CN117672545A - Method for verifying effectiveness of pulmonary artery high-pressure targeted drug - Google Patents

Abstract

The invention discloses a method for verifying the effectiveness of a pulmonary arterial hypertension targeted drug, which uses TTCI (time to clinical improvement) to verify the effectiveness of PAH (advanced drug delivery system) targeted drugs. Compared with clinical deterioration time, more positive endpoint events can be observed within 24 weeks by adopting TTCI, the research period of the TTCI is short, the required research sample size is small, and the TTCI can be used in short-period research. The TTCI employed in this application is not affected by patient baseline risk stratification, and is hooked up to patient long-term survival, relative to 6MWD. In addition, TTCI can identify that the 6MWD failed to detect therapeutic differences, the overall effect is superior to 6MWD, a more suitable clinical surrogate endpoint for short-cycle validation of PAH targeted drug effectiveness. The TTCI shortens the research period of clinical trials of PAH targeted drugs, can promote the research efficiency of the effectiveness of the targeted drugs, reduces the follow-up time of patients and more rapidly identifies the effective drugs. Meanwhile, the study of the ineffective medicine can be stopped in time, and the injury of the long-term treatment of the ineffective medicine to study population is avoided.

Description

Method for verifying effectiveness of pulmonary artery high-pressure targeted drug

Technical Field

The invention relates to the technical field of effectiveness evaluation of medicines, in particular to a method for verifying effectiveness of a pulmonary artery high-pressure targeted medicine.

Background

Pulmonary arterial hypertension (Pulmonary Arterial Hypertension, PAH) is a major group of pathophysiological diseases characterized by progressive pulmonary arterial remodeling and elevated pulmonary vascular resistance, the first major group of pulmonary hypertension (Pulmonary Hypertension, PH), also known as arterial pulmonary hypertension. PAH is a multidisciplinary disease involved in departments such as clinical cardiology, respiratory department, rheumatics, gynaecology and obstetrics, and is also called as "malignant tumor" in cardiology because of its high mortality rate. The diagnosis standard is that the hemodynamic parameters of the invasive right heart catheterization simultaneously meet the average pulmonary artery pressure (mPAP) of more than or equal to 25mmHg, the Pulmonary Artery Wedge Pressure (PAWP) of less than or equal to 15mmHg and the Pulmonary Vascular Resistance (PVR) of more than or equal to 3Wood Unit. PAH under the modern classification contains multiple subclasses, with Idiopathic Pulmonary Arterial Hypertension (IPAH) being the most frequently occurring subclass worldwide.

The issue of how to verify effectiveness has been accompanied by the birth of PAH targeted drugs. The 6MWD can better reflect exercise tolerance of a patient under daily activities, is relatively safe, does not need excessive professional equipment, is convenient to develop in medical centers at all levels, and is widely applied to curative effect and prognosis evaluation of cardiovascular diseases and chronic respiratory diseases. The 6MWD also has the advantage of being non-invasive, easily reproducible and acceptable to patients relative to the hemodynamic parameters measured with right heart catheters.

Six minute walking distance (6-Miutes Walk Distance,6 MWD) test method: the patient walks in a corridor which is 30m long and marked every 5 m. The patient should walk the longest distance in 6 minutes as full as possible, and the patient can adjust the walking speed according to his own situation during the test. The tester reminds the patient of the test time that has been performed every minute, except that no other prompt is made. When the reciprocal count is 15s, the patient is lifted to finish the test, and when the patient says 'time is up', the patient does not stop suddenly but keeps forward at a slow speed, so that the heart rate and the blood pressure are prevented from being rapidly reduced due to sudden stop of exercise, and cardiovascular adverse events are induced. Before and after the test, the blood pressure, heart rate and peripheral blood oxygen saturation of the patient were measured, the Borg dyspnea index (grade 0-10) was recorded, the number of patient walking turns was recorded and the 6-minute walking distance of the patient was calculated.

WHO-FC judgment criteria: stage I: physical activity of the patient is not limited, and daily physical activity does not cause dyspnea, hypodynamia, chest pain or near syncope; stage II: the physical activity of the patient is slightly limited, and the patient has no discomfort during rest, but the daily activity can cause dyspnea, hypodynamia, chest pain or near syncope; class III: the physical activity of the patient is obviously limited, and the patient has no discomfort during rest, but dyspnea, hypodynamia, chest pain or near syncope can occur below the daily activity; grade IV: the patient cannot perform any physical activity. Symptoms of right heart failure exist, dyspnea and/or hypodynamia can occur during rest, and symptoms can be aggravated by any physical activity.

