Intra-Erythrocyte Dexamethasone Sodium Phosphate in Ataxia Telangiectasia Patients

NCT ID: NCT02770807

Last Updated: 2024-05-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 176 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-02
• Study Completion Date: 2021-05-13

Brief Summary

Objectives:

The objective of study was to evaluate the safety and the efficacy of EryDex (Dexamethasone sodium phosphate encapsulated in autologous erythrocytes, using the EryDex System - EDS) at two dose levels (low dose and high dose DSP/infusion), compared to placebo, on Neurological Symptoms in Patients With Ataxia Telangiectasia.

Initial Double-Blind Treatment Period (0 to 6 Months)

Primary Efficacy Objective:

• Evaluate the effect of EryDex at two dose levels (low dose and high dose DSP/infusion), compared to placebo, on central nervous system (CNS) symptoms measured by the change in the Modified International Cooperative Ataxia Rating Scale (mICARS) from baseline to Month 6 (Visit 9) in patients with ataxia telangiectasia (A-T).

Secondary Efficacy Objectives:

• Evaluate the effect of EryDex, compared to placebo, on the Clinical Global Impression of Change (CGI-C) in patients with A-T from baseline to Month 6 (Visit 9).
• Evaluate the effect of EryDex, compared to placebo, on measures of Clinical Global Impression of Severity (CGI-S; structured) in patients with A-T from baseline to Month 6 (Visit 9)
• Evaluate the effect of EryDex, compared to placebo, on measures of Adaptive behavior measures in patients with A-T by the Vineland Adaptive Behavior Scales (VABS) from baseline to Month 6 (Visit 9).

Safety Objectives:

• Evaluate the safety and tolerability of two non-overlapping doses of EryDex, compared to placebo, in patients with A-T over the 12-month double-blind study duration.

Extension Treatment Period (6-12 Months):

Primary Objective:

• Evaluate the efficacy of EryDex at two dose levels (low dose and high dose DSP/infusion) compared to placebo, in treating CNS symptoms in A-T patients during longer-term treatment (up to 12 months), as measured by the mICARS.

Secondary Objectives:

• Evaluate the longer-term (up to 12 months) safety and tolerability of EryDex in A-T patients.
• Compare the effects of EryDex on the CGI-C and CGI-S (structured), VABS, and QoL using the EQ-5D-5L scale.

Detailed Description

This was an international, multi-center, one-year, randomized, prospective, double-blind, placebo-controlled, phase III study.

This study was divided into three periods: Screening (Days -30 to -1), 6-month Initial Treatment Period (Months 1-6; Visits 1-9), and 6-month Extension Treatment Period (Months 7-12; Visits 10-15).

A total of 175 patients, of the 180 planned, met all selection criteria at baseline, and were randomized in a 1:1:1 fashion to one of the two EDS-EP dose levels or placebo.

These patients were randomly assigned to receive one of the two doses of EDS-EP or placebo, as follows:

• Group 1: EDS-EP dose range of ~5-10 mg DSP/infusion (low dose), 59 pts
• Group 2: EDS-EP dose range of ~14-22 mg DSP/infusion (high dose), 57 pts
• Group 3: Placebo EDS infusion, 59 pts

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

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

• Patients originally randomized to one of the two dose levels of EryDex (low dose or high dose; Groups 1 or 2) continued in the same treatment arm.
• Patients originally randomized to the Placebo group (Group 3) were re-allocated as defined at the initial randomization in equal proportions (1:1) and received either the EryDex low dose or high dose as follows:

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

Conditions

Nervous System Disease; Genetic Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

EryDex Low Dose DSP

EDS-EP dose range of ~5-10 mg DSP/infusion. This study treatment was to be administered by IV infusion once per month for 12 consecutive months (6 months Initial Treatment Period + 6 months Extension Treatment Period). Each patient underwent a 30-day Screening Period, during which any previous treatments with other corticosteroid compounds were withdrawn (washout from previous treatment).

