METHOD FOR PREDICTING DECOMPENSATION EVENTS IN NASH PATIENTS

Abstract

Disclosed is a method for predicting a decompensation event in a patient suffering from NASH, including performing a .sup.13C methacetin breath test on a patient; calculating a PDR-peak value of the patient, based on the .sup.13C methacetin breath test; and identifying the patient as having high-risk of developing a decompensation event within 1 year from the performing of the breath test, if the PDR-peak value is at or below a predetermined threshold value; wherein the predetermined threshold value is 15%/h.

Claims

1.-26. (canceled)

27. A method for predicting progression in a MELD-score of a patient suffering from NASH, the method comprising: performing a .sup.13C methacetin breath test on a patient; the patient suffering from NASH and having a baseline MELD-score; calculating a PDR-peak value of the patient, based on the .sup.13C methacetin breath test; identifying the patient as having high-risk of MELD-score progression if the PDR-peak value is at or below a predetermined threshold value, wherein progression of the MELD score comprises an increase of at least 2 points from the baseline MELD-score within 1 year from the performing of the breath test and wherein the predetermined threshold value is 15%/h; intensifying monitoring of the patient if the patient is identified as having high risk of MELD-score progression as compared to patients identified with a lower risk of MELD-score progression.

28. The method of claim 27, further comprising promoting the priority of the patient on a transplant list, if the patient is identified as having high risk of MELD-score progression vis-à-vis patients identified with a lower risk of MELD-score progression.

29. The method of claim 27, wherein the predetermined threshold value is 5.5%/h.

30. The method of claim 27, further comprising predicting a decompensation event in the patient if the PDR-peak value is at or below of the predetermined threshold value.

31. The method of claim 27, wherein the decompensation event comprises occurrence of at least one of: new onset or worsening of hepatic encephalopathy, new onset or refractory ascites, variceal hemorrhage or occurrence of large gastroesophageal varices or any varices with red wale sign, portal hypertensive gastropathy hemorrhage, spontaneous bacterial peritonitis, hepatorenal syndrome, liver-specific or all-cause death or any combination thereof.

32. The method of claim 27, wherein the patient is suffering from cirrhotic NASH or decompensated cirrhotic NASH.

33. The method of claim 27, wherein the method comprises identifying the patient as having a high-risk of experiencing an at least 2-point increase in MELD-score within 6 months of the breath-test, if the PDR-peak value is at or below the predetermined threshold value.

34. The method of claim 27, further comprising providing a monthly accumulated risk score, based on the PDR-peak value.

35. A method for prioritizing NASH patients for allocation of liver transplants, the method comprising: obtaining or producing a transplantation priority list for allocation of transplants; obtaining a baseline MELD-score from a patient appearing on or being a candidate to the transplantation priority list; the patient suffering from NASH obtaining .sup.13C methacetin breath test results of the patient; obtaining or calculating a PDR-peak value of the patient, based on the .sup.13C methacetin breath test; and if the calculated PDR-peak value at or below a predetermined threshold value, promoting the priority of the patient on the transplant priority list, relative to patients having a similar MELD-score and a PDR-peak value above the predetermined threshold value; wherein the predetermined threshold value is 15%/h.

36. The method of claim 35, wherein the predetermined threshold value is 5.5%/h.

37. The method of claim 35, wherein the patient is suffering from cirrhotic NASH or decompensated cirrhotic NASH.

38. A method for predicting a decompensation event in a patient suffering from NASH, the method comprising: performing a .sup.13C methacetin breath test on a patient; calculating a PDR-peak value of the patient, based on the .sup.13C methacetin breath test; identifying the patient as having high-risk of developing a decompensation event within 1 year from the performing of the breath test, if the PDR-peak value is at or below a predetermined threshold value; wherein the predetermined threshold value is 15%/h; and intensifying monitoring of the patient if the patient is identified as having high risk of developing a decompensation event, as compared to patients identified with a lower risk of developing a decompensation event.