In 1996, r.j. Barst et al verified that the first PAH targeted drug, epoprostenol, could significantly improve the 6MWD of PAH patients for 12 weeks, after which the PAH targeted drug, which was born for more than 20 years, mostly followed the 6MWD as the primary surrogate endpoint for validation, including the three-phase clinical trial stellor study of the latest PAH targeted drug, sotatept. The study period of these studies is mostly 12 to 24 weeks, so that PAH targeted drug effectiveness can be verified in a short period of time. However, the drawbacks of 6MWD are also gradually revealed in long-term observations, where the failure to reflect most of the therapeutic effects, no significant correlation with long-term survival, are two major reasons that 6MWD is questioned, and therefore the art is calling for a more suitable effective surrogate endpoint.

Beginning with the 2013 Ma Xiteng SERAPHIN study, researchers tried to verify efficacy in a three-phase clinical trial using the compound endpoint, the time of clinical exacerbation, as the primary surrogate endpoint. On the basis of total death, the end point is also added with malignant events such as hospitalization and heart-lung transplantation due to PAH deterioration to form a composite end point index. Compared with the simple mortality, the clinical exacerbation time increases the incidence of the event, and the incidence of the clinical exacerbation event of PAH patients treated by Ma Xiteng for 3 years is about 35%. Mclaughlin et al also subsequently validated the correlation between the incidence of clinical exacerbation events in patients and long-term survival. However, the clinical deterioration time is adopted to verify the effectiveness, so that the research period is obviously prolonged, and the three-phase clinical research period for verifying the effectiveness of the PAH targeted drug is prolonged from 12 to 24 weeks to 3 to 4 years. To ensure a positive patient count for the event achieved, a larger sample size is also required for the study. In addition, the endpoint events included in each study are not completely consistent, and the clinical exacerbation events have not yet formed strict uniform criteria. So currently most PAH targeted drugs are still used initially with 6MWD as the primary endpoint indicator for short term validation of drug effectiveness. The major surrogate endpoint problem of seeking more suitable short term validation of PAH targeted drug effectiveness has not been addressed.

With the advent and perfection of the concept of risk stratification, there has been a call in the art to shift the effective surrogate end point from worsening event targeting to treatment targeting. 2009 edition ESC/ERS guidelines for the first time suggest that treatment should be judged to be adequate based on the clinical status of PAH patients. The 2015 edition ESC/ERS guideline firstly provides a concept and a judging method of risk stratification, namely patients are classified into low-risk, medium-risk and high-risk according to the annual death rate of <5%,5-10% and >10% of the patients, and the patients are recommended to reach a low-risk state as the targets of follow-up and full treatment. However, since the risk stratification of the initial edition is complicated, and then various simplified versions of risk stratification studies are developed for each registration study, then it is also found that the three-layer risk stratification method of the 2015 guideline has a low degree of discrimination for medium-risk patients, more than 60% of patients are at medium risk, and the annual mortality rate of medium-risk and high-risk patients is higher than expected. Thus, the sparr algorithm attempts to further classify medium-risk patients into medium-low and medium-high risk. The COMPERA2.0 four-layer risk stratification method further simplifies the SPARR algorithm, predicts annual survival rate of European COMPERA queue patients according to right heart function related indexes of 0-3%,2-7%,9-19% and >20%, divides the patients into low risk, medium and high risk, and verifies annual survival rate in samples of more than 2000 patients in French FPHN registration queues. Specific rules of the COMPERA2.0 algorithm are as follows: in one follow-up visit, 6WMD >440, 320-440, 165-319, <165 meters are 1, 2, 3, 4 points respectively; WHO-FC I, II, III, IV are 1, 3, 4 respectively; BNP <50, 50-199, 200-800, >800ng/L is 1, 2, 3, 4 minutes, respectively; in determining the patient risk level, at least 2 of the above 3 indices must be used. The final score of the patient is calculated by dividing the score points of the indexes by the number of the indexes and rounding, wherein the final scores of 1, 2, 3 and 4 are the risk grades of the patient, 1 is low risk, 2 is medium and low risk, 3 is medium and high risk and 4 is high risk. The COMPERA2.0 algorithm was eventually adopted by the latest 2022 edition of european ESC/ERS, guidelines for pulmonary arterial hypertension clinical diagnosis and treatment, as a tool for assessing risk stratification in PAH patients.

The recent world pulmonary hypertension conference (the 6th World Symposia on Pulmonary Hypertension,6thWSPH) again notes the problem of short-term efficacy of pulmonary hypertension drugs with inadequate end points, and advocates subsequent studies that can incorporate patient risk stratification as a surrogate end point, and that can also use clinically improved time to replace clinically worsening time. From 6thWSPH, corresponding calls are successively made to study, composite clinical improvement events are adopted as exploratory endpoints, the number of the studies is not great, the studies are limited to the definition of the clinical improvement events in the modes of improving the percentage by the traditional indexes such as 6MWD and the like, the results and the treatment targets are not hooked, the occurrence rate of the clinical improvement events is counted, and the combination of improvement time is not considered. In summary, short-term clinical surrogate endpoints targeted for patient treatment remain to be studied further. Clinical improvement events are defined in conjunction with risk stratification, and improvement achievement times are fully considered, potentially being suitable clinical surrogate endpoints for short-term validation of PAH targeted drug effectiveness.