Other Names:

EryDex System end product Low dose DSP

Group Type: EXPERIMENTAL

EryDex Low dose DSP

Intervention Type: DRUG

EDS-EP dose range of \~5-10 mg DSP/infusion

EryDex High Dose DSP

EDS-EP dose range of ~14-22 mg DSP/infusion. This study treatment was to be administered by IV infusion once per month for 12 consecutive months (6 months Initial Treatment Period + 6 months Extension Treatment Period). Each patient underwent a 30-day Screening Period, during which any previous treatments with other corticosteroid compounds were withdrawn (washout from previous treatment).

Other Names:

EryDex System end product High dose DSP

Group Type: EXPERIMENTAL

EryDex High dose DSP

Intervention Type: DRUG

EDS-EP dose range of \~14-22 mg DSP/infusion

Placebo

Patients were treated with autologous erythrocytes prepared with the EDS process using a placebo solution. Placebo was to be administered by IV infusion once per month for 12 consecutive months (6 months Initial Treatment Period + 6 months Extension Treatment Period).

Each patient underwent a 30-day Screening Period, during which any previous treatments with other corticosteroid compounds were withdrawn (washout from previous treatment).

Group Type: PLACEBO_COMPARATOR

Pooled Placebo

Intervention Type: DRUG

EDS processed autologous erythrocytes using a sodium chloride \[NaCl\] solution.

Interventions

EryDex Low dose DSP

EDS-EP dose range of \~5-10 mg DSP/infusion

Intervention Type: DRUG

EryDex High dose DSP

EDS-EP dose range of \~14-22 mg DSP/infusion

Intervention Type: DRUG

Pooled Placebo

EDS processed autologous erythrocytes using a sodium chloride \[NaCl\] solution.

Intervention Type: DRUG

Other Intervention Names

EryDex System end product; EryDex System end product; Placebo EDS infusion

Eligibility Criteria

Inclusion Criteria

1. Patient met clinical criteria for diagnosis of A-T. The neurological signs of A-T (incoordination of the head and eyes in lateral gaze deflection, gait ataxia associated with an inappropriately narrow base) must have been documented. Such signs of A-T illustrated the body systems in which changes were confirmed, but the listed changes were examples and other changes in those systems may have been observed and documented to confirm the diagnosis of A-T.

2. Patient was in autonomous gait or was helped by periodic use of a support (i.e., score for Item 1 of the full ICARS - Walking Capacities between 0 and 4, included).

3. Patient was investigated for the proven genetic diagnosis of A-T (prior documentation or by central laboratory test report).

4. Patient was at least 6 years of age.

5. Body weight was >15 kg.

6. The patient and parent/caregiver (if below the age of consent), or a legal representative, provided written informed consent to participate. If consent was provided solely by the caregiver in accordance with local regulations, the patient must have provided assent to participate in the study.

Exclusion Criteria

General

1. Females that were:

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

2. Of childbearing potential, pregnant, or breast-feeding (for US and Rest of World countries) not using adequate birth control, as determined by their Healthcare Provider.

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

3. Current participation in another clinical study.

Medical History and Current Status

4. Cluster differential 4 positive (CD4+) lymphocytes count <400/mm3 (for patients 6 years of age) or <150/mm3 (for patients >6 years). In presence of oral infections, like oral candidiasis, documented at the screening or recurrent as per medical history documentation, the limit increased to <200/mm3 (for patients >6 years).

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

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

7. History of severe impairment of the immunological system.

8. Severe or unstable pulmonary disease.

9. Uncontrolled diabetes.

10. Any other severe, unstable, or serious disease or condition that in the Investigator's opinion put the patient at risk for imminent life-threatening morbidity, need for hospitalization, or mortality.

11. Any clinically significant abnormality on standard laboratory examinations (hematology, biochemistry, urinalysis) at screening that remains abnormal on repeat testing. Eligibility of patients with abnormal laboratory test values was determined by the Investigator in consultation with the Medical Monitor.

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

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

Prior/Concomitant Medication

14. Any previous oral or parenteral steroid use within 4 weeks before Baseline. Treatment with inhaled or intranasal steroids for asthma or allergies, as well as use of topical steroids will be permitted.

