Extension Treatment Using EryDex System in Patients With AT Who Participated in the ATTeST-IEDAT-02-2015 Study
- Conditions
- Ataxia TelangiectasiaGenetic Syndrome
- Interventions
- Combination Product: EryDex System
- Registration Number
- NCT03563053
- Lead Sponsor
- Quince Therapeutics S.p.A.
- Brief Summary
Primary Objective
To monitor and evaluate the long-term safety and tolerability of EDS-EP in AT patients.
Secondary Objective
To evaluate the long-term effect of EDS-EP on health-related Quality of Life (QoL; EQ-5D-5L scale).
Exploratory Objective:
To evaluate the long-term effect of EDS-EP in treating central nervous system (CNS) symptoms, as measured by the "Modified" International Cooperative Ataxia Rating Scale (mICARS), and Clinical Global Impression of severity and change (CGI-S/C).
- Detailed Description
This was an international (North America, Europe, Africa, Asia and Australia), multi-center, prospective, open-label treatment study, designed to continue to provide the study medication to all patients who completed 12 months of treatment (including those treated with placebo) in the ATTeST-IEDAT-02-2015 trial, completed the study assessments, do not present safety contraindication to continuation of treatment, and provided informed consent.
The study aimed to collect information on the long-term safety and efficacy of the trial treatment.
Patients meeting all selection criteria received monthly infusions of EDS-EP (dose range of \~14-22 mg DSP/infusion). If this dose of EDS-EP was not tolerated, the patient was discontinued from the study.
During the study, long-term efficacy assessments were performed every 6 months, while safety parameters were assessed at each monthly visit. The Schedule of Visits and assessments for the first 12 months were replicated for the second year onwards for patients who continued EryDex treatment beyond 12 months.
The analysis of the EryDex long-term safety and tolerability was based on the occurrence of Treatment-Emergent Adverse Events (TEAEs), including Serious AEs and discontinuations due to AEs. The long-term effect was measured by the "Modified" International Cooperative Ataxia Rating Scale, (mICARS), Rescored mICARS, Clinical Global Impression of severity and change (CGI-S/C) and health-related Quality of Life (QoL; EQ-5D-5L scale).
The ICARS, EQ-5D-5L and the CGI-C / S were administered by a properly qualified rater identified at each site who performed the ratings on the efficacy measures. The ICARS rater remained blinded to other assessments and did not have access to the safety data. The CGI rater did not have access to the ICARS ratings or safety data but was able to refer to other scales in scoring the CGI.
All patients enrolled in this study have participated in Study ATTeST-IEDAT-02-2015, and there was no de novo enrollment of new patients.
EryDel S.p.A (now Quince Therapeutics) decided to discontinue the IEDAT-03-2018 study in India due to the COVID-19 pandemic. On 13 Apr 2022, after the last patient completed one year of EryDex treatment, EryDel S.p.A. communicated the end of the open label extension study IEDAT-03-2018 and the stop of the EryDex treatment for patients in the context of this study.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 104
- Patient completed the double-blind period in the ATTeST study and completed the final (Visit 15 / Month 12) Efficacy Assessments of ATTeST or discontinued the study during the COVID-19 pandemic.
- Patient tolerated the study medication, without any evidence of steroid adverse events, or treatment-related severe events / serious adverse events.
- Body weight > 15 kg.
- The patient and his / her parent / caregiver (if below the age of consent), or a legal representative, provided written informed consent to participate. If consent was provided solely by the caregiver in accordance with local regulations, the patient also was asked to provide their assent to participate in the study.
- Patient did not present safety contraindication for continuation of treatment, as determined by the Principal Investigator (PI) according to the procedures described below.
Moreover, patients who were discontinued from the ATTeST study during the COVID-19 pandemic were eligible to receive the EryDex treatment in the IEDAT-03-2018 study, in the absence of safety contraindications to continuation of the treatment, and after signing the informed consent.
There were no de novo enrolled patients.