Briefly summarized, long-term practice in the field of pulmonary arterial hypertension has found that improvement in 6MWD is affected by the baseline value of the patient itself, and that improvement in 6MWD also shows no obvious correlation with patient long-term survival rate, raising a debate in the field. The art is therefore calling for more suitable effective clinical surrogate endpoints. Researchers have turned to using clinical exacerbation time to verify targeted drug effectiveness for nearly 10 years, but verifying effectiveness with clinical exacerbation time also significantly lengthens the study period, resulting in a three-phase clinical study period of 3 to 4 years from 12 to 24 weeks of 3 to 4 years of validating PAH targeted drug effectiveness. To ensure a positive patient count for the event achieved, a larger sample size is also required for the study. In addition, the endpoint events included in each study are not completely consistent, and the clinical exacerbation events have not yet formed strict uniform criteria. So currently most PAH targeted drugs are still used initially with 6MWD as the primary endpoint indicator for short-cycle validation of drug effectiveness. The major surrogate endpoint problem of seeking more suitable short-cycle verification of PAH targeted drug effectiveness has not been addressed. Thus, the present invention provides a novel method of verifying the effectiveness of pulmonary arterial hypertension targeted drugs.

Disclosure of Invention

In order to overcome the defects in the prior art, a method for verifying the effectiveness of a pulmonary arterial hypertension targeted drug is provided.

The invention is realized by the following scheme:

a method of verifying the effectiveness of a pulmonary arterial hypertension targeted drug, the method using a clinically improved time to TTCI to verify PAH targeted drug effectiveness.

The TTCI is the time to risk stratification improvement in PAH patients.

The improvement of risk stratification in the PAH patient is at least one level after the PAH patient receives targeted drug therapy.

The time is the time that the risk stratification is improved and there is no clinical deterioration after the PAH patient receives targeted drug therapy.

The risk stratification is calculated according to the compra 2.0 algorithm.

The COMPERA2.0 algorithm is specifically defined as follows: in one follow-up visit, the 3 indexes of 6WMD, WHO heart function grading and BNP are respectively counted as 1 score, 2 scores, 3 scores and 4 scores, at least 2 of the 3 indexes are required to be used in the process of determining the risk grade of a patient, the final score is calculated by taking the average value of the indexes and rounding, and finally the obtained 1 score, 2 score, 3 score and 4 score are the risk grade of the patient, the 1 score is low risk, the 2 score is medium and low risk, the 3 score is medium and high risk, and the 4 score is high risk.

The index scoring method of the 6WMD comprises the following steps: in one follow-up visit, the 6WMD is more than 440 meters, the 6WMD is 320-440 meters, the 6WMD is 165-319 meters, and the 6WMD is less than 165 meters and is 1 minute, 2 minutes, 3 minutes and 4 minutes respectively.

The index scoring method of WHO heart function grading comprises the following steps: in one follow-up, WHO heart function was classified as class I, class II, class III, class IV, respectively, 1, 2, 3, 4.

The index scoring method of BNP comprises the following steps: in one follow-up, BNP less than 50ng/L, BNP is 50-199ng/L, BNP and 200-800ng/L, BNP is greater than 800ng/L and is respectively counted as 1 minute, 2 minutes, 3 minutes and 4 minutes.

The clinical exacerbations include total mortality, hospitalization for PAH exacerbations, alteration or addition of other PAH targeting drugs.

The beneficial effects of the invention are as follows:

1. the TTCI employed in the present application can observe more positive endpoint events within 24 weeks, i.e., a high rate of improvement in accumulation within 24 weeks, relative to the time of clinical exacerbation. Compared with clinical deterioration time, the TTCI has short research period and small required research sample size, and can be used in short-period research.

2. The TTCI employed in this application is not affected by patient baseline risk stratification, relative to 6MWD. In addition, TTCI may identify that the 6MWD failed to detect a therapeutic discrepancy. The overall effect is better than 6MWD, and is a more suitable clinical surrogate endpoint for verifying the effectiveness of PAH targeted drugs in a short period.

3. Patients with improved risk stratification have been shown to have better long term survival, i.e., TTCI of the present application coupled with patient long term survival, over 6MWD.

