To evaluate the safety and efficacy of nicotinamide adenine dinucleotide in the treatment of immune thrombocytopenia in patients who have not responded adequately or relapsed after first-line treatment and at least one second-line therapy including Anti-CD20 Antibody and/or TPO-RA.
Immune thrombocytopenia (ITP) is an organ-specific autoimmune disease, which is characterized by decreased platelet count and skin and mucosal bleeding. ITP is a kind of disease with increased platelet destruction and impaired platelet production caused by autoimmunity. Conventional treatment of adult ITP includes first-line glucocorticoid and immunoglobulin therapy, second line TPO and TPO receptor agonist, splenectomy and other immunosuppressive treatments (such as rituximab, vincristine, azathioprine, etc.). ITP is one of the most common hemorrhagic diseases. At present, the treatment response of ITP is not good, and a considerable number of patients need drug maintenance treatment, which seriously affects the quality of life of patients and increases the economic burden of patients. Therefore, there is still a lack of effective treatment for adult ITP, especially for recurrent and refractory ITP patients, which is one of the problems that have attracted more attention and need to be solved urgently. The main pathogenesis of ITP is the loss of platelet autoantigen immune tolerance, which leads to abnormal activation of humoral and cellular immunity. It is characterized by antibody mediated platelet destruction and insufficient platelet production by megakaryocytes. The residual long-term autoreactive plasma cells may be a source of therapeutic resistance to autoimmune cytopenia. Antiplatelet specific plasma cells have been detected in the spleen of patients with rituximab refractory ITP. Therefore, the strategy of simply eliminating B cells may not work, because LLPC will continue to produce pathogenic antibodies. However, targeting LLPC becomes a new strategy to treat autoimmune diseases. CM313, a kind of anti-CD38 antibody, is a new type of monoclonal antibody targeting CD38. It targets plasma cells and has carried out some clinical studies in multiple myeloma, with good therapeutic effects. We treated patients with refractory/relapsed ITP using CM313 and achieved good therapeutic outcomes, which may provide a new strategy for treating ITP. Current research shows that CD38, as a metabolic enzyme, can hydrolyze nicotinamide adenine dinucleotide (NAD+), leading to a decrease in intracellular NAD+. Additionally, during aging and inflammation, CD38 is highly expressed on macrophages, and the downregulation of NAD+ levels. Based on the current mechanistic studies of CD38 monoclonal antibody treatment for ITP, we found that macrophages in ITP patients exhibit a shift towards M1 polarization. We hypothesize that CD38 antibodies may reduce platelet destruction by macrophages by upregulating NAD+ levels, which in turn inhibits M1 polarization. Therefore, increasing NAD+ levels may have therapeutic potential for ITP. Since nicotinamide adenine dinucleotide (NAD+) has been used in clinical practice as an adjunctive treatment for leukopenia, coronary artery disease as well as myocarditis, and nicotinamide mononucleotide (NMN) has been explored in clinical trials, we will further investigate the therapeutic efficacy and safety of these compounds in ITP patients. Therefore, the investigators designed this clinical trial to evaluate the safety and efficacy of Nicotinamide Adenine Dinucleotide (Coenzyme I for Injection, NAD+) and nicotinamide mononucleotide (NMN) in the treatment of primary immune thrombocytopenia in patients who are steroid-refractory or steroid-dependent, and fail to respond to at least one previous second-line therapy, including rituximab and/ or TPO agonist.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Drug: intravenous nicotinamide adenine dinucleotide (Coenzyme I for Injection) administration This study adopts a prospective, single arm, open design method. Twenty subjects were enrolled in the study and were treated with nicotinamide adenine dinucleotide (100mg/d) for 1 week. Drug: oral nicotinamide mononucleotide administration This study adopts a prospective, single arm, open design method. Twenty subjects were enrolled in the study and were treated with nicotinamide mononucleotide 450mg BID for 2 weeks. The first stage is the main research stage (d0-w2), which is the core treatment period. The aim is to observe the safety and efficacy during treatment. The second stage (w2-w8) is the stage of withdrawal from the visit, mainly to observe the safety and continuous efficacy after treatment.
Chinese Academy of Medical Science and Blood Disease Hospital
Tianjin, Tianjin Municipality, China
RECRUITINGEvaluation of overall efficacy response after nicotinamide adenine dinucleotide/NMN treatment within 2 weeks
Proportion of subjects with a platelet count ≥ 50 × 10\^9/L (two consecutive measurements at least 1 day apart) within 2 weeks after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period
Time frame: [Time Frame: 2 weeks]
incidence of treatment-emergent Adverse Events and TRAE
Incidence, severity, and relationship of treatment emergent adverse events after nicotinamide adenine dinucleotide/NMN treatment
Time frame: [Time Frame: 8 weeks]
Evaluation of the efficacy at each visit period
Proportion of subjects with a platelet count ≥ 50 × 10\^9/L at week 1, week 2, week 3, week 4, week 6,week 8 in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period
Time frame: [Time Frame: 8 weeks]
Duration from treatment initiation to platelet count ≥30×10^9/L (at least two times of baseline platelet count) and ≥50×10^9/L
Duration from treatment initiation to platelet count ≥30×10\^9/L (at least two times of baseline platelet count) and ≥50×10\^9/L without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids
Time frame: [Time Frame: 8 weeks]
Platelet count at each visit time point
Platelet count values at each visit time point including day0, week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8.
Time frame: [Time Frame: 8 weeks]
Emergency treatment
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The proportion of subjects who received emergency treatment within 2 weeks and during the entire study period.
Time frame: [Time Frame: 8 weeks]
Cumulative weeks of platelet ≥30×10^9/L (at least two times of baseline platelet count) and platelet ≥50×10^9/L
Cumulative weeks of platelet ≥30×10\^9/L (at least two times of baseline platelet count) and platelet ≥50×10\^9/L without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids
Time frame: [Time Frame: 8 weeks]
The change in bleeding score before treatment and 2 weeks after treatment assessed using the world health organization (WHO) bleeding scale
The change in bleeding score before treatment and 2 weeks after treatment according to the reported World Health Organization's Bleeding Scale. The WHO Bleeding Scale is a measure of bleeding severity with the following grades: grade 0 = no bleeding, grade 1= petechiae, grade 2= mild blood loss, grade 3 = gross blood loss, and grade 4 = debilitating blood loss.
Time frame: [Time Frame: 2 weeks]
Evaluation of the efficacy during the first 4 weeks
Proportion of subjects achieving platelet counts ≥ 50×10\^9/L at least once in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the first 4 weeks
Time frame: 4 weeks
The response rate within 4 weeks
Proportion of subjects whose platelet counts ≥ 30×10\^9/L and at least two times of baseline platelet count in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids within 4 weeks(two consecutive measurements at least 7 days apart).
Time frame: 4 weeks