CN115364106A - Application of all-trans retinoic acid in combination with high-dose dexamethasone in ITP - Google Patents
Application of all-trans retinoic acid in combination with high-dose dexamethasone in ITP Download PDFInfo
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Abstract
The invention discloses application of all-trans retinoic acid in combination with high-dose dexamethasone in ITP. The invention claims the application of the combination of all-trans retinoic acid and dexamethasone in preparing a product for treating immune thrombocytopenia. The invention also claims the application of the combination of all-trans retinoic acid and dexamethasone in preparing a product for relieving bleeding. The present invention performs a first open, multicenter, randomized controlled, phase 2 clinical trial to evaluate the effectiveness and safety of ATRA in combination with HD-DXM as a first-line treatment regimen for ITP.
Description
Technical Field
The invention relates to application of all-trans retinoic acid in combination with high-dose dexamethasone in ITP.
Background
Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and thrombocytopenia due to immune intolerance, and by single thrombocytopenia 1,2 . First line treatment regimens include glucocorticoids, intravenous immunoglobulin (IVIg), anti-D immunoglobulin (anti-D) 3,4 However, approximately 1/3 of ITP patients have poor therapeutic effect by applying the above scheme 5 . In addition, ITP has a low long-term remission rate and a high recurrence rate. For treatment-naive patients with ITP, the current first-line treatment regimen is still not ideal 6 。
High doses of dexamethasone (HD-DXM) were the first-line treatment for ITP in primary adults. Dexamethasone acts as a platelet-increasing agent, primarily by inhibiting ITP platelet destruction 3,7 . Research shows that the scheme can quickly induce the increase of platelet count, and the initial remission rate is as high as 73-90 percent 8-11 . However, only 40-50% of patients maintain sustained remission within half a year of withdrawal.
All-trans-retinoic acid (ATRA) is a natural metabolic intermediate of vitamin A and is involved in various biological metabolic processes 13 . Recent studies have found that ATRA plays a regulatory role in both non-specific and specific immunity 14,15 . ATRA is used for the treatment of several autoimmune diseases, including ITP, with encouraging results 16-20 . We previously reported a prospective, multiple treatment of recurrent, hormone-resistant ITP with ATRAThe results of clinical experiments of central and random control show that the ATRA combined with danazol can achieve 82% of initial remission rate and 62% of one-year sustained remission rate, and patients have good tolerance and few side effects 21 . Patinger I et al evaluated that the ATRA regimen was more effective and less toxic than other two-line treatment regimens in treating relapse or hormone-resistant ITP 22-24 . Another group of studies also reported that the treatment regimen of hormone-combined ATRA was effective in 54.3% of chronic refractory ITP.
Disclosure of Invention
The invention aims to provide application of all-trans retinoic acid in combination with high-dose dexamethasone in ITP.
The characteristic that dexamethasone is used as a powerful immunosuppressant but cannot continuously relieve ITP patients promotes the emergence of a combined application thrombopoietic drug scheme. Megakaryocytes mature, localize and release platelets into the blood circulation in the bone marrow microenvironment, which may be associated with megakaryocytopoiesis disorders in ITP 25 . Our previous series of studies suggest that ATRA can correct megakaryocytopoiesis disorders in bone marrow in ITP by restoring mesenchymal stem cell function, balancing macrophage polarization 26-28 . ATRA promotes platelet production in the bone marrow microenvironment providing an important new concept for treatment to achieve sustained remission.
The invention claims the application of the combination of all-trans retinoic acid and dexamethasone in preparing a product for treating immune thrombocytopenia.
The invention also claims the application of the combination of all-trans retinoic acid and dexamethasone in preparing a product for relieving bleeding.
The invention also claims a product for treating immune thrombocytopenia, which consists of all-trans retinoic acid and dexamethasone.
The invention also claims a product for alleviating bleeding, which consists of all-trans retinoic acid and dexamethasone.
Specifically, the combination of all-trans retinoic acid and dexamethasone comprises the following components: on the day of intravenous dexamethasone injection, all-trans retinoic acid was taken orally.
When dexamethasone is injected into the vein, the dosage is 40 mg/day, and the dexamethasone is continuously injected for 4 days.
