1) hypotheses for the efficacy analysis of change from baseline in the 
‘Modified’ ICARS total score are:  
H0: There is no difference between Group 2 (EDS-EP ~14-22 mg Dose) and the Placebo group with 
respect to ‘Modified’ ICARS; 
H1: There is a difference between Group 2 (EDS-EP ~14-22 mg Dose) and the Placebo group with 
respect to ‘Modified’ ICARS. 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 106 of 121 
Statistical significance for efficacy and the study as a whole will be declared if: 
The null hypothesis for the primary efficacy analysis (no statistical difference between Group 2 
[EDS-EP ~14-22 mg] and the Placebo group) with respect to change from baseline in ‘Modified’ 
ICARS is rejected at the 0.05 two-sided significance level.  
Efficacy of the ~5-10 mg dose EDS-EP versus Placebo 
If the null hypothesis for the primary efficacy analysis (no statistical difference between EDS-EP 
~14-22 mg and Placebo) with respect to change from baseline in ‘Modified’ ICARS is rejected, the 
efficacy of EDS-EP ~5-10 mg versus Placebo with respect to change from baseline in ‘Modified’ 
ICARS will be tested at the 0.05 two-sided significance level.  
Key Secondary Efficacy Endpoint 
•
CGI-C at the follow-up assessments at Days 90 and 180.
Other Secondary Efficacy Endpoints 
•
The change of CGI-S score from baseline to follow-up based on repeated measures at Days 90 and
180
•
The change of VABS score from baseline to follow-up based on repeated measures at Days 90 and
180.
Tertiary Efficacy Endpoint 
•
The change of QOL scores (AD-50 or SQL scale) from baseline to follow-up based on repeated
measures at Days 90 and 180.
 Randomization  
The milestones for the randomization process are depicted in Figure 1 and described in items 1- 4 below. 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 107 of 121 
Figure 1. Trial periods and randomization/re-randomization time points 
1.
Initial Randomization. This will occur at the start of the double-blind period. Because this trial will
enroll patients with a rare condition, the sample size will be limited. Important balancing factors include
gender and age (age < 10, age > 10), and region. There are three treatment groups. For this situation,
probabilistic baseline randomization (pBAR), or equivalently, probabilistic covariate baseline
minimization is desirable. The re-randomizations discussed in (2)-(4) will be performed at the time of
the initial randomization. (See Figure 2)
2.
Re-randomization of remaining placebo patients after 6 months of the Initial Double Blind treatment
assignment. Among patients randomized to placebo who complete their initial 6 months of double-
blind dosing, every third such placebo patient will be randomized 1:1 to active dose at either the ~14-
22 mg or ~5-10 mg dose level.
3.
Re-randomization of remaining placebo patients after 9 months of the Initial Double Blind treatment
assignment.  Among patients randomized to placebo who complete their initial 9 months of double-
blind dosing, every other such placebo patient will be randomized 1:1 to active dose at either the ~14-
22 mg or ~5-10 mg dose level.
4.
Re-randomization of remaining placebo patients after 12 months of the Initial Double Blind treatment
assignment.  For patients randomized to placebo who complete their initial 12 months of double-blind
dosing, all such placebo patients will be randomized 1:1 to active dose at either the ~14-22 mg or ~5-
10 mg dose level. These treatment assignments will be made in the open-label extension study (Study
IEDAT-03-2018) for those placebo patients who continue treatment in this study.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Figure 2. Randomization schematic 
The randomization scheme presented in Figure 2 assumes that no patients discontinue from the study. For 
patients randomized to placebo at baseline, random assignments to switch to either of the active treatment 
groups (EDS-EP ~14-22 mg or ~5-10 mg) at Month 6 or 9, or to remain on placebo throughout the study, 
will be done at baseline to avoid any bias in selecting placebo patients for the switch to EDS-EP.   
When the design of the pBAR randomization is in place, simulations will be used to test the randomization 
system. The simulations will be designed 
1.
to subject the pBAR implementation to conditions beyond the control of the study team, such as
the order that patients arrive for randomization, to assess the robustness of the algorithm. The ability
of the system to handle re-ordering of the arrival order of patients will be examined to see how well
the desired balance is achieved.