4. The TTCI shortens the research period of clinical trials of PAH targeted drugs, can promote the research efficiency of the effectiveness of the targeted drugs, reduces the follow-up time of patients and more rapidly identifies the effective drugs. Meanwhile, the study of the ineffective medicine can be stopped in time, and the injury of the long-term treatment of the ineffective medicine to study population is avoided.

Drawings

FIG. 1 is a patient group entry condition in an example;

FIG. 2 bit 6MWD, WHO-FC, TASPE/PASP and improvement of risk stratification (LOCF) within 24 weeks (ITT set);

FIG. 3 is a Kaplan-Meier analysis of TTCI (A), two risk stratification subgroups TTCI (B), two treatment subgroups TTCI (C), TTCW (D);

fig. 4 is a flow chart of a method of using TTCI.

Detailed Description

Preferred embodiments of the present invention will be further described with reference to the accompanying drawings:

in this application: the English of the clinical improvement time is: time to Clinical Improvement, in this application the clinical improvement time english abbreviation TTCI. The english abbreviation for WHO heart function classification is WHO-FC. In this example, the COMPERA2.0 algorithm is based on the latest European guideline adoption by PAH.

The technical scheme of the application is as follows: a method of verifying the effectiveness of a pulmonary arterial hypertension targeted drug, the method using a clinically improved time to TTCI to verify PAH targeted drug effectiveness. The TTCI is the time to risk stratification improvement in PAH patients. The improvement of risk stratification in the PAH patient is at least one level after the PAH patient receives targeted drug therapy. The time is the time that the risk stratification is improved and there is no clinical deterioration after the PAH patient receives targeted drug therapy. The clinical exacerbations include total mortality, hospitalization for PAH exacerbations, alteration or addition of other PAH targeting drugs. The TTCI usage flow is shown in fig. 4.

TTCI, which is not affected by baseline risk stratification of PAH patients, can be used as the primary endpoint of efficacy testing in study populations containing multiple risk stratification states. TTCI can identify treatment differences not identified by 6MWD, and the study results are more sensitive than 6MWD. Particularly in the research of researching the superiority and inferiority of different treatment schemes or different treatment medicines, the problem that the 6MWD is not obviously improved before and after the treatment due to the higher baseline 6MWD of the incorporated population can be avoided. Patients with improved risk stratification have been shown to have better long term survival, i.e., TTCI hooked with long term survival of patients, than 6MWD.

The application method specifically comprises the following steps: when verifying the effectiveness of a certain PAH targeting drug or comparing the advantages and disadvantages of two different PAH treatment schemes, taking PAH patients as a study population, enabling a single group or multiple groups of PAH patients to receive the targeting drug or the two different PAH treatment schemes for 24 weeks, taking TTCI within 24 weeks of treatment as a main endpoint of a test, and carrying out survival analysis on TTCI of the study population at the end of the study. The results are presented as cumulative improvement rate of TTCI in study population over 24 weeks, median improvement time, and differences in TTCI between study populations. Thus, the effectiveness of the PAH targeting drug is judged, or the two different PAH treatment schemes are compared. Compared with the defects of long test period and large required sample size of clinical deterioration time, the invention provides a novel clinical substitution endpoint for verifying the effectiveness of PAH targeted drugs, which has short research period and small required research sample size. Compared with the defect that 6MWD is influenced by the baseline state of the patient and has poor correlation with the long-term survival rate, the invention provides a novel clinical surrogate endpoint which is related with the long-term survival rate of the patient, has strong sensitivity and is not influenced by the baseline state of the patient and is used for verifying the effectiveness of the PAH targeted drug.

The risk stratification is calculated according to the compra 2.0 algorithm. The COMPERA2.0 algorithm is specifically defined as follows: in one follow-up visit, the 3 indexes of 6WMD, WHO heart function grading and BNP are respectively counted as 1 score, 2 scores, 3 scores and 4 scores, at least 2 of the 3 indexes are required to be used in the process of determining the risk grade of a patient, the final score is calculated by taking the average value of the indexes and rounding, and finally the obtained 1 score, 2 score, 3 score and 4 score are the risk grade of the patient, the 1 score is low risk, the 2 score is medium and low risk, the 3 score is medium and high risk, and the 4 score is high risk. The index scoring method of the 6WMD comprises the following steps: in one follow-up visit, the 6WMD is more than 440 meters, the 6WMD is 320-440 meters, the 6WMD is 165-319 meters, and the 6WMD is less than 165 meters and is 1 minute, 2 minutes, 3 minutes and 4 minutes respectively. The index scoring method of WHO heart function grading comprises the following steps: in one follow-up, WHO heart function was classified as class I, class II, class III, class IV, respectively, 1, 2, 3, 4. The index scoring method of BNP comprises the following steps: in one follow-up, BNP less than 50ng/L, BNP is 50-199ng/L, BNP and 200-800ng/L, BNP is greater than 800ng/L and is respectively counted as 1 minute, 2 minutes, 3 minutes and 4 minutes.