In the oral all-trans retinoic acid, the dosage is 10mg once and 2 times a day.
The total time for the combination of all-trans retinoic acid and dexamethasone was 12 weeks.
The mitigation is initial mitigation and/or sustained mitigation;
the sustained relief is at least half a year in duration.
The treatment is first line treatment.
ATRA and HD-DXM may have a synergistic effect on the mechanism of reduced platelet production and increased destruction, and the combined use of both drugs may be superior to the single drug therapy. Therefore, we hypothesized that the sustained remission rate of ATRA in combination with HD-DXM treatment ITP is superior to HD-DXM monotherapy and performed the first open, multi-center, randomized control, phase 2 clinical trial to evaluate the efficacy and safety of ATRA in combination with HD-DXM as a first-line treatment regimen for ITP.
Drawings
Fig. 1 is a clinical trial: subjects were randomly assigned to either the ATRA combination HD-DXM treatment group or the HD-DXM monotherapy group at a ratio of 1. Dexamethasone was administered intravenously at a dose of 40 mg/day for 4 consecutive days in both groups. Patients who did not reach remission on day 10 repeat the 4-day dexamethasone course again. The combination treatment group was treated with oral ATRA (10 mg each, 2 times daily) simultaneously for 12 weeks.
FIG. 2 shows the experimental data: ITP, immune thrombocytopenia; DM, diabetes; HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
FIG. 3 is time to relapse in patients who achieved initial (A) and complete (B) remission: recurrence was defined as a platelet count below 30X 10 after reaching remission 9 /L。
Fig. 4 is the median platelet count in the intent-to-treat population: error bars represent IQR. HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
Figure 5 is a proportion of patients with clinically significant bleeding (WHO bleeding score 2-4) in both groups: HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
FIG. 6 is the mean change in ITP-PAQ score from baseline: p-values were calculated from the change in score from baseline score to week 26 for each treatment group. HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
Fig. 7 is an adverse event: adverse events reported in the ATRA combination HD-DXM treatment group and the HD-DXM monotherapy group. AE, adverse event; HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
Fig. 8 is the time of the first bleeding event. Refers to the time from the random assignment of the group to the occurrence of the first bleeding event. HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
Figure 9 is the time of the first rescue treatment. Refers to the time from random assignment into the group to the need for the first rescue treatment. HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Example 1
Method
Experimental design and case screening
Our designed open, multicenter, randomized controlled, phase 2 clinical trial was conducted in 6 tertiary hospitals in china. This study was reviewed by each central ethical committee and was in compliance with the helsinki declaration and clinical practice guidelines.
ITP diagnosis according to Standard procedures 2,3,29 Wherein the age is more than 18 years and the platelets are less than 30 × 10 9 /L or platelets with bleeding symptoms less than 50X 10 9 Initial treatment of newly diagnosed ITP patients enrolled. Patients with life-threatening bleeding symptoms (e.g., intracranial hemorrhage) failed to be enrolled for experimental safety.
Our inclusion criteria also exclude patients who had been treated for ITP or treated for diseases other than ITP using hormones, immunosuppressive agents within the first 6 months of inclusion. Patients with malignant tumor, pregnancy/lactation, osteoporosis, HBV/HCV infection, HIV infection, current disease infection, acute coronary syndrome, heart failure, severe liver/renal insufficiency and significant adverse reaction of previous hormone therapy are not allowed to be included. Patients were enrolled into groups at the time of routine outpatient visits, and all patients had signed informed consent prior to participation in clinical trials.
Randomization and blinding
After confirming that the grouping standard is met, the interactive network response system is used for randomly grouping the patients into an ATRA combined HD-DXM treatment group and an HD-DXM single-medicine treatment group according to the proportion of 1. Due to the openness of the experiment, the grouping of the experiment does not conceal the researchers and the testees.