2.
to examine the extent to which random fluctuation will disturb the balance, both overall, and within
the desired strata.
3.
to subject the IVRS/IWRS system implementation to various stresses, as a validation.
Handling of Dropouts and Missing Data 
Patients who discontinue treatment prematurely are defined as dropouts. Those patients who discontinue 
treatment prematurely but return for scheduled efficacy assessments at 6, 9 and 12 months are defined as 
RDOs. Missing data will be handled as described in the analysis of primary efficacy parameter. Retrieved 
dropouts will be used in sensitivity analyses. 
Page 108 of 121

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Analysis of the Primary Efficacy Parameter 
The primary efficacy variable, change from baseline in ‘Modified’ ICARS total score, will be analyzed 
using a Mixed Model Repeated Measures (MMRM) approach, with the baseline value as covariate and age, 
treatment, region, baseline value and treatment interaction, visit and treatment-by-visit interaction as fixed 
effects.  The estimated treatment difference, together with the associated two-sided 95% CI and p-value, 
will be calculated. Unstructured covariance matrices will be used. Model effect estimation will be based on 
restricted maximum likelihood (REML). The region and treatment interaction can be tested in a separate 
model and if a significant interaction is found, then forest plot will be used to present the region specific 
treatment difference and associated 95% confidence interval. 
The primary MMRM analysis will assume missing at random (MAR) as a means of handling missing data. 
Sensitivity analyses will be performed to evaluate the MAR assumption. For this, ANCOVA with missing 
data imputed using Last Observation Carried Forward (LOCF), Observed Case (OC), and OC + RDO will 
be used. 
Analysis of the Key Secondary Efficacy Parameter 
The analysis of the key secondary efficacy measure, CGI-C, will be performed using ANCOVA, with age, 
sex, treatment, region, visit and treatment-by-visit interaction as fixed effects. The estimate of the treatment 
difference parameter, together with the associated two-sided 95% CI and p-value at will be calculated.  
In this analysis, LOCF will be used for missing data. Sensitivity analyses will use OC, OC + RDO for 
imputing missing values. 
Hypothesis Testing and Handling of Multiple Comparisons 
The ~14-22 mg dose of the primary efficacy end point will be tested at the two-sided significance level of 
0.05. With this requirement, the overall family-wise error rate (FWER) can be no greater than 0.05 
two-sided. The study will be judged statistically significant if the ~14-22 mg dose of the primary efficacy 
endpoint is significant. 
The ~5-10 mg dose of the primary efficacy endpoint will be tested only if the ~14-22 mg dose is found to 
be statistically significant compared to placebo. In this way, the 0.05 two-sided significance level will be 
maintained and no adjustment will be necessary. 
Following the testing for the primary endpoint, an ordered hierarchical testing (step-down) of the key 
secondary endpoint (CGI-C), and other secondary endpoints, i.e. CGI-S, followed by VABS, will be 
performed, according to the methodology described by Dmitrienko and D’Agostino (2013), as shown in 
Figure 3.  
Page 109 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Figure 3. Hierarchical Testing Procedure for Primary and Secondary Endpoints 
Secondary endpoints will be tested in the following order (see also Figure 3 flowchart). A sequential testing 
approach will be used, for which the ~14-22 mg dose versus placebo for the secondary endpoints will be 
tested in the following order: 1) CGI-C, 2) CGI-S, and 3) VABS. This is to be followed by testing the same 
secondary 
variables 
in 
the 
same 
order 
for 
the 
~5-10 
mg 
dose 
versus 
placebo: 
1) CGI-C, 2) CGI-S, and 3) VABS. All tests will be performed at the 0.05 two-sided significance level, and 
testing will continue to the next variable/dose level only if significance is achieved for the current test.
The analytic approach for these variables will use ANCOVA with missing value imputed using LOCF, OC, 
and OC + RDO. 
The analyses of the EQ-5D-5L will be exploratory. 
Efficacy Analysis – Extension Treatment Period 
For the Extension Treatment Period, comparisons will be made for the ‘Modified’ ICARS, CGI-S, VABS, 
and QoL [EQ-5D-5L] using ANCOVA with missing values imputed using LOCF, OC, and OC + RDO.  
