Clinical trial NCT02770807: Intra-Erythrocyte Dexamethasone Sodium Phosphate in Ataxia Telangiectasia Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Nervous System Disease
Genetic Syndrome
Keywords: Ataxia Teleangiectasia
AT
EryDex system
Dexamethasone
Dexamethasone sodium phosphate
Lead sponsor: Quince Therapeutics S.p.A.
Sponsor class: INDUSTRY
First posted: 2016-05-12
Enrollment: 176
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change From Baseline in Modified International Cooperative Ataxia Rating Scale (mICARS)
timeFrame: to Month 6 (Visit 9)
Secondary outcomes:
measure: Number of Patients With Improving, Stable or Worsening Score Using a Clinical Global Impression of Change (CGI-C)
timeFrame: to Month 6 (Visit 9)
measure: 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
timeFrame: to Visit 9 (Month 6)
measure: Change From Baseline of Vineland Adaptive Behavior Scale (VABS-II) Scores - Last Observation Carried Forward (LOCF)
timeFrame: to Visit 9 (Month 6)
measure: Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 6
timeFrame: to Visit 9 (Month 6)
measure: Number of Patients With at Least One Treatment-Emergent Adverse Event (TEAE) at Month 12
timeFrame: to Visit 15 (Month 12)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA-Ataxia Center and HD Center of Exellence
state: California
city: Baltimore
country: United States
facility: The Ataxia-Telangiectasia Clinical Center, The Johns Hopkins Hospital
state: Maryland
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Houston
country: United States
facility: UT Health
state: Texas
city: Melbourne
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Leuven
country: Belgium
facility: Laboratoriumgeneeskunde
city: Frankfurt
country: Germany
facility: Klinik für Kinder- und Jugendmedizin Pädiatrische Allergologie, Pneumologie und Mukoviszidose, Universitätsklinikum Frankfurt
state: Hessen
city: Bangalore
country: India
facility: National Institute of Mental Health and Neurosciences
state: Karnataka
city: Kochi
country: India
facility: Amrita Institute of Medical Sciences and Research Centre
state: Kerala
city: Mumbai
country: India
facility: Jaslok Hospital and Research Centre
state: Maharashtra
city: Mahim
country: India
facility: PD Hinduja National Hospital and Medical Research
state: Mumbai
city: Chennai
country: India
facility: Vijaya Health Centre, Department of Neurology
state: Tamil Nadu
city: Hyderabad
country: India
facility: Nizam's Institute of Medical Sciences
state: Telangana
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
city: Tel HaShomer
country: Israel
facility: Sheba Medical Center
city: Brescia
country: Italy
facility: U.O. Neurologia e Psichiatria dell'Infanzia e dell' Adolescenza. ASST Spedali Civili, Piazzale Spedali Civili, 1
city: Rome
country: Italy
facility: Dipartimento di Pediatria e Neuropsichiatria Infantile, Università Sapienza di Roma, Azienda Policlinico Universitario Umberto I
city: Oslo
country: Norway
facility: Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital
city: Warsaw
country: Poland
facility: Department of Clinical Immunology The Children's Memorial Health Institute
city: Madrid
country: Spain
facility: Hospital Universitario La Paz.
city: Manouba
country: Tunisia
facility: El Razi Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust - Queen's Medical Centre
state: Nottinghamshire
Study officials:
affiliation: EryDel S.p.A
name: Guenter R. Janhofer, MD, PhD
role: STUDY_DIRECTOR
References: