Australian public assessment report for Terlipressin
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- Evaluator’s overall conclusions on pharmacokinetics
- Evaluator’s conclusions on clinical efficacy for the treatment of HRS Type 1
- Evaluator’s overall conclusions on clinical safety
- List of questions The evaluator made recommendations to the Delegate regarding the PI but these are beyond the scope of this AusPAR. Clinical summary and conclusions
- Recommendation regarding authorisation
IV. Clinical findingsA summary of the clinical findings is presented in this section. Further details of these clinical findings and the published references discussed can be found in Attachment 2. IntroductionThe company submitted the following clinical information:
The revised search strategy for the literature was approved by the TGA. The Addenda included addenda to the population PK study and to Study 0401that are considered under the relevant listings for the original studies and a 4 month New Drug Application (NDA) update that summarises the postmarketing data and literature published since the finalisation of the original sponsor Summary of Clinical Safety, they were reported as Addenda to the sponsor’s Clinical Overview and Summaries of Clinical Efficacy and Safety. These were considered under safety and efficacy in this evaluation where relevant. PharmacokineticsA submitted population pharmacokinetic (PK) study was based on Study OT-0401 (since HRS Type 1 patients have severe hepatic and renal impairment). Supportive literature on PK in healthy volunteers was provided. Evaluator’s overall conclusions on pharmacokineticsWhile the statements in the first two paragraphs of the PK section of the PI are supported by the population PK study they are based on limited data and this is indicated in the PI. Plate (1995)18 stated that: The half-life of terlipressin is reported to be approximately 24 minutes (Nilsson 1990, Forsling et al. 1980), the half-life of vasopressin is reported to be only six minutes. In our measurements, terlipressin and LVP were completely degraded after sixty minutes. Based on the assumption of a delayed terlipressin uptake in the organs, a maximum duration of action of two to three h can be extrapolated. This assumption corresponds well to the statements made by Forsling et al. in 1980 regarding a biological half-life of approximately 24 minutes and the findings by Kohaus regarding a clinical duration of action of two to three hours. Since a drug normally is excreted after five half-lives, a maximum duration of action of two h can also be extrapolated from the half-life. This would mean that in clinical applications terlipressin should be administered every two to three hours. The manufacturers' recommendations, however, are intervals of four to six hours. Forsling 198019 showed that the decay of terlipressin activity could be approximated to a double exponential. Taking the initial rapid decay phase, a mean half-life (t1/2) for the disappearance of terlipressin was 24.2 ± 1.9 min (standard error (SE)). Nilsson 199020 showed a t1/2α of 8-9 min and a t1/2β of 51-66 min. The PK modelling in healthy subjects gave a t1/2α of 7 min and a t1/2β of 42min. PharmacodynamicsVasopressin is a potent vasoconstrictor. Pressor responses occur only with vasopressin concentrations significantly higher than those required for maximal antidiuresis; the vasopressin response reduces blood flow to nonessential organs, including the splanchnic bed, and increasing systemic blood flow with an increase in mean arterial pressure. In HRS patients and healthy volunteers receiving terlipressin the plasma level of lysine-vasopressin attained corresponds to the higher levels of vasopressin (>50 pg/mL) that activate V1 receptors compared to the antidiuretic effect via V2 receptors, which reach their maximum effect at lower concentrations (4-20 pg/mL). Additionally, a weaker agonist but in much higher concentrations, terlipressin has a vasopressin V1 to V2 receptor selectivity ratio of 2.2 compared to 1.0 for vasopressin. The proposed PI contains under Mechanism of Action the statement that: In HRS patients with hyperdynamic circulation, the V1 receptor-mediated vasoconstrictor activity of terlipressin, particularly in the splanchnic area, results in an increase in effective arterial volume. The associated references21, 22, 23 do not contain statements that terlipressin resulted in an increase in effective arterial volume. The literature supports that terlipressin produces in HRS an increase in mean arterial pressure (MAP), while studies TAHRS & 0401 (p = 0.333) showed no effect and Study 0401 showed significant (p = 0.017) increase compared to placebo but this was minimal (2.36mmHg), most of the difference being due to a fall in the placebo group. The literature showed a non significant decrease in heart rate (HR) with terlipressin, as did Studies 040124 and TAHRS.25 While the literature showed that terlipressin produces in HRS normalisation of endogenous vasoconstrictor systems (renin-angiotensin-aldosterone and sympathetic nervous system), the Studies TAHRS and 0401 showed no significant change. The literature supports that terlipressin increases renal blood flow in cirrhotic patients with refractory ascites. The literature shows that in cirrhotic patients terlipressin increases systemic vascular resistance and decreases cardiac output. The report gives graphical evidence of the average difference in pre and post dose MAP, but these are not given in numerical form. The range of differences reported for the systolic and diastolic pressures is much greater than suggested in the proposed PI for MAP.