Analyses for the various randomization periods 
The primary analysis will compare the treatment groups as specified in Figure 3 (in the “Primary Testing” 
panel) after 6 months of treatment. Only these 6-month evaluations will be controlled at the Type I FWER 
of 0.05 two-sided.  
Further analyses will make the same comparisons after 9 months of treatment, and again, after 12 months 
of treatment. Because these later analyses will be very underpowered, these analyses will be for descriptive 
purposes only. However, p-values will be presented strictly as an aid to understanding the results, but will 
provide no basis for statistical inference.   
Page 110 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 111 of 121 
Maintenance of the blind for the Extension Treatment Period 
The blind will be broken after all patients have completed the 6-month, double-blind, Initial Treatment 
Period, and the database for this period has been locked, so that the primary efficacy analysis can be 
performed.  Therefore, procedures will be implemented to ensure that the blind is maintained for the 
6-month, double-blind, Extension Treatment Period, so that the analyses of the data collected in this
extension period are valid.  Procedures will be put in place to ensure that the investigators, site staff, Sponsor
personnel, and CRO personnel, including Data Managers, Project Managers, Clinical Research Associates
(CRAs), Medical Monitors, Pharmacovigilance personnel, Medical Writers, etc., who will have access to
the data from the Extension Treatment Period, are not made aware of the treatment assignments of any
patients continuing treatment in this extension period, prior to the last patient completing the extension
period and the database being locked.  The personnel mentioned above should have no reason to require
access to the individual patient treatment assignments, except in the case of an emergency unblinding
necessitated by a significant adverse event.
In contrast, the Biostatistics team [statistician(s), programmer(s), CDISC engineer, etc.] that has been 
assigned to work on the 6-month Initial Treatment Period, and is responsible for unblinding and performing 
the primary analysis for the study on the data from this period, will need to have access to the treatment 
assignments.  Therefore, this team will not be involved in the analysis of data for the extension period.  
Instead, a second Biostatistics team will be trained prior to the start of the unblinded analysis, and will take 
responsibility from the start of the unblinded analysis through to the completion of the trial.  
To further ensure that the blind is maintained, the following restrictions on communications within the 
CRO, and between the CRO and the Sponsor, will be put in place: 
•
The Unblinded Biostatistics team will have no direct communication with any blinded personnel
within the CRO, other than for purposes of oversight. Any requests for clarifications of data will
come through the Sponsor to the Project Manager, Project Management Associate and the Lead
Data Manager.
•
The Unblinded Statistical team will be removed from all mail circulation lists and from all meeting
invites related to the ongoing extension period of the study. Separate oversight calls will be
arranged with the CRO Project Manager, Unblinded Biostatistics team and the Sponsor.
•
Any communications or documentation generated during the primary efficacy analysis will be filed
outside the Trial Master File (TMF) and will be incorporated into the TMF at the end of the study
to meet requirements of GCP. The nature of this repository will be agreed with the Sponsor in
advance of the primary analysis.
Additional details of the procedures that will be followed to maintain the blind in the Extension Treatment 
Period, after unblinding of treatment assignments for the Initial Treatment Period, will be included in the 
Statistical Analysis Plan and Data Management Plan prepared by the CRO.  

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
17 ETHICS 
Ethical Considerations 
The study will be carried out in accordance with the Declaration of Helsinki, as amended by the 64th General 
Assembly of the World Medical Association, Fortaleza, Brazil, October 2013 (Appendix 1).  
Subject Information and Informed Consent 
The Informed Consent Form, as well as the Subject Information Sheet, must be approved by the IRB/IEC 
together with the Study Protocol, before the start of the study.  
All subjects, or if necessary their parent/caregiver or legal representative (with assent by the subject), must 
sign and personally date an approved Informed Consent Form after receiving detailed written and verbal 
information about the reason, the nature, the required procedures, the intended duration and the possible 
risks and benefits and any discomfort associated with the study. Each subject should be informed that 
his/her participation in the study is voluntary and that he/she may refuse to participate or withdraw from 
the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled. 
The language used in the oral and written information about the trial, including the written Informed 
Consent Form should be as non-technical as practical and should be understandable to the subject. The 
subject must be given ample time to read and to understand the Subject Information Sheet and opportunity 
to inquire and ask any clarification about the trial before signing the Informed Consent Form. 