39. The method of claim 38, further comprising promoting the priority of the patient on a transplant list if the patient is identified as having high risk of developing a decompensation event vis-à-vis patients identified with a lower risk of developing a decompensation event.

40. The method of claim 38, wherein the predetermined threshold value is 5.5%/h.

41. The method of claim 38, wherein the decompensation event comprises occurrence of at least one of: new onset or worsening of hepatic encephalopathy, new onset or refractory ascites, variceal hemorrhage or occurrence of large gastroesophageal varices or any varices with red wale sign, portal hypertensive gastropathy hemorrhage, spontaneous bacterial peritonitis, hepatorenal syndrome, at least 2-point progression in MELD score, liver-specific or all-cause death or any combination thereof.

42. The method of claim 38, wherein the patient is suffering from cirrhotic NASH cirrhosis or from decompensated cirrhotic NASH.

43. The method of claim 38, wherein the method comprises identifying the patient as having a high-risk of experiencing a decompensation event within 6 months of the breath-test, if the PDR-peak value is at or below the predetermined threshold value.

44. The method of claim 38, further comprising providing a monthly accumulated risk score, based on the calculated PDR-peak value.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0044] Some embodiments of the disclosure are described herein with reference to the accompanying figures. The description, together with the figures, makes apparent to a person having ordinary skill in the art how some embodiments of the disclosure may be practiced. The figures are for the purpose of illustrative discussion and no attempt is made to show details of an embodiment in more detail than is necessary for a fundamental understanding of the teachings of the disclosure.

[0045] FIG. 1 is a flowchart of a method for predicting progression in a MELD-score of a patient suffering from NASH, according to some embodiments;

[0046] FIG. 2 is a flowchart of a method for predicting occurrence of a decompensation event in a patient suffering from NASH, according to some embodiments;

[0047] FIG. 3 is a flowchart of a method for prioritizing NASH patients for allocation of liver transplants, according to some embodiments;

[0048] FIG. 4 shows results obtained when evaluating the capability of the method to predict occurrence of a decompensation events.

DETAILED DESCRIPTION

[0049] In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the disclosure.

[0050] Reference is now made to FIG. 1 which is a flowchart of a method 100 for predicting progression in a MELD-score of a patient suffering from NASH and having a predetermined baseline MELD-score.

[0051] In step 110 a .sup.13C methacetin breath test is performed on the patient followed by a calculating of at least a PDR-peak value of the patient, based on the .sup.13C methacetin breath test (step 120). In step 130 the patient is identified as having high-risk of MELD-score progression, if the PDR-peak value is at or below a predetermined threshold value, wherein progression of the MELD score is defined as an increase of at least 4 points from the predetermined baseline MELD-score within 1 year (or less) from the performing of the breath test. According to some embodiments, the predetermined threshold value is at or below a PDR-peak value in the range of 5%/h-15%/h. The actual threshold value chosen is a question of risk-management and preferences. It is understood that when the threshold is set closer to 15%/h (e.g. 11%/h) the risk of wrongful exclusion of a high-risk patient is diminished however many non-high-risk patients may be included thus reducing the specificity of the method. On the other hand, if a threshold close to 5% is chosen (e.g. 5.5%) the risk of wrongful exclusion of a high-risk patient is increased however the certainty of patients identified as being high-risk actually being high risk significantly improved.

[0052] Optionally, method 100 may further include a step 140a of intensifying monitoring of the patient if the patient is identified as having high risk of MELD-score progression, as compared to patients identified with a lower risk of MELD-score progression. Additionally or alternatively, method 100 may further include a step 140b of promoting the priority of the patient on a transplant priority list, if the patient is identified as having high risk of MELD-score progression vis-à-vis patients identified with a lower risk of MELD-score progression, optionally despite the other patient having a same or similar base-line MELD-score (e.g. ±2 points) and optionally even despite the other patient having a higher MELD-score than the patient identified as having a high risk of MELD-score progression. According to some embodiments, the method may further include a step of determining the urgency of the patient's condition, i.e. a risk of MELD-score progression as a function of time, based at least on the PDR-peak value and optionally further on the predetermined baseline MELD score (step not shown).

