Nephropathic Cystinosis
Conditions
Keywords
Cystinosis, Nephropathic cystinosis, Lysosomal storage disorder, CTNS gene, DFT383, Cellular gene therapy, Cysteamine, Renal Fanconi syndrome
Brief summary
An open-label, multi-center, phase I/II study to assess the safety, tolerability and efficacy of DFT383 in pediatric participants with nephropathic cystinosis, followed by a long-term extension phase. The purpose of this clinical study is to assess safety, tolerability, and efficacy of DFT383 in participants aged 2 to 5 years with nephropathic cystinosis. The study consists of a Core Phase and a long-term Extension Phase. DFT383 is a cellular gene therapy. This study includes an active arm (Cohort 1) of participants treated with study treatment DFT383 and a concurrent reference arm (Cohort 0). Participants in Cohort 0 will not receive study treatment and will only participate in the Core Phase of the study. The study is not randomized and Cohort 0 aims to collect prospective and concurrent data in this rare disease.
Detailed description
This study is an open-label, multi-center, phase I/II study to assess the safety, tolerability, and efficacy of DFT383 in participants aged 2 to 5 years with nephropathic cystinosis, followed by a long-term extension phase. The study includes two Treatment Groups (Cohort 1 and Cohort 0) and consists of a Core Phase and a long-term Extension Phase. Participants in Cohort 1 will receive DFT383 and participate in both the Core and Extension Phase. Participants in Cohort 0 will not receive study treatment and will participate in the Core Phase only. The two cohorts will be run in parallel. Investigational sites may participate in one or both cohorts. Cohort 1 Approximately 15 participants will receive treatment with DFT383 in 3 (sub) cohorts (1A, 1B and 1C) dosed in a staggered approach. The total study duration for a participant in Cohort 1 will be up to 32 months in the core phase and up to 13 years for the long-term extension phase. Cohort 0 Approximately 15 participants meeting similar inclusion/exclusion criteria and receiving SoC will be enrolled. The Schedule of Activities will be reduced for this Cohort. This cohort 0 is not a direct control but will provide essential context for interpreting the results observed in the participants receiving DFT383. The total study duration for a participant in Cohort 0 will be up to 24 months.
Interventions
GENETICDFT383
DFT383 is an autologous hematopoietic stem cell (HSC) gene therapy.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 5 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Participants eligible for inclusion in this study must meet all the following criteria: 1. Informed consent in writing from parent(s) or legal guardian(s) must be provided 2. 2 to 5 years of age (including 5 years and 364 days old) at Screening 3. Weight-for-stature is ≥ the third percentile, and is ≥ 10 kg 4. Oral cysteamine therapy for at least 6 months 5. Historic clinical diagnosis of nephropathic cystinosis 6. Laboratory evidence of of renal fanconi syndrome (RFS) 7. Relatively preserved kidney function (eGFR ≥ 60mL/min/1.73m2) 8. Received all age-appropriate vaccinations Key
Exclusion criteria
for Cohort 1 and 0 1. A history of kidney transplantation 2. A prior or planned bone marrow or stem cell transplantation or prior treatment with gene therapy 3. History of malignancy 4. A severe or uncontrolled medical disorder 5. Major surgery within 90 days Additional Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Core Phase - Incidence of adverse events (Cohort 1) | Up to 32 months | Number and proportion of participants with adverse events (AEs) and serious adverse events (SAEs) |
| Core Phase - Number of participants with hematological reconstitution (Cohort 1) | 42 days post DFT infusion | Hematological reconstitution by Day 42 post-DFT383 infusion |
| Core Phase - Proportion of participants with reversal of renal Fanconi syndrome (RFS) | Up to 32 months | Proportion of participants with reversal of renal Fanconi syndrome (RFS) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Core Phase - Number of participants independent from cysteamine | up to 24 months | Independence from oral and ophthalmic cysteamine |
| Core Phase - Health-related quality of life (HRQOL) | Up to 32 months | Health-related quality of life (HRQOL) as measured by QUALIFY (cystinosis-specific PRO)- Currently under development |
| Core Phase - Time from infusion to reversal of RFS (Cohort 1) | Up to 24 months | Time from infusion to reversal of renal Fanconi syndrome (RFS) |
| Core Phase - Time from screening to reversal of RFS (Cohort 0) | Up to 24 months | Time from screening to reversal of renal Fanconi syndrome (RFS) |
| Core Phase - Duration of reversal of RFS | Up to 24 months | Duration of reversal of renal Fanconi syndrome (RFS) |
| Core Phase - Change from baseline on urine protein to creatinine ratio (UPr/CR) | Up to 27 months | Change from baseline on urine protein to creatinine ratio (UPr/CR) |
| Core Phase - Change from baseline on urine amino acids | Up to 27 months | Change from baseline on urine amino acids |