No study procedure can be performed (including the screening visit) before the informed consent 
form has been signed. The informed consent procedure must be done according to the guidelines provided 
in the Declaration of Helsinki and the ICH E6 Guideline for Good Clinical Practice.  
The subject must be made aware and agree that personal information may be scrutinized during audit / 
inspection by competent authorities and properly authorized persons.  However, personal information will 
be treated as strictly confidential and will not be publicly available. 
By signing the Investigator Statement (Appendix 3), the Investigator assures EryDel Pharmaceuticals that 
Informed Consent will be obtained.  
Original signed Informed Consent Forms will be filed with the Investigator’s File. 
IEC/IRB Approval 
The protocol, Investigator’s Brochure, Subject Information Sheet, Informed Consent Form and any 
advertisement for the recruitment of subjects must be reviewed and approved by an appropriately 
constituted IEC/IRB, as required in Chapter 3 of the ICH E6 Guideline. A copy of the Committee’s dated 
approval and a list of the members of the IEC/IRB will be given to the Sponsor for the Sponsor's files. A 
copy will be also included in the Final Report. Written IEC/IRB approval must be obtained by the Sponsor 
prior to shipment of study agent or subject enrollment.  Any amendments to the protocol, Informed Consent 
Form (ICF) or Subject Information Sheet, other than administrative ones, must be approved by this 
committee.   
Page 112 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 113 of 121 
18 ADMINISTRATIVE CONSIDERATIONS 
Regulatory Requirements: Sponsor/Investigator Obligations 
This study will be conducted in accordance with the Declaration of Helsinki and the ICH E6 Guideline 
(Good Clinical Practice, see Appendix 2).  To ensure compliance the Investigator agrees, by written consent 
to this protocol, to fully cooperate with compliance checks by allowing access to all documentation, 
including subjects’ hospital files (the source documents), by authorized individuals. 
Curriculum Vitae 
The Investigator and any co-Investigator(s) must provide the Sponsor with current copies of their own 
curriculum vitae. 
Investigator and Study Administrative Structure 
The administrative structure of the study (e.g., Investigators, monitoring and evaluation personnel, 
laboratory facilities, clinical trial supply management) is presented in the Trial Master File. 
The listing should include: 
a)
The Investigator(s);
b)
Any other person carrying out observations of primary or other major efficacy or safety
variables, such as a nurse, physician's assistant, clinical psychologist, clinical pharmacist or
house staff physician.
Investigator’s Statement 
This document, signed and dated by the Principal Investigator, describes the Investigator’s obligations. The 
standard text is appended to the protocol (Appendix 3). 
Monitoring Procedures 
Study Monitoring 
A CRO will be selected by the Sponsor to oversee the conduct of the trial.  An appropriate representative 
of the CRO (Study Monitor) will maintain contact with the Investigator and will visit the study site for the 
purpose of discussing and/or retrieving data. An initiation (pre-study) visit will be made by the Study 
Monitor to discuss with the Investigator the protocol and the obligations of both the Sponsor and the 
Investigator.  The Investigator must allow the Study Monitor to perform periodic, interim monitoring visits.  
The purposes of these visits are: 
• To verify that written Informed Consent was obtained prior to each subject’s participation in the trial.
• To assess the progress of the study.
• To review the compliance with the study protocol.
• To determine whether all adverse events were appropriately reported.
• To determine whether the Investigator is maintaining the essential documents.
• To discuss any emergent problem.
• To check the Case Report Forms (CRFs) for legibility, accuracy and completeness.

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
• To validate the contents of the CRFs against source documents.
• To collect completed CRFs.
• To assess the status of drug storage, dispensing and retrieval.
The Investigator will make available the source documents for inspection.  This information will be 
considered as confidential. Violations of and deviations from the protocol must be notified to the Study 
Monitor as soon as possible. 
The Study Monitor will perform a closeout visit at the time when all CRFs have been retrieved and all 
queries have been answered.  
Case Report Forms (CRFs) 
Electronic Case Report Forms (eCRFs) will be provided for each subject. The study Monitor will review 
the forms at each site visit.  