[0053] Reference is now made to FIG. 2 which is a flowchart of a method 200 for predicting progression in a MELD-score of a patient suffering from NASH and having a predetermined baseline MELD-score.

[0054] In step 210 a .sup.13C methacetin breath test is performed on the patient followed by a calculating of at least a PDR-peak value of the patient, based on the .sup.13C methacetin breath test (step 220). In step 230 the patient is identified as having high-risk of decompensation event occurrence within 1 year (or less) from the performing of the breath test, if the PDR-peak value is at or below a predetermined threshold value. The decompensation event may be defined as occurrence of at least one of: new onset or worsening of hepatic encephalopathy, new or refractory ascites, variceal hemorrhage, occurrence of large gastroesophageal varices or any varices with red wale sign, portal hypertensive gastropathy hemorrhage, spontaneous bacterial peritonitis, hepatorenal syndrome, at least 2-point, at least 3-point or at least 4-point progression in MELD score, death (liver-specific or all-cause) or any combination thereof.

[0055] According to some embodiments, the predetermined threshold value is at or below a PDR-peak value in the range of 5%/h-15%/h. The actual threshold value chosen is a question of risk-management and preferences. It is understood that when the threshold is set closer to 15%/h (e.g. 11%/h) the risk of wrongful exclusion of a high-risk patient is diminished however many non-high-risk patients may be included thus reducing the specificity of the method. On the other hand, if a threshold close to 5% is chosen (e.g. 5.5%) the risk of wrongful exclusion of a high-risk patient is increased however the certainty of patients identified as being high-risk actually being high risk significantly improved.

[0056] Optionally, method 200 may further include a step 240a of intensifying monitoring of the patient if the patient is identified as having high risk of developing a decompensation event, as compared to patients identified with a lower risk of developing a decompensation event. Additionally or alternatively, method 200 may further include a step 240b of promoting the priority of the patient on a transplant priority list, if the patient is identified as having high risk of decompensation event occurrence vis-à-vis patients identified with a lower risk of developing a decompensation event, optionally despite the other patient having a same or similar base-line MELD-score (e.g. ±2 points) and optionally even despite the other patient having a higher MELD-score than the patient identified as having a high risk of MELD-score progression.

[0057] According to some embodiments, the method may further include a step of determining the urgency of the patient's condition, i.e. a risk of developing a decompensation event as a function of time, based at least on the PDR-peak value and optionally further on the predetermined baseline MELD score of the patient (step not shown).

[0058] Reference is now made to FIG. 3 which is a flowchart of a method 300 for prioritizing NASH patients for allocation of liver transplants.

[0059] In step 310 a transplantation priority list for allocation of transplants is obtained or being generated; in step 320 medical data of a patient who suffers from NASH and who is on the transplantation priority list of who is a candidate to enter the transplantation priority list are obtained. The data include at least a baseline MELD-score and .sup.13C methacetin breath test results of the patients. According to some embodiments, the .sup.13C methacetin breath test results may be “raw” data in which case step 320 includes calculating a PDR-peak value of the patient, based on the raw .sup.13C methacetin breath test data. Alternatively, the PDR-peak value of the patient may be precalculated and directly obtained.

[0060] In step 330 a priority of the patient may be determined (number on list) based on the patient's PDR-peak value. That is, if the PDR-peak value is at or below a predetermined threshold value, the patient may receive a higher priority on the transplant priority list relative to patients having a similar baseline MELD-score but a PDR-peak value above the predetermined threshold value.

[0061] According to some embodiments, the predetermined threshold value is at or below a PDR-peak value in the range of 5%/h-15%/h. The actual threshold value chosen is a question of risk-management and preferences. It is understood that when the threshold is set closer to 15%/h (e.g. 11%/h) the risk of wrongful exclusion of a high-risk patient (i.e. providing him/her with a lower than “deserved” priority) is diminished; however many non-high-risk patients may be included (thus providing them with a higher than “deserved” priority). On the other hand, if a threshold close to 5% is chosen (e.g. 5.5%) the risk of wrongful exclusion of a high-risk patient is increased; however, the certainty of patients identified as being high-risk actually being high risk significantly improved.