Example (for verifying the effectiveness of domestic ambrisentan with TTCI as the primary endpoint)

Study design: open label, single arm, prospective cohort study attended by 8 medical centers in our country. Patients in the proposed group were confirmed to meet the inclusion criteria, not the exclusion criteria, by review of the right cardiac catheter and were included in the study after collecting patient baseline and baseline data. All eligible patients will then receive ambrisentan treatment once a day, 5 milligrams each time, during the initial treatment period of 12 weeks prior to the study. If the patient does not have an event during the initial treatment period that would lead to the patient exiting the study, then an extended period of treatment for 12 weeks is followed during which the patient can maintain a 5 mg dose or titrate to a dose of 10 mg once a day. The total time for patients to receive ambrisentan treatment was 24 weeks, followed every 6 weeks. The trial had TTCI within 24 weeks of treatment as the primary endpoint of effectiveness and 6MWD, WHO-FC, BNP, echocardiogram, clinical exacerbation events for 24 weeks of treatment as the secondary endpoint of effectiveness. The adverse reaction is taken as a safety endpoint.

Study population: qualified PAH patients were continuously included in 8 medical centers in our country who were diagnosed during the period of 2018, 9, to 2022, 2. The group entering standard is as follows: the new diagnosis or the established diagnosis of the patients with the first large pulmonary arterial hypertension in the WHO latest clinical classification in China; WHO heart function classification (WHO-FC) is class II to class III; age between 18-75 years old; PAH targeted drug treatment with endothelin receptor antagonists was not received within 4 weeks prior to group entry; patients undergoing treatment with other types of PAH-targeted drugs should remain at a stable dose for at least 4 weeks; the baseline 6-minute walk distance is at least 150 meters; right heart catheterization was performed within 6 months prior to the group entry and met the following hemodynamic criteria: average pulmonary artery pressure (PASP) is more than or equal to 25mmHg, pulmonary Vascular Resistance (PVR) is more than or equal to 3Wood Unit, pulmonary artery wedge pressure or left ventricular end diastole pressure (PAWP or PCWP) is less than or equal to 15mmHg; lung function tests were performed within the first 6 months of the group and met the following criteria: the total lung is more than or equal to 60% of normal predicted value, and the forced expiratory volume per second (FEV 1) is more than or equal to 55% of normal predicted value. The exclusion criteria were: serum alanine transferase (ALT) or aspartate transferase (AST) levels > 2-fold ULN; serum bilirubin levels >1.5 times ULN; severe liver dysfunction (Child-Pugh grade C); severe renal insufficiency (creatinine clearance <30 ml/min); hemoglobin concentration <100g/L or hematocrit <30%; severe hypotension (diastolic <50mmHg or systolic <90 mmHg); patients who have been treated with endothelin receptor antagonists (e.g., bosentan) but have terminated such drug treatment due to safety or tolerability issues (non-drug induced liver dysfunction); clinically significant aortic or mitral valve disease, pericardial stenosis, restrictive or congestive cardiomyopathy, fatal arrhythmia, left ventricular ejection fraction < 45%, left ventricular outflow tract obstruction, symptomatic coronary heart disease, spontaneous hypotension; a history of malignancy, basal cell carcinoma of the skin and carcinoma of the cervical in situ within 5 years of group entry; pregnant women and lactating women; laboratory tests, physical tests, medical history or other tests find treatment contraindications.

Study results:

1. study population inclusion: a total of 83 patients were successfully included in the initial treatment period. Due to the drug disruption caused by the novel coronavirus, the failure of 9 patients to obtain ambrisentan drug after completion of the initial treatment period resulted in disruption of the treatment, and the study was exited, with the other 74 patients entering an extended treatment period (see fig. 1). The first patient group time was 2018, 12 months, the last patient follow-up time was 2021, 9 months, and the average time to treatment for all patients was 160.1 (44.4) days. 1 patient did not have ITT set due to lack of baseline efficacy endpoint data, and a total of 82 patients included ITT set. Of these 48 patients were newly diagnosed with PAH (new diagnostic group), never received PAH drug treatment, and 34 patients were receiving PAH targeted drug treatment of a non-endothelin receptor antagonist class and maintained at a steady dose (basal treatment group). Figure 1 is a patient group entry. Wherein: 1 patient was excluded from diagnosis of hypoxia-related PAH; 1 patient baseline measurements for the lack of efficacy endpoint were not included in ITT set; other classes of PAH targeted drugs include phosphodiesterase type 5 inhibitors, guanylate cyclase agonists, prostacyclin analogs, and prostacyclin receptor agonists.