| Core Phase - Change from baseline on urinary glucose to creatinine ratio | Up to 27 months | Change from baseline on urinary glucose to creatinine ratio |
| Core Phase - Change from baseline on tubular maximum reabsorption of Phosphate/Glomerular Filtration Rate ratio (TmP/GFR) | Up to 27 months | Change from baseline on tubular maximum reabsorption of Phosphate/Glomerular Filtration Rate ratio |
| Core Phase - Change from baseline on urine retinol-binding protein/creatinine ratio (RBP/Cr) | Up to 27 months | Change from baseline on urine retinol-binding protein/creatinine ratio |
| Core Phase - Number of participants with improvement of proximal tubular function | Up to 27 months | Improvement of proximal tubular function as defined by 2-fold change from Baseline of at least 4 out of 5 RFS parameters (urine protein to creatinine ratio, urine amino acids, urinary glucose to creatinine ratio, tubular maximum reabsorption of Phosphate/Glomerular Filtration Rate, urine retinol-binding protein/creatinine ratio). Improvement will also be considered if the change from Baseline is less than 2-fold but the value falls within the definition for normalization. |
| Core Phase - Corneal cystine crystal content | Up to 27 months | Corneal crystal content by anterior segment optical coherence tomography (AS-OCT) |
| Core Phase - Number of participants with clinically significant changes in vital signs, physical examinations, laboratories, and ECG (Cohort 1) | Up to 27 months | Vital signs, physical examinations, laboratories (eg., chemistry, hematology, liver function tests), and ECG |
| Core Phase - Number of participants with presence/emergence of replication-competent lentivirus (Cohort 1) | Up to 27 months | Number of participants with presence/emergence of replication-competent lentivirus |
| Core Phase - Number of participants with malignancy (Cohort 1) | Up to 27 months | Number of participants with malignancy |
| Core Phase - Time to hematological reconstitution (Cohort 1) | Up to 24 months | Time to hematological reconstitution |
| Core Phase - Time to platelet engraftment (Cohort 1) | Up to 24 months | Time to platelet engraftment |
| Core Phase - Incidence of Adverse Events (Cohort 0) | up to 24 months | Number and proportion of participants with adverse events (AEs) and serious adverse events (SAEs) |
| Extension Phase Primary Objective - Incidence of Adverse events (Cohort 1) | Up to 15 years and 8 months | Number and proportion of participants with adverse events (AEs) and serious adverse events (SAEs) |
| Extension Phase - Number of participants with malignancy (Cohort 1) | Up to 15 years and 3 months | Number of participants with malignancy |
| Extension Phase - Number of participants with presence/emergence of replication-competent lentivirus (Cohort 1) | Up to 15 years and 3 months | Number of participants with presence/emergence of replication-competent lentivirus |
| Extension Phase - Number of participants with clinically significant changes in vital signs, physical examinations, laboratories, and ECG (Cohort 1) | Up to 15 years and 3 months | Vital signs, physical examinations, laboratories (eg., chemistry, hematology, liver function tests), and ECG |
| Extension Phase - Change from baseline on urine protein to creatinine ratio (UPr/CR) (Cohort 1) | Up to 15 years and 3 months | Change from baseline on urine protein to creatinine ratio (UPr/CR) |
| Extension Phase - Change from baseline on urine amino acids (Cohort 1) | Up to 15 years and 3 months | Change from baseline on urine amino acids |
| Extension Phase - Change from baseline on urinary glucose to creatinine ratio (Cohort 1) | Up to 15 years and 3 months | Change from baseline on urinary glucose to creatinine ratio |
| Extension Phase - Change from baseline on tubular maximum reabsorption of Phosphate/Glomerular Filtration Rate ratio (TmP/GFR) (Cohort 1) | Up to 15 years and 3 months | Change from baseline on tubular maximum reabsorption of Phosphate/Glomerular Filtration Rate ratio |
| Extension Phase - Change from baseline on urine retinol-binding protein/creatinine ratio (RBP/Cr) (Cohort 1) | Up to 15 years and 3 months | Change from baseline on urine retinol-binding protein/creatinine ratio |
| Extension Phase - Duration of reversal of RFS (Cohort 1) | Up to 15 years | Duration of reversal of renal Fanconi syndrome (RFS) |
| Extension Phase - Number of participants with kidney failure (Cohort 1) | Up to 15 years | Number of participants with kidney failure |
| Extension Phase - Number of participants independent from cysteamine (Cohort 1) | Up to 15 years | Independence from oral and ophthalmic cysteamine |
| Extension Phase - Corneal cystine crystal content (Cohort 1) | Up to 15 years and 3 months | Corneal crystal content by anterior segment optical coherence tomography (AS-OCT) |
| Extension Phase - Health-related quality of life (HRQOL) (Cohort 1) | Up to 15 years and 8 months | Health-related quality of life (HRQOL) as measured by QUALIFY (cystinosis-specific PRO)- Currently under development |
Countries
United States
Contacts
CONTACTNovartis Pharmaceuticals
Outcome results
None listed