Patients who met one or more of the following criteria were not considered to be eligible to participate in the study:
General
-
Females that were:
- Pregnant, or were breast-feeding (for EU countries only)
- Of childbearing potential, pregnant, or were breast-feeding (for US and Rest of World countries).
Females of childbearing potential using adequate birth control, as determined by their Health Care Provider, were eligible.
-
A disability that may prevent the patient from completing all study requirements.
-
Current participation in another clinical study with another investigational drug.
Medical History and Current Status
-
Cluster differential 4 positive (CD4+) lymphocytes count < 400 / mm3 (for patients 6 years of age) or < 150 / mm3 (for patients > 6 years). In presence of oral infections, like oral candidiasis, documented at the screening or recurrent as per medical history documentation, the limit increases to < 200 / mm3 (for patients > 6 years).
-
Current neoplastic disease.
-
Severe impairment of the immunological system.
-
Severe or unstable pulmonary disease.
-
Uncontrolled diabetes. Patients with diabetes that had been stabilized (i.e., no hypoglycemic or hyperglycemic episodes in the past 3 months) were eligible.
-
Any other severe, unstable, or serious disease or condition that in the Investigator's opinion would put the patient at risk for imminent life-threatening morbidity, need for hospitalization, or mortality.
-
Eligibility of patients with abnormal laboratory test values were determined by the Investigator.
-
Confirmed haemoglobinopathies, e.g., haemoglobin C disease, sickle cell anaemia, or thalassemia.
-
Moderate or severe renal and / or hepatic impairment.
-
Patients who experienced moderate / severe steroid side effects, or moderate / severe adverse events associated with the EryDex treatment administered in the ATTeST study.
Prior / Concomitant Medication
-
Requires treatment with an oral or parenteral steroid. Treatment with inhaled or intranasal steroids for asthma or allergies, as well as use of topical steroids were permitted.
-
Requires any other concomitant medication prohibited by the protocol.
-
Use of any drug that is a strong inducer / inhibitor of Cytochrome P450 3A4 (CYP3A4).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description active drug EryDex System \~14-22 mg dexamethasone sodium phosphate (DSP) for 12 months. The duration of EryDex treatment could be extended further and continue until patients eventually withdrew consent, or the Investigator decided to discontinue treatment based on a risk / benefit assessment.
- Primary Outcome Measures
Name Time Method Number of Treatment-Emergent Adverse Event (TEAE), Treatment-emergent Serious Adverse Events (TESAE), and Adverse Events of Special Interest (AESI) Throughout the Study From Baseline (Visit 1 - Day 0) to Follow-up (~60 days after last infusion, i.e. up to 50.5 months) Assessment of TEAEs, treatment-emergent serious adverse events (TESAE), and adverse events of special interest (AESI) were performed throughout the study, from the time of signing of the ICF at Baseline Visit through to the Final Study Visit (Month 12 or early discontinuation). All patients were to 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 was longer.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Quality of Life Using EQ-5D-5L Scale to Month 36 From Baseline (Visit 1- Day 0) to Month 36 The EQ-5D included single item measures of 5 health dimensions:
* mobility,
* self-care,
* usual activities,
* pain / discomfort, and
* anxiety / depression. The EQ-5D-5L included 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. These levels were scored from 1 = no problems to 5 = extreme problems: from 5, min/worst, to 25, best/max).The EQ-5D results were converted into a continuous index score: as for this index score, the closer the value is to 1, the better is the health status.
The efficacy data focus mainly up to Month 36 as afterwards the number of patients / assessments dropped below 20% of the initial sample size, which was required for the efficacy evaluations.Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C) From Baseline (Visit 1- Day 0) to Month 36 From Baseline (Visit 1- Day 0) to Month 36 The CGI-C scale assesses the change in the patient's clinical status from baseline using a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. Clinicians were required to conduct a full clinical interview and examination of the patient.
The interview and examination assessed various aspects of the patient's appearance (grooming, evidence of falls, etc.), ataxia, cognition (orientation, calculation ability, language, ability to follow commands, memory, etc.), apraxia, dysarthria, extrapyramidal motor symptoms, activities of daily living, and mood. The higher the score the worse the outcome.
The efficacy data focus mainly up to Month 36 as afterwards the number of patients / assessments dropped below 20% of the initial sample size, which was required for the efficacy evaluations.Number of Patients With None to Severe (0 to 4) Scores in Clinical Global Impression of Severity (CGI-S)-Structured of Neurological Symptoms of AT From Baseline (Visit 1 - Day 0) to Month 36 From Baseline (Visit 1- Day 0) to Month 36 The CGI-S scale measures global severity of illness at a given point in time, and is usually rated on a 7-point, Likert-type scale ranging from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). No version of the CGI-S exists which has been specifically adapted for use in patients with A-T; therefore, a 5-point version was developed that considered the severity of the following symptoms of A-T: ataxia (walking), dysarthria, dysmetria, extrapyramidal symptoms (chorea, myoclonus, dystonia, and tremor), and eye movements. Ratings of none (0), mild (1), moderate (2), severe (3), and very severe (4) were selected based on the level of symptomatology. The higher the score the worse the outcome.
The efficacy data focus mainly up to Month 36 as afterwards the number of patients / assessments dropped below 20% of the initial sample size, which was required for the efficacy evaluations.Change From Baseline of the Modified International Cooperative Ataxia Rating Scale (mICARS) Until Month 36 From Baseline (Visit 1- Day 0) to Month 36 The International Cooperative Ataxia Rating Scale (ICARS) was an assessment of the degree of impairment in patients with cerebellar ataxia and was administered in its entirety; however, the primary efficacy assessment was based on the modified (m)ICARS, which excluded the Oculomotor domain (items 17 to 19) and items 8 to 12 of the Kinetic Functions domain of the ICARS. The mICARS was a 54 points maximum score (min 0) questionnaire divided into 3 sections:
* Posture and Gait Disturbance section-7 items (min score 0, max score 34)
* Kinetic Function-2 items (min 0, max 12)
* Speech Disorder- 2 items (min 0, max 8). An higher scores - both for total and subscores - indicate a higher level of disease impairment. The subscores are added to give the total score.
The efficacy data focus mainly up to Month 36 as afterwards the number of patients / assessments dropped below 20% of the initial sample size, which was required for the efficacy evaluations.
Trial Locations
- Locations (17)
Vijaya Health Centre, Department of Neurology
🇮🇳Chennai, Tamil Nadu, India
Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital
🇳🇴Oslo, Norway
Nottingham University Hospitals NHS Trust - Queen's Medical Centre
🇬🇧Nottingham, Nottinghamshire, United Kingdom
Ataxia Center and HD Center of Excellence - UCLA
🇺🇸Los Angeles, California, United States
Division of Pediatric Allergy and Immunology - Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Department of Pediatrics Division of Child and Adolescent Neurology Mitochondrial Clinic - University of Texas Medical School
🇺🇸Houston, Texas, United States
Department of Neurology Royal Children's Hospital
🇦🇺Parkville, Victoria, Australia
Laboratory of Pediatric Immunology UZ Leuven
🇧🇪Leuven, Belgium
Klinik für Kinder- und Jugendmedizin, Allergologie, pneumologie und Mukoviszidose, Universitätsklinikum Frankfurt
🇩🇪Frankfurt, Germany
National Institute of Mental Health and Neurosciences (NIMHANS) Department of Neurology
🇮🇳Bangalore, India
Nizam's Institute of Medical Sciences Department of Neurology
🇮🇳Hyderabad, India
Jaslok Hospital and Research Center Department of Pediatric Neurology
🇮🇳Mumbai, India
Dipartimento Neuroscienze umane e salute mentale, Policlinico Umberto I Università La Sapienza
🇮🇹Roma, Italy
Department of Clinical Immunology - The Children's Memorial Health Institute
🇵🇱Warsaw, Poland
Servicio de Neurolgia Pediatrica, Hospital Materno-Infantil La Paz
🇪🇸Madrid, Spain
Razi Hospital, Clinical Investigation Center-Neuroscience
🇹🇳Tunis, Tunisia