Population/baseline characteristics are detailed in table 1. The study subjects were mainly females (80.7%), with a median age of 36 years, all in the han group. The patient had a baseline 6MWD of 403.5 (78.0) meters. The baseline risk stratification is mainly medium risk, 36 cases (43.9%) are medium and low risk, 45 cases (54.9%) are medium and high risk, and no low risk patients exist. The patients who used sildenafil in combination were the largest (85.3%) in the basal treatment group. Other demographic/baseline characteristics, except for age (p=0.034), were not significantly different between the new diagnostic group and the basal treatment group.

TABLE 1 population/baseline characteristics (ITT set)

2. Primary and secondary endpoint of effectiveness condition:

TTCI: a total of 30 (36.6%) and 53 (64.6%) patients improved at least one level of four risk stratification with no clinical deterioration within 12 and 24 weeks (fig. 2D and table 2). Kaplan-Meier analysis showed a median improvement time for TTCI of 131 days (95% ci: 125.4-136.7) with a 24 week cumulative improvement of 75.1% (fig. 3A and table 2). TTCI was not significantly different in medium and low risk patients and medium and high risk patients (median improvement time 133[95% ci:73.9-178.1] days vs.126[95% ci:128.6-137.4] days, log-rank p=0.51, fig. 3B). TTCI was significantly shorter in the new diagnostic group than in the basal treatment group (median improvement time and cumulative improvement rate 94.0[95% ci:55.6-132.4] days, 84.1% vs.173.0[95% ci:121.4-224.6] days, 57.9%, log-rank p=0.008, fig. 3C and table 2). Single factor COX regression analysis showed that baseline and treatment subgroups, tame, tasp/PASP and 24 weeks of treatment 6MWD, WHO-FC front-to-back variability was the influencing factor for TTCI. The 6MWD, WHO-FC front-to-back variation of the treatment subgroup, 24 weeks, was shown by the multi-factor COX regression analysis to be an independent contributor to TTCI with risk ratios of 0.314 (95% CI:0.164-0.603, P < 0.001), 1.009 (95% CI:1.002-1.016, P=0.017), 2.974 (95% CI:1.703-5.191, P < 0.001), respectively (see Table 4).

6MWD and other secondary endpoints: as shown in fig. 2 and table 2, the 6MWD improved faster early in the treatment, a significant statistical improvement in 6MWD was observed from week 6 (24.62 m, p < 0.0001), followed by further significant clinical improvement at week 12 (42.2 m, p < 0.0001) and week 24 (53.4 m, p < 0.0001). WHO-FC, borg dyspnea score, BNP, TAPSE, and TAPSE/PASP showed significant improvement after 12 weeks and 24 weeks of treatment, consistent with 6MWD. The 6MWD subgroup analysis was consistent with the overall results, with no significant statistical differences seen between the subgroups (see table 3). At 24 weeks, no significant statistical differences were seen in the efficacy index for both the new diagnostic and basal treatment groups (see table 2).

Clinical exacerbation event and adverse reaction: a total of 3 (3.6%) patients had a clinical exacerbation event within 24 weeks. 1 patient was hospitalized with PAH, 2 patients were added with other PAH targeting drugs during the study (1 with sildenafil and 1 with tadalafil), and no patient had all-cause death or lung transplantation during the study (table 5). Adverse reactions occurred in 45 patients (54.2%). The most common adverse events were facial flushing (14.5%), palpitations (9.6%) and peripheral edema (8.4%). 1 patient was withdrawn from the study due to an increase in glutamate pyruvate transaminase (ALT) of more than 3 times ULN (see Table 5), and all other adverse effects were mild to moderate.

TABLE 2 end of effectiveness (ITT set)

#: p <0.05 indicates a statistical difference between baseline and follow-up; * : p <0.05 indicates a statistical difference between the new diagnostic group and the basal treatment group; an1=61, n2=40, n1=19, n2=21; n1=79, n2=79, n1=49, n2=30; clinical improvement, defined as improvement of risk stratification of at least grade 1 without clinical deterioration; abbreviations: delta 6MWD, the change in six-minute walk distance from baseline; the abbreviations are shown in Table 1.