Case Report Forms must be completed for all subjects who sign Informed Consent, even if the subject fails 
to complete the study. No section of the CRFs is to be left blank without an appropriate explanation by the 
Investigator, since the lack of such explanation may necessitate discarding an otherwise usable observation. 
If requested, copies of the CRFs are to be made available to the appropriate regulatory agencies. 
Auditing/Inspecting 
The Investigator will make all pertinent records available, including source documentation, for inspection 
by regulatory authorities and for auditing by the Sponsor.  This information will be considered as 
confidential. Audits/Inspections may occur any time from start to after conclusion of the study. When an 
Investigator signs the protocol, he/she agrees to allow regulatory authorities and EryDel auditors to inspect 
his/her study records. 
Archiving of Records 
Copies of the protocol, subject identification codes, eCRFs, source data, Informed Consent Forms and other 
documents pertaining to the study conduct must be kept for the maximum period of time as required by the 
study center. This time period must be at least two years after the last approval of the marketing application 
of the study agent in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region, or at least two years have elapsed since the formal discontinuation of clinical development 
of the study agent. 
No study document should be destroyed without prior written agreement between the Sponsor and the 
Investigator. Originals of all documentation and copies of outgoing correspondence concerning the study 
will be stored and retained by the Sponsor in a safe area in the Trial Master File for the lifetime of the 
product. In particular, the final report sent by the Investigator to the IRB/IEC must be retained by the 
Sponsor, or the subsequent owner, for five years beyond the lifetime of the study agent. 
Final Clinical Study Report 
The Final Clinical Study Report (CSR) will be written by the CRO, according to specifications to be defined 
by EryDel.  
Page 114 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 Study Documentation and Publication of Results 
Study Documentation 
All unpublished documentation (including the protocol, CRFs and Investigator's Brochure) given to the 
Investigator is strictly confidential.  All recipients must agree not to disclose the information herein 
contained to any person not connected with the study without the prior written authorization of EryDel 
S.p.A.  The submission of these documents to the IRB/IEC is expressly permitted.  The involved parties 
agree that the results of this study will be used in their original form and/or in a global report for submission 
to governmental and regulatory authorities of any country.
All information communicated to the investigator(s) by EryDel is the exclusive property of EryDel S.p.A. 
The Principal Investigator will ensure this information shall be kept strictly confidential by him/her or any 
other person connected with the study and shall not be disclosed to any third party without the prior written 
consent of EryDel. 
Publication of Results 
Any formal presentation or publication of the data from this trial will be considered as a joint publication 
by the Investigator(s) and EryDel.  Authorship will be determined by a Publication Committee consisting 
of the lead investigator(s) from the trial, representatives from EryDel, and an external consultant with 
expertise in the field. For multi-center studies, it is mandatory that the first publication is based on data 
from all centers, analyzed as stipulated in the protocol by a statistician designated by EryDel.  Investigators 
participating in this study agree not to present or publish data gathered from a single center or sub-group of 
centers before the full initial publication, unless agreed to by all other investigators and EryDel.  Authorship 
of any publication resulting from this trial will include members of each of the contributing centers and key 
contributors to the design and execution of the study, including EryDel personnel. 
EryDel will form a study publication committee to coordinate and develop a publication policy and help in 
its implementation.  The publication committee will be comprised of the Principal Investigators from each 
of the countries (to be determined by EryDel), based on their contributions to study conduct and their status 
in the field.  The other members of the publication committee will include a representative of EryDel and 
an external consultant.  Members of the publication committee cannot serve as first authors of more than 
one primary publication.  
The authorship of the first multicenter paper will be comprised of members of the publication committee, 
Principal Investigators of the three sites with the highest numbers of valid patients, and EryDel 
representatives who have made significant contributions to the design, conduct and analysis of the results. 
The Principal Investigators of all contributing centers will be acknowledged in the publication.  The 
Publication Committee will decide on the content, journal, and sequence of publications /presentations. 