Experimental procedure
Dexamethasone was administered intravenously at a dose of 40 mg/day for 4 consecutive days in both groups, and the 4-day course of dexamethasone was repeated again in patients who did not reach remission on day 10. Combination treatment patients were treated with ATRA (10 mg once, 2 times daily) orally for 12 weeks at the same time. Patients in either group presented serious, life threatening side effects or were withdrawn from the experiment upon subjective request. Rescue therapy is used to develop life-threatening bleeding symptoms or platelets below 10 x 10 9 Patients at platelet levels of 10X 10 in the case of/L 9 from/L to 30X 10 9 And whether the rescue treatment is applied to the patients between the/L is determined according to clinical evaluation and the patient will, and finally whether the rescue treatment is performed needs to comprehensively evaluate factors such as bleeding severity, the patient will, life style, execution difficulty of special treatment, bleeding related co-morbidities, tolerance degree of side effects and the like. If the patient has a platelet count greater than 300X 10 for 2 consecutive times 9 /L (2 assays at least 2 weeks apart) ATRA treatment was discontinued.
The frequency of follow-up was once every 2 days for the first 2 weeks, then once every 2 weeks to week 26. At each follow-up visit, we performed a clinical assessment of the patient's complete blood cell count, urine routine, liver and kidney function, fasting and post-prandial blood glucose levels, and recorded the application of rescue treatment, bleeding score and side effects. We also performed an assessment of health-related quality of life (HRQoL) by patient filled primary immune thrombocytopenia patient quality of life assessment scale (ITP-PAQ), with minimal clinically significant differences (MIDs) used to assess the clinical significance of changes in ITP-PAQ scores.
Ending of the run
The primary observation endpoint was sustained remission rate (SR), defined as patient platelets continuing to be greater than 30 x 10 at 6 months of follow-up 9 2 times or more of the basic value, no bleeding symptoms and no rescue treatment 8,11,31 . Rescue therapy is defined as any treatment for the prevention of bleeding, platelet elevation, including platelet count infusions, IVIg and splenectomy, among others, that is newly applied. Patients receiving rescue treatment or quitting for any reason are defined as non-remissions 21,31,32 。
Secondary endpoints of the study were initial remission rate, time to achieve remission, relapse rate, duration of remission, whether rescue treatment was needed, time to rescue treatment was needed, bleeding, HRQoL, and safety. We define remission (R) as platelets at or above 30X 10 9 At least twice the baseline value and no bleeding symptoms; complete Remission (CR) is defined as platelets at or above 100X 10 9 L and no bleeding symptoms; unrelieved (NR) is defined as platelets less than 30X 10 9 /L or not reaching twice the baseline value or with bleeding symptoms 29,33 . Both groups assessed whether the patients enrolled in the group achieved initial remission at day 14. At least two measurements (at least 7 days apart) are required for platelet value in determining CR or R 8 , 11,31 . We define the time to achieve remission as the time from the start of treatment to the achievement of CR or R. The time to cessation of remission is defined as platelets under 100X 10 9 (ii) either hemorrhagic symptoms (previously achieved CR) or platelets less than 30X 10 9 L, not reaching twice baseline or with bleeding symptoms (previously reached R) 29,33 . The time from the time the mitigation is achieved to the time the mitigation terminates is defined as the duration of the mitigation. The time required for rescue treatment is defined as the time from the start of treatment to the time required to receive rescue treatment. Basis of bleeding WHO criteria were scored: 0, no bleeding; 1, bleeding point; 2, mild blood loss; 3, massive blood loss; 4, life threatening hemorrhage 34 . Definition of Adverse Events (AEs) is made according to the fifth edition of the Universal adverse reaction terminology Standard 35 。
Data analysis
Based on our preliminary studies and literature, we hypothesized that the proportion of patients with 6-month sustained remission will rise from 40% to 65% following combined ATRA treatment. We used a 0.05 level bilateral Pearson χ 2 test to assess the superiority of the combination treatment and allowed a 10% withdrawal rate, with 66 subjects per group to achieve 80% test efficacy.
Efficacy endpoint and baseline profile analysis a full data set analysis of all randomized participants was used. The safety analysis data set included all randomly assigned participants who took at least one dose of study medication. Patient data is summarized as categorical variables (frequency and percentage) and continuous variables (median and interquartile range (IQR)). The Fisher exact test was used to assess the difference between the primary endpoint and the adverse event. We also calculated Odds Ratios (OR) and 95% Confidence Intervals (CIs). We compared the differences between the two groups using the Pearson χ 2 test for categorical variables, student t test for continuous variables, or the Mann-Whitney U test. Duration of remission, time to rescue treatment and time to first bleeding event occurred were counted using the Kaplan-Meier method and the log rank test was used to assess potential differences between groups. We assessed the relevance of risk factors to 6 months of sustained remission using logistic regression, with only factors with P values <0.1 in the single factor analysis being included in the multi-factor analysis.
All statistical tests used a two-sided test, with P <0.05 being statistically significant. All statistical analyses were performed by SPSS Statistics 25 (IBM SPSS Statistics, armonk, NY, USA). This experiment was registered with clinical trials. Gov, number NCT04217148.
Results
Case grouping and follow-up
From 6 months 2015 to 7 months 2018, we screened 180 eligible cases, of which 48 were excluded. A total of 132 patients were included in the ITT analysis: 66 patients received ATRA combined with HD-DXM treatment, and 66 patients received HD-DXM monotherapy. Of the 132 randomly assigned patients, 3 received no intervention due to withdrawal of informed consent and were not included in the safety analysis. The 7 (10.6%) patients in the ATRA combined HD-DXM treatment group and 5 (7.6%) patients in the HD-DXM single-drug treatment group stopped treatment halfway, and the reasons for stopping the treatment are similar in the two groups, and the most common reasons are missed visits and adverse reactions (figure 2).
The baseline characteristics of the ATRA combined HD-DXM treated group and the HD-DXM single-drug treated group were well balanced (Table 1). The median age of all subjects was 41.0 years (28.0-56.5) years, with over 60% of patients in both groups being female. The median platelet count at time of group entry was 20 (14-24). Times.10 9 And L. A total of 81 patients had hemorrhagic symptoms at study enrollment, generally mild to moderate, with a WHO bleeding score median of 1 (0-2). WHO bleeding scores were either 0 or 1 for the majority of patients in both groups (table 1). 11 (16.7%) of the ATRA combination HD-DXM treatment group and 10 (15.2%) of the HD-DXM monotherapy group received an additional 1 course of dexamethasone treatment (P = 0.812).
TABLE 1 Baseline characteristics of the enrolled cases
Data are expressed as a percentage (%) or median (interquartile range). HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
Platelet count
Initial mitigation
TABLE 2 remission and prognosis comparison of ATRA combination HD-DXM treatment group and HD-DXM monotherapy treatment group
Data are expressed as a percentage (%) or median (interquartile range).
CR, complete remission; HD-MP, high dose methylprednisolone or methylprednisolone; IVIg, intravenous immunoglobulin; rhTPO, recombinant human thrombopoietin; TPO-RA, a thrombopoietin receptor agonist; HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
As shown in table 2, initial remission (P = 0.572) was achieved in 60 patients (90.9%) in the ATRA combination HD-DXM treatment group and 58 patients (87.9%) in the HD-DXM monotherapy group. At 1 week, the platelet count of more than 75% of patients is greater than 30X 10 9 L (52 cases (78.8%) in the ATRA combination HD-DXM treatment group, and 50 cases (75.8%) in the HD-DXM monotherapy group, P = 0.678). After the first course of dexamethasone, remission was achieved in 53 patients in the ATRA combination HD-DXM treatment group and 53 patients in the HD-DXM single drug treatment group. 42 (63.6%) of the ATRA combination HD-DXM treatment group and 41 (62.1%) of the HD-DXM monotherapy group reached initial CR (P = 0.857). On day 30, 60 (90.9%) patients receiving ATRA in combination with HD-DXM treatment and 57 (86.4%) patients receiving HD-DXM monotherapy had platelet counts exceeding 30X 10 9 /L(P＝0.411)。
For patients who achieved initial remission, the median Time To Remission (TTR) in the ATRA combined HD-DXM treatment group was 6 (IQR 4-8) days and the median peak platelet count was 174X 10 9 L, 6 (IQR 4-6) days and 156X 10 days in HD-DXM single-drug treatment group 9 L (TTR: P =0.065, peak platelet count: P = 0.063); in CR patients, the mean CR time for the two groups was 10 days (8-14) and 14 days (8-14), respectively (P = 0.194).