FIG. 2 shows improvement in 6MWD, WHO-FC, TASPE/PASP and risk stratification (LOCF) over 24 weeks (ITT set). Wherein:

(A) Increased by 24.6 (4.2) m,42.2 (4.7) m,50.5 (5.3) m, and 53.4 (5.6) m (p < 0.0001), respectively, over baseline;

(B) The composition ratio of WHO-FC at 24 weeks was grade I (11.0%), grade II (58.5%), and grade III (30.5%). WHO-FC in 25 (30.5%) patients improved by at least grade 1 over 24 weeks;

(C) The composition ratio of TAPSE/PASP at week 24 was <0.19 (32.9%), 0.19-0.32 (36.7%), >0.32 (30.4%). A total of 26 (32.9%) patients had at least 1 improvement in tame/PASP over 24 weeks;

(D) The composition ratio of the dangerous stratification at 24 weeks is low-risk (35.4%), medium-low-risk (41.5%), medium-high-risk (22.0%), and high-risk (1.2%). The risk stratification of 53 total (64.6%) patients improved at least grade 1 within 24 weeks without clinical deterioration; abbreviations: delta 6MWD, the change in six-minute walk distance from baseline; WHO-FC, WHO cardiac function stratification.

Discussion of results: in the study of this example, we demonstrate that homemade ambrisentan can significantly improve 6MWD and risk stratification in adult PAH patients in our country. While the TTCI features indicate that TTCI is more suitable than 6MWD as a clinical surrogate endpoint for PAH efficacy tests.

Since the first use of 6MWD as the primary efficacy endpoint for the evaluation of epoprostenol by Barst in the 90 s of the 20 th century, most of the PAH drug efficacy tests employed this surrogate endpoint as the primary efficacy endpoint. A meta-analysis combines 10 PAH targeted drug randomized controlled studies prior to 2012 to find that a 41.8m improvement in 6MWD can be a threshold for fewer clinical exacerbation events within 12 weeks. In this example, the 6MWD was increased by 42.2 (42.9) m and 53.4 (50.9) m at weeks 12 and 24 of treatment, respectively, demonstrating that homemade ambrisentan is effective in treating adult PAH patients in our country (see table 2 and figures 2A-C). The 6MWD sub-group analysis results were similar to the pattern noted in the population as a whole, and there was no statistical difference in 6MWD between the sub-groups (see table 3). Most adverse reactions were mild to moderate, consistent with the results of the peer study, indicating that homemade ambrisentan had good tolerability in PAH patients in our country (see Table 5).

The risk stratification is a complex endpoint. The study by Hoeper et al demonstrated a higher long-term survival in patients with improved risk stratification. Their studies showed that WHO-FC for 35.2% of patients and risk stratification for 51% of patients improved by at least one stage over 3-12 months. In this example, risk stratification for WHO-FC for a total of 25 (30.5%) patients and 53 (64.6%) patients improved at least one stage over 24 weeks, consistent with the trend of the Hoeper study. The domestic ambrisentan significantly improved the risk stratification of adult PAH patients in our country (P <0.0001, see table 2 and figure 2D).

This example may be the first prospective study to combine clinical improvement time and risk stratification as surrogate endpoints. In this example, we define a clinical improvement event (TTCI) with at least one level of improvement in risk stratification. Similar to TTCW, the limited occurrence of a possible positive event may also be the limiting factor for TTCI in short-term trials. A higher positive rate of endpoint events is beneficial in reducing the need to study sample size. The results of the examples of the present application show that the end-point positive events of TTCI were 53 cases (64.5%) and the cumulative improvement rate was 75.1% within 24 weeks, respectively (fig. 3A). The results indicate that TTCI has the advantages of smaller sample size requirements and shorter follow-up time.

Regression analysis of the single factor Cox model showed that TTCI was independent of risk stratification, 6MWD, WHO-FC or BNP levels for the baseline status of the subject, indicating that the improvement event occurred largely due to the treatment itself (table 3). Previous studies have shown that 6MWD has a "ceiling effect", i.e. individuals with higher baseline 6MWD values often observe lower Δ6MWD after treatment in the whole population. In contrast, TTCI is not affected by baseline risk conditions (fig. 3B), which is superior to 6MWD.

Multifactor Cox regression analysis showed that 6MWD, WHO-FC front-to-back variability in the treatment subgroup, 24 weeks, was an independent contributor to TTCI (table 3). Patients in the new diagnostic group had shorter TTCI (median improvement time 94vs.173 days, log-rank p=0.008, fig. 3C) and more risk improvement (p=0.043, table 2) than the basal diagnostic group, while 6MWD and other traditional efficacy endpoints did not see significant differences between the two groups. The results suggest that TTCI may be able to identify differences in efficacy that cannot be detected using only 6MWD or other conventional efficacy endpoints, but this requires further investigation to demonstrate.

It must be noted that the shorter TTCI of the new diagnostic group does not conflict with the currently clinically recommended combination therapy. Similar results were also observed for McLaughlin et al. They found that the addition of bosentan to sildenafil treatment did not improve the clinical exacerbation time better than sildenafil monotherapy. This is probably because the patients in the basal treatment group have received a stable dose of PAH targeted drug therapy and some have had clinical improvement, so that fewer improvement events occur after ambrisentan addition.