Any publication, abstract, or paper of any information or material relating to or arising out of the present 
clinical study shall be sent to EryDel for review at least sixty (60) days before presentation at any congress, 
or publication of the final form(s) by any journal. EryDel will inform the Investigator of any changes or 
deletions necessary to preserve EryDel’s confidential and proprietary technical information. All rights and 
interests worldwide in any inventions, know-how or other intellectual or industrial property rights, which 
arise during the course and/or as a result of the present clinical study or which arise from the information 
or materials supplied under this Agreement, shall be assigned to, vest in and remain the property of EryDel 
S.p.A.
Financial Agreement 
A financial agreement (separate from the protocol) will be made and signed by EryDel S.p.A. or their 
designee and by a representative of the Institution where the study will be conducted.  
Page 115 of 121 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 Termination of Study 
In the event that the Investigator is unable to continue the study, another suitable sub-Investigator at the 
site will be designated to serve as the Investigator in the interim, until a new Investigator can be identified. 
This interim Investigator, if approved by the site IRB/IEC will carry out the responsibilities of the 
Investigator. Documentation testifying to this will be submitted to the Study Monitor within 10 days of the 
change. Within 6 months of the appointment of the interim Investigator, the new Principal Investigator 
must be identified and approved by both EryDel S.p.A. and the IRB/IEC for the study to continue at the 
site.  
If the Sponsor and/or the Investigator should discover conditions arising during the study that indicate it 
should be terminated, an appropriate schedule for termination will be instituted.  If the Investigator 
terminates the study, an explanatory letter will be provided to EryDel. Should the study be discontinued 
due to a decision by EryDel, the Investigator will be reimbursed for reasonable expenses incurred and for 
the subjects actually treated according to the study protocol. 
 Study Discontinuation by the Sponsor 
The Sponsor may terminate the entire study, or the study at an individual site, at any time, for any of the 
following reasons: 
•
failure to enroll subjects;
•
protocol violations or deviations;
•
inaccurate or incomplete data;
•
non GCP compliance;
•
completion of enrolment;
•
administrative reasons.
 Study Discontinuation by the Investigator 
The Investigator may terminate his/her participation in the study in consultation with the Sponsor due to 
the occurrence of significant adverse events and/or adverse drug reactions endangering the health of 
subjects, which make it ethically unacceptable to continue. 
 Insurance Policy 
EryDel S.p.A., or its designee, will provide insurance coverage for damages emerging from the trial and 
involving the subjects treated with the test compound, provided that the Investigator(s) have adhered to the 
terms and provisions of the protocol. The principal Investigator will be supplied with all data concerning 
the insurance company and policy number for a maximum sum insurable. 
 Financial Disclosure 
The Principal Investigator and sub-Investigators will provide the Sponsor with adequate and accurate 
financial information (PD35) to ensure that the Sponsor can make complete and accurate financial 
certification of disclosure statements to concerned regulatory authorities.  It is the duty of the Investigator 
to promptly update previous information provided to the Sponsor if there are salient changes that occur 
during the course of the study, and for a period of one year following its completion (last patient last visit). 
The study will be performed under a US IND; therefore, all Investigators/sub-Investigators, contractors, 
etc., are expected to comply with the obligations as specified in the CFR (21 CFR part 54) by the US 
FDA, 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 117 of 121 
including requirements for full Financial Disclosure (Guidance for Clinical Investigators, Industry and FDA 
Staff: Financial Disclosure by Clinical Investigators, February 2013). 

Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
 
Page 118 of 168 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 119 of 121 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 120 of 121 
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Clinical Study Protocol IEDAT-02-2015   
 
 
EDS in Ataxia Telangiectasia Patients 
Version 1.0, 09May2015; Version 2.1, 16Nov2015; Version 3.0 (Amend. 1), 01Feb2016; Version 3.1 (Amend. 2), 
28Apr2016; Version 3.2 (Amend. 3), 25May2016; Version 4.0 (Amend. 4), 29Nov2016; Version 5.0 (Amend. 5, 
Site-specific), 20Sep2017; Version 6.0 (Amend. 6), 29Sep2017; Version 7.1 (Amend. 7.1), Final 13 March 2018, 
Version 8.0 (Amend. 8.0), Final 23 April 2018; Version 10.0 (Amend. 10), Final 16 April 2019; Version 11.0 
(Amend. 11), Final 24 Jun 2020 
Page 121 of 121
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