EfficacyEvaluator’s conclusions on clinical efficacy for the treatment of HRS Type 1The introduction to Study report OT-0401 gives a median survival time in HRS Type 1 of 2-4 weeks. Also, patients with HRS who receive transplants have more complications and higher in-hospital mortality than those without HRS26, 27, 28). In addition HRS Type 1 patients may not survive long enough to receive a liver transplant. Bataller quotes Rimola as a reference and makes the following comments: Immediately after transplantation a further impairment in renal function may be observed and more than one third of patients require haemodialysis (35% of patients with HRS as compared with 5% of cirrhotic patients without HRS). Patients transplanted with HRS have more complications, spend more days in the ICU and in the hospital, and have a higher in-hospital mortality rate than patients transplanted without HRS. Despite this increased morbidity, long-term survival of patients transplanted with HRS is excellent, the probability of survival 3 years after transplantation being of 60%. This survival is only slightly reduced compared with that of patients transplanted without HRS (which ranges between 70% and 80%). Thus, based on this the maximum improvement possible in 3 year survival in patients with HRS would be 30%. Against this being possible Rimola found that there were 2 other independent variables apart from preoperative renal dysfunction that affected survival, and Bataller proposes a continuum of renal dysfunction in these patients. “suggests that in cirrhotic patients with ascites there is a continuum of changes in renal perfusion and HRS is the end of this spectrum.” While it is assumed that HRS reversal improves outcome, Bataller makes no such claim: In this regard (poor prognosis), the use of therapeutic methods (TIPS, vasoconstrictor agents, dialysis) to improve renal function temporally and act as a "bridge" to liver transplantation may be of most benefit. Nevertheless, the efficacy of these methods should be evaluated in controlled investigations. The Study OT-0401 showed significant differences in HRS reversal and change in SCr with minimal overlap of CIs. The interpretation of the abandoned study TAHRS and the submitted literature do not refute these results but the numbers are small. Does this translate to a difference in outcome of HRS? This was the answer sought29 by the TAHRS study which was terminated after 4 years (enrolled 46 patients) where the estimated sample size required to demonstrate a significant treatment difference was 431 patients/group. Neither study could show a significant difference in survival, though the Cochrane review (criticised above) did. Study 0401 also failed to show a difference in transplant free survival. Overall in Study 0401, terlipressin-treated patients received their transplants later (31 days) compared with the placebo-treated patients (21 days), however this depends more on the availability of transplant. The mean SCr concentration in responders was 3.2 mg/dL in the terlipressin group and 3.0 mg/dL in the placebo group. The highest SCr of a responder patient was 5.6 mg/dL for terlipressin and 4.7mg/dL for placebo. Excluding patients with baseline SCr ≥ 5.0 mg/dL, the incidence in the MTIT at Day 14 population of reversal of HRS in the terlipressin group was 17/33 (51.5%) while Treatment Success (sustained reversal HRS) was 13/33(39%) versus 7/34 (21%) in the placebo group for both parameters. Among those ten in the placebo group with SCr ≥ 5.0 mg/dL, none had treatment success or HRS reversal and there was 1/9 in the terlipressin group. There was no difference in Dialysis rates in Study OT-0401 between the treatment groups and ICU/hospital stay was not reported, while in TAHRS there was no significant difference in hospital stay and dialysis rates were not reported. A comparison of the terlipressin group responders versus non responders showed a significant difference between in survival in Study OT-0401. However, the baseline SCr affected HRS reversal (and survival), so was survival an effect arising from HRS reversal or was HRS reversal another screening test for likely survival? For the Terlipressin group the survival and transplant free survival was