Sustained relief
The sustained remission rate in the ATRA combined HD-DXM treated group was significantly higher than in the HD-DXM monotherapy group (68.2% vs.40.9%, P =0.002, or =3.095 (1.516-6.318)) at a follow-up visit of 6 months. Patients with remission after the second course of HD-DXM had no significant difference in the likelihood of achieving sustained remission compared to patients with remission after the first course (P = 0.763).
In the 6-month follow-up visit, 15 relapses (25.0%) in the ATRA combination HD-DXM treatment group and 31 relapses (53.4%) in the HD-DXM monotherapy group (P = 0.002). The overall R and CR duration was longer in the ATRA combined HD-DXM treatment group than in the HD-DXM monotherapy treatment group throughout the follow-up period (fig. 3R P =0.0022, CR: P = 0.0073. The platelet count median of patients treated by ATRA combined with HD-DXM and HD-DXM single drug is 71.0-108.5 × 10 at follow-up 1-6 months 9 L and 29.0 to 99.5X 10 9 the/L range, where the median platelet count was higher in the combination treatment group when counted at most time points (fig. 4).
8 of the ATRA combination HD-DXM treatment group (12.1%) received rescue treatment, while 20 of the HD-DXM single drug treatment group (30.3%) received rescue treatment (OR 0.317, 95% ci 0.128-0.785 p = 0.011. During ATRA combined HD-DXM treatment and HD-DXM monotherapy 4 (6.1%) and 6 (9.1%) patients received platelet infusions and 2 (3.0%) HD-DXM monotherapy groups received splenectomy. Patients receiving ATRA combined HD-DXM treatment required less rescue treatment (19 (28.8%) vs.39 (59.1%), OR =0.280 (0.136-0.577), P < 0.001) than patients receiving HD-DXM monotherapy. Kaplan-Meier estimates showed that patients in the ATRA combination HD-DXM treatment group required a more advanced first rescue treatment time than the HD-DXM monotherapy treatment group (P = 0.0062) (fig. 9).
We continued the exploratory analysis to investigate possible predictors of achieving 6-month sustained remission in both groups of patients. Initial CR is a latent variable associated with 6 months sustained remission. Age, sex, platelet count and bleeding score at group entry were independent of 6 month SR (table 3).
Table 3 Logistic regression evaluates the correlation between baseline parameters and sustained remission
CR, complete remission; OR, odds ratio; CI, confidence interval; HD-DXM, high dose dexamethasone; ATRA, all-trans retinoic acid.
Bleeding of blood
The bleeding rate in both groups of patients decreased by about 70% during the post-treatment period. Patients receiving HD-DXM monotherapy had the first bleeding event earlier in time (figure 8). 28 (42.4%) patients receiving ATRA in combination with HD-DXM and 46 (69.7%) patients receiving HD-DXM monotherapy had at least one bleeding event between weeks 2 and 26. The severe bleeding event comprises 29 patients with WHO bleeding score of 3 (19 patients in HD-DXM single-drug treatment group, 10 patients in ATRA combined HD-DXM treatment group) and 3 patients with WHO bleeding score of 4 (2 patients in HD-DXM single-drug treatment group, 1 patient in ATRA combined HD-DXM treatment group). The odds of clinically significant hemorrhage and hemorrhage in the ATRA combination HD-DXM treatment group were 61.9% and 95.1% of HD-DXM monotherapy group (OR 0.371, 95% ci 0.184-0.751 p =0.005 and OR 0.594, 95% ci 0.184-1.922 p =0.381, respectively).
Health-related quality of life
A total of 114 subjects were available for analysis, and there was no difference in baseline HRQoL scores for patients receiving ATRA combined HD-DXM treatment (n = 57) and patients receiving HD-DXM monotherapy (n = 57). As shown in fig. 6, the ITP-PAQ scores of both groups were significantly improved over the baseline score at week 26. Both sets of scores varied over MID in terms of mental health and social activity. The improvement in symptoms, fatigue, fear, work, social activity and overall quality of life of the ATRA combination HD-DXM treatment group was statistically significantly higher than the HD-DXM single drug treatment group, where the changes in symptoms and overall quality of life scores were higher for the ATRA combination HD-DXM treatment group than MID, while the HD-DXM single drug treatment group was lower than MID.