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

16. Has participated in any other trial with an investigational drug and received a dose within 30 days or 10 half-lives (whichever is greater) from the start of the 30-day Screening Period.

17. Has participated in a previous trial with EryDex.

18. Requires any concomitant medication prohibited by the protocol.

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

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

• Minimum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Quince Therapeutics S.p.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Guenter R. Janhofer, MD, PhD

Role: STUDY_DIRECTOR

EryDel S.p.A

Locations

UCLA-Ataxia Center and HD Center of Exellence

Los Angeles, California, United States

The Ataxia-Telangiectasia Clinical Center, The Johns Hopkins Hospital

Baltimore, Maryland, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

UT Health

Houston, Texas, United States

Royal Children's Hospital

Melbourne, Victoria, Australia

Laboratoriumgeneeskunde

Leuven, , Belgium

Klinik für Kinder- und Jugendmedizin Pädiatrische Allergologie, Pneumologie und Mukoviszidose, Universitätsklinikum Frankfurt

Frankfurt am Main, Hesse, Germany

National Institute of Mental Health and Neurosciences

Bangalore, Karnataka, India

Amrita Institute of Medical Sciences and Research Centre

Kochi, Kerala, India

Jaslok Hospital and Research Centre

Mumbai, Maharashtra, India

PD Hinduja National Hospital and Medical Research

Mahīm, Mumbai, India

Vijaya Health Centre, Department of Neurology

Chennai, Tamil Nadu, India

Nizam's Institute of Medical Sciences

Hyderabad, Telangana, India

All India Institute of Medical Sciences

New Delhi, , India

Sheba Medical Center

Tel Litwinsky, , Israel

U.O. Neurologia e Psichiatria dell'Infanzia e dell' Adolescenza. ASST Spedali Civili, Piazzale Spedali Civili, 1

Brescia, , Italy

Dipartimento di Pediatria e Neuropsichiatria Infantile, Università Sapienza di Roma, Azienda Policlinico Universitario Umberto I

Rome, , Italy

Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital

Oslo, , Norway

Department of Clinical Immunology The Children's Memorial Health Institute

Warsaw, , Poland

Hospital Universitario La Paz.

Madrid, , Spain

El Razi Hospital

Manouba, , Tunisia

Nottingham University Hospitals NHS Trust - Queen's Medical Centre

Nottingham, Nottinghamshire, United Kingdom

Countries

United States; Australia; Belgium; Germany; India; Israel; Italy; Norway; Poland; Spain; Tunisia; United Kingdom

References

Koenig MK, Leuzzi V, Gouider R, Yiu EM, Pietrucha B, Stray-Pedersen A, Perlman SL, Wu S, Burgers T, Borgohain R, Kandadai RM, Meyts I, Bucciol G, Udwadia-Hegde A, Yadav R, Roberts D, Dane A, Roden M, Thye D, Horn B, Lederman HM, Whitehouse WP. Long-term safety of dexamethasone sodium phosphate encapsulated in autologous erythrocytes in pediatric patients with ataxia telangiectasia. Front Neurol. 2025 Jan 23;15:1526914. doi: 10.3389/fneur.2024.1526914. eCollection 2024.

Reference Type: DERIVED

PMID: 39917433 (View on PubMed)

Zielen S, Crawford T, Benatti L, Magnani M, Kieslich M, Ryan M, Meyts I, Gulati S, Borgohain R, Yadav R, Pal P, Hegde A, Kumar S, Venkateswar A, Udani V, Vinayan KP, Nissenkorn A, Fazzi E, Leuzzi V, Stray-Pedersen A, Pietrucha B, Pascual SI, Gouider R, Koenig MK, Wu S, Perlman S, Thye D, Janhofer G, Horn B, Whitehouse W, Lederman H. Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2024 Sep;23(9):871-882. doi: 10.1016/S1474-4422(24)00220-5.

Reference Type: DERIVED

PMID: 39152028 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-005241-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

IEDAT-02-2015

Identifier Type: -

Identifier Source: org_study_id