FIG. 3 is a Kaplan-Meier analysis of TTCI (A), two risk stratification subgroups TTCI (B), two treatment subgroups TTCI (C), TTCW (D). Abbreviations: TTCI, time to clinical improvement, defined as the time from onset of treatment to first risk stratification improvement of at least one stage within 24 weeks without clinical deterioration; RISK-2, medium and low RISK; RISK-3, medium and high RISK; ttci_n Group, TTCI for the new diagnostic Group, patients not receiving PAH targeted drug treatment; ttci_ad Group, TTCI for the basal treatment Group, who was receiving a stable dose of other PAH-targeted drug prior to ambrisentan addition; TTCI-low, defined as the time from the start of treatment to the first time a low risk condition is reached within 24 weeks without clinical deterioration; TTCW, time to clinical exacerbation, defined as the time from initiation of treatment to the first occurrence of clinical exacerbation, including total cause death, hospitalization for PAH, replacement or augmentation of PAH targeted drug.

TABLE 3.6 sub-analysis of 24 week variation of MWD (ITT post)

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#: paired t-test, P <0.05 indicated a statistical difference between baseline and week 24; * : single factor analysis of variance, P <0.05 indicates statistical differences between subgroups; all abbreviations are shown in tables 1 and 2.

TABLE 4 one-factor/Multi-factor COX regression analysis of TTCI

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* New diagnostic or basic treatment groups; all abbreviations are shown in tables 1 and 2.

TABLE 5 clinical exacerbation event and adverse reaction (. Gtoreq.3%) (SS set)

* :1 patient had a 3-fold increase in glutamate pyruvate transaminase (ALT) and all other adverse effects were mild to moderate.

While the invention has been described and illustrated in considerable detail, it should be understood that modifications and equivalents to the above-described embodiments will become apparent to those skilled in the art, and that such modifications and improvements may be made without departing from the spirit of the invention.

Claims (10)

1. A method for verifying the effectiveness of a pulmonary arterial hypertension targeted drug, comprising: the method uses TTCI to verify PAH targeting drug effectiveness.

2. A method of verifying the effectiveness of a pulmonary hypertension targeted drug as in claim 1, wherein: the TTCI is the time to risk stratification improvement in PAH patients.

3. A method of verifying the effectiveness of a pulmonary hypertension targeted drug as in claim 2, wherein: the improvement of risk stratification in the PAH patient is at least one level after the PAH patient receives targeted drug therapy.

4. A method of verifying the effectiveness of a pulmonary hypertension targeted drug as in claim 2, wherein: the time is the time that the risk stratification is improved and there is no clinical deterioration after the PAH patient receives targeted drug therapy.

5. A method of verifying the effectiveness of a pulmonary hypertension targeted drug as in claim 2, wherein: the risk stratification is calculated according to the compra 2.0 algorithm.

6. The method for verifying the effectiveness of a pulmonary hypertension targeted drug of claim 5, wherein the COMPERA2.0 algorithm is specifically defined as: in one follow-up visit, the 3 indexes of 6WMD, WHO heart function grading and BNP are respectively counted as 1 score, 2 scores, 3 scores and 4 scores, at least 2 of the 3 indexes are required to be used in the process of determining the risk grade of a patient, the final score is calculated by taking the average value of the indexes and rounding, and finally the obtained 1 score, 2 score, 3 score and 4 score are the risk grade of the patient, the 1 score is low risk, the 2 score is medium and low risk, the 3 score is medium and high risk, and the 4 score is high risk.

7. The method for verifying the effectiveness of a pulmonary arterial hypertension targeted drug of claim 6, wherein the index scoring method of 6WMD is: in one follow-up visit, the 6WMD is more than 440 meters, the 6WMD is 320-440 meters, the 6WMD is 165-319 meters, and the 6WMD is less than 165 meters and is 1 minute, 2 minutes, 3 minutes and 4 minutes respectively.

8. The method of verifying the effectiveness of a pulmonary hypertension targeted drug of claim 6, wherein the index scoring method of WHO cardiac function classification is: in one follow-up, WHO heart function was classified as class I, class II, class III, class IV, respectively, 1, 2, 3, 4.

9. The method for verifying the effectiveness of a pulmonary hypertension targeted drug of claim 6, wherein the index scoring method of BNP is as follows: in one follow-up, BNP less than 50ng/L, BNP is 50-199ng/L, BNP and 200-800ng/L, BNP is greater than 800ng/L and is respectively counted as 1 minute, 2 minutes, 3 minutes and 4 minutes.

10. A method of verifying the effectiveness of a pulmonary hypertension targeted drug as defined in claim 4, wherein: the clinical exacerbations include total mortality, hospitalization for PAH exacerbations, alteration or addition of other PAH targeting drugs.