Maciej Zieliński1,2, Magdalena Żalińska3, Dorota Iwaszkiewicz-Grześ1,2, Mateusz Gliwiński1,2, Matylda Hennig3, Anna Jaźwińska-Curyłło4, Halla Kamińska5, Justyna Sakowska1,2, Anna Wołoszyn-Durkiewicz3, Radosław Owczuk6, Wojciech Młynarski7, Przemysława Jarosz-Chobot5, Artur Bossowski8, Agnieszka Szadkowska9, Janusz Siebert10, Małgorzata Myśliwiec2,3, Natalia Marek-Trzonkowska2,10,11, Piotr Trzonkowski1,2. 1. Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland. 2. Poltreg S.A., Gdańsk, Poland. 3. Department of Pediatric Diabetology and Endocrinology, Medical University of Gdańsk, Gdańsk, Poland. 4. Regional Center of Blood Donation and Treatment, Gdańsk, Poland. 5. Department of Children's Diabetology, Medical University of Silesia, Katowice, Poland. 6. Department of Anaesthesiology and Critical Care, Medical University of Gdańsk, Gdańsk, Poland. 7. Department of Paediatrics, Oncology and Haematology, Medical University of Lodz, Lodz, Poland. 8. Department of Peadiatrics, Endocrinology, Diabetology with Cardiology Division, Medical University of Bialystok, Białystok, Poland. 9. Department of Pediatrics, Diabetology, Endocrinology and Nephrology, Medical University of Lodz, Lodz, Poland. 10. Department of Family Medicine, Laboratory of Immunoregulation and Cellular Therapies, Medical University of Gdańsk, Gdańsk, Poland. 11. International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland.
Abstract
AIMS: Monotherapy with autologous expanded CD4+ CD25high CD127- T regulatory cells (Tregs) or rituximab has been documented to slow disease progression in patients with recent-onset type 1 diabetes mellitus (T1DM). Whether a combined therapy including both drugs would further benefit this patient population is unknown. MATERIALS AND METHODS: We conducted a three-arms clinical trial to explore the efficacy and safety of the combined treatment with Tregs and rituximab in paediatric patients with T1DM. The patients were allocated to three groups: Tregs only (n = 13), Tregs + rituximab (n = 12) and control (n = 11). The key primary efficacy analyses were C-peptide levels (mixed meal tolerance test) and the proportion of patients in remission at 12 and 24 months. RESULTS: At month 24, as compared with the control, both treatment groups remained superior in the area under the curve of C-peptide mixed meal tolerance test, whereas in the analysis of all visits only the combined therapy improved area under the curve at 12 and 24 months. The proportion of patients in remission was significantly higher in the combined group than in the control group at 3, 6, 9 and 21 months but not at 18 and 24 months. There was no significant difference between the Tregs only group and control group. Adverse events occurred in 80% patients, mostly in the combined group and Tregs only group. No adverse events led to the withdrawal of the intervention or death. All comparisons were performed with alpha level of 5%. CONCLUSIONS: Over 2 years, combined therapy with Tregs and rituximab was consistently superior to monotherapy in delaying T1DM progression in terms of C-peptide levels and the maintenance of remission.
AIMS: Monotherapy with autologous expanded CD4+ CD25high CD127- T regulatory cells (Tregs) or rituximab has been documented to slow disease progression in patients with recent-onset type 1 diabetes mellitus (T1DM). Whether a combined therapy including both drugs would further benefit this patient population is unknown. MATERIALS AND METHODS: We conducted a three-arms clinical trial to explore the efficacy and safety of the combined treatment with Tregs and rituximab in paediatric patients with T1DM. The patients were allocated to three groups: Tregs only (n = 13), Tregs + rituximab (n = 12) and control (n = 11). The key primary efficacy analyses were C-peptide levels (mixed meal tolerance test) and the proportion of patients in remission at 12 and 24 months. RESULTS: At month 24, as compared with the control, both treatment groups remained superior in the area under the curve of C-peptide mixed meal tolerance test, whereas in the analysis of all visits only the combined therapy improved area under the curve at 12 and 24 months. The proportion of patients in remission was significantly higher in the combined group than in the control group at 3, 6, 9 and 21 months but not at 18 and 24 months. There was no significant difference between the Tregs only group and control group. Adverse events occurred in 80% patients, mostly in the combined group and Tregs only group. No adverse events led to the withdrawal of the intervention or death. All comparisons were performed with alpha level of 5%. CONCLUSIONS: Over 2 years, combined therapy with Tregs and rituximab was consistently superior to monotherapy in delaying T1DM progression in terms of C-peptide levels and the maintenance of remission.