Safety feature
Figure 7 is a graph of the incidence of two groups of adverse events. The incidence of adverse events in the two groups is similar, and the total weight is lighter. No mortality events occurred during the study, and no grade 4 or more adverse events occurred. In the ATRA combination HD-DXM treatment group, 2 patients were discontinued from treatment related adverse events and insomnia, anxiety or mood disorders, and 2 HD-DXM single drug treatment groups were discontinued from treatment for insomnia, anxiety or mood disorders. Insomnia or mood disorders were present in 2 patients receiving ATRA combined HD-DXM and 3 patients receiving HD-DXM monotherapy (grade 3). Of the 64 patients treated with ATRA in combination with HD-DXM, 31 (48.4%) had dry skin, which is considered a manifestation of ATRA treatment. Patients are well tolerated without dose reduction or treatment discontinuation. In addition, more than 10% of the patients in group 2 developed insomnia, anxiety or mood disorders. The headache symptoms appeared in 12 of 64 patients (18.8%) in the ATRA combination HD-DXM treatment group compared to 6.2% in the HD-DXM single-dose treatment group. Over 5% of patients in both groups developed gastrointestinal disease, hypertension and hyperglycemia. Other adverse events that occur in treatment include elevated liver enzymes, amenorrhea, edema, palpitations, fatigue and acneiform skin rash.
Claims (10)
1. The application of the combination of all-trans retinoic acid and dexamethasone in preparing products for treating immune thrombocytopenia.
2. The application of the combination of all-trans retinoic acid and dexamethasone in preparing a product for relieving bleeding.
3. A product for treating immune thrombocytopenia comprises all-trans retinoic acid and dexamethasone.
4. A product for relieving hemorrhage comprises all-trans retinoic acid and dexamethasone.
5. Use according to claim 1 or 2 or product according to claim 3 or 4, characterized in that: the combination of all-trans retinoic acid and dexamethasone comprises the following steps: on the day of intravenous dexamethasone injection, all-trans retinoic acid was administered orally.
6. Use or product according to claim 5, characterized in that: when dexamethasone is injected into the vein, the dosage is 40 mg/day, and the injection is continuously carried out for 4 days.
7. Use or product according to any of claims 1 to 6, characterized in that: in the oral all-trans retinoic acid, the dosage is 10mg once, and 2 times a day.
8. Use or product according to any of claims 1 to 7, characterized in that: the total time for the combination of all-trans retinoic acid and dexamethasone was 12 weeks.
9. Use or product according to any of claims 1 to 8, characterized in that: the mitigation is initial mitigation and/or sustained mitigation;
the sustained relief has a duration of at least half a year.
10. Use or product according to any of claims 1 to 9, characterized in that: the treatment is first line treatment.
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Citations (4)
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| US20120309847A1 (en) * | 2011-06-01 | 2012-12-06 | NBI Pharmaceuticals, Inc. | Dosing regimens and methods for treating or preventing promyelocytic leukemia |
| US20170112792A1 (en) * | 2014-03-21 | 2017-04-27 | Beth Israel Deaconess Medical Center, Inc. | Enhanced atra-related compounds derived from structure-activity relationships and modeling for inhibiting pin1 |
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| CN112513073A (en) * | 2018-06-08 | 2021-03-16 | 阿根思公司 | Compositions and methods for treating immune thrombocytopenia |
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| US20120309847A1 (en) * | 2011-06-01 | 2012-12-06 | NBI Pharmaceuticals, Inc. | Dosing regimens and methods for treating or preventing promyelocytic leukemia |
| US20170112792A1 (en) * | 2014-03-21 | 2017-04-27 | Beth Israel Deaconess Medical Center, Inc. | Enhanced atra-related compounds derived from structure-activity relationships and modeling for inhibiting pin1 |
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