[0062] The following examples are presented in order to more fully illustrate some embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

EXAMPLES

Example 1— Verification of Predictive Capacity of the Method

[0063] 138 patients suffering from decompensated NASH cirrhosis underwent a .sup.13C methacetin breath test using a BreathID® Breath Test Device, every 24 weeks for 1 year.

[0064] The medical baseline data of the patients are outlined in Table 1 below

TABLE-US-00001 TABLE 1 n = 138 Females 72 (52.2%) Age (SD) 61.1 (8.5) years BMI (SD) 33.9 (6.2) kg/m.sup.2 MELD (SD) 10.4 (3.2)

[0065] The below list sets forth events that the prediction clinically evaluated using the herein disclosed method: [0066] All-cause Mortality [0067] MELD score progression defined as any increase ≥4 points from baseline [0068] New onset of Hepatic Encephalopathy [0069] New onset of Ascites [0070] Bleeding Varices

[0071] All events were reviewed and adjudicated blinded to the .sup.13C methacetin breath test results before efficacy analysis.

[0072] Table 2 below outlines the events identified in 38 of the 138 patients evaluated, as determined based on clinical evaluation.

TABLE-US-00002 TABLE 2 Decompensation Event n = 38 MELD Progression 25 New onset of Hepatic Encephalopathy 1 New onset of Ascites 1 Bleeding Varices 7 Death 4

[0073] A PDR-peak value was calculated for each of the 138 patients and a PDRpeak threshold value was set to 5.5%/h, i.e. patients having a PDRpeak at or below 5.5% were considered to be ‘high risk’ patients.

[0074] The .sup.13C methacetin breath test results were then tested for their ability to significantly predict event-free survival using the Cox proportional hazards regression model using the above identified threshold value.

[0075] As seen from FIG. 4, the breath test using the 5.5% threshold value provided a hazard ratio (HR) of 4.2 (95% CI: 1.75-10.07 p=0.00131) meaning that patients having a PDR-peak value at or below the threshold were more likely to experience a decompensation event, (in particular an at least 4-point increase in MELD-score (˜66% of the events)). In fact, 52% of the patients ( 11/22) having a PDR-peak value at or below the threshold experienced a decompensation event during the study, as opposed to 23% of the patients having a PDR-peak value above the threshold ( 27/117).

[0076] In comparison, the best cut-off using the MELD score was ≥14, resulting in a HR of 2.4 (95% CI: 1.03-5.57 p=0.0414) and the best cut off using the Child-Turcotte-Pugh (CTP) Score was ≥8, resulting in a HR of 2.63 (95% CI: 1.23-5.59 p=0.0123).

[0077] In fact, as shown in table 3, multivariate analyses showed that the herein disclosed PDRpeak≤5.5%/h had an independent predictive value superior to currently used predictors such as MELD or CTP scores (whether separately or combined).

TABLE-US-00003 TABLE 3 Multivariate Cox Regression with best cut-offs Multivariate Cox Regression HR 95% Cl p-value PDR.Peak ≤ 5.5 4.39  1.8, 10.71 0.00117 MELD ≥ 14 2.31 0.89, 5.98 0.08502 CTP ≥ 8 1.79 0.77, 4.15 0.17402

[0078] Furthermore, as seen from Table 4 below, the herein disclosed method enabled predicting events occurring half a year and 1 year after the breath test with a similar confidence (HR of 4.72 and 4.27, respectively).

TABLE-US-00004 TABLE 4 N = 138, PDR.sub.peak ≤ 5.5%/h HR 95% CI P-value One Year 4.27 1.72-10.61 0.00177 14 year 4.72 1.49-14.93 0.00836

[0079] While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.