statistically greater to Day 90 in the Treatment Success and HRS reversal patients compared to the other terlipressin patients without these; but there were no differences in survival for HRS reversal or Treatment Success in the placebo group. How did the placebo success or responders compare in survival with the terlipressin? The numbers were small but some similarity is seen in Overall Survival out to Day 30 and 90 for Treatment Success and for HRS reversal; while this holds true for Transplant Free Survival for Treatment Success patients, terlipressin HRS reversal patients were transplanted earlier (not statistically tested and only sourced for ITT). Table 3. Survival of Treatment Success patients Study OT-0401 ITT Population
Table 4. Survival of HRS reversal patients Study OT-0401 ITT Population
Table 5. Summary of Overall Survival up to Days 14, 30, 90 and 180 (Observed Cases ITT population) 
a From a two-sample log-rank test stratified by baseline strata (alcoholic hepatitis present or not). Includes data up to and including the time point. b Includes patients without a known death on or before the specified time point. cCalculated using product limit estimates. Cross Reference: Data Listings 10.1, 19, 24 and 25 Table 6. Status of HRS Responders During Follow-up (ITT) 
Number of patients with transplants is cumulative. Figure 2. Summary of Terlipressin Population Overall Survival for HRS Reversal versus No HRS Reversal (ITT)
Note: From a two-sample log-rank test stratified by strata (alcoholic hepatitis present or not). Includes data up to and including the time point. Figure 3. Summary of Terlipressin Population Transplant-Free Survival for Treatment Success versus Not Treatment Success (ITT)
Note: From a two-sample log-rank test stratified by strata (alcoholic hepatitis present or not). Includes data up to and including the time point. Figure 4. Summary of Terlipressin Population Transplant-Free Survival for HRS Reversal versus No HRS Reversal (ITT)
Note: From a two-sample loge rank test stratified by strata (alcoholic hepatitis present or not). Includes data up to and including the time point. Figure 5. Summary of placebo Population Overall Survival for HRS Reversal versus No HRS Reversal (ITT)
Note: From a two-sample log-rank test stratified by strata (alcoholic hepatitis present or not). Includes data up to and including the time point. Figure 6. Summary of Placebo Population Transplant-Free Survival for Treatment Success versus Not Treatment Success (ITT)
Note: From a two-sample log-rank test stratified by strata (alcoholic hepatitis present or not). Includes data up to and including the time point. Figure 7. Summary of placebo Population Transplant-Free Survival for HRS Reversal versus No HRS Reversal (ITT)
Note: From a two-sample log-rank test stratified by strata (alcoholic hepatitis present or not). Includes data up to and including the time point. SafetySafety data from the OT-0401 and TAHRS studies were not pooled because OT-0401 had a double-blind design and TAHRS was an open-label study. In addition, there were some differences in dosing schedules (regimen and maximum allowable dose; Pharmacokinetics above) and patients in TAHRS who were randomised to the albumin arm were allowed to receive rescue (crossover) treatment with terlipressin. The sponsor also made comparisons of safety results between the two despite the small numbers involved. Evaluator’s overall conclusions on clinical safetyThe patient numbers in the pivotal study for safety evaluation were small (56) these were subjected to intense review and comparison with those from TAHRS (23). Most of these patients had terlipressin for < 6 days. The adverse event (AE) spectra across the databases, literature and trials are consistent and relate to the PDs of the drug: Gastrointestinal disorders; in particular abdominal pain/cramps Cardiovascular disorders; relating to vasoconstriction and including angina/infarction and skin ischaemia/necrosis Bronchospasm was a cause of death in the literature. QT30 prolongation was reported in the literature and who database. In the Study OT-0401 2/56 patients developed a QTcF interval > 500 ms. The number of patients assessed for frequency of treatment–related AEs was 56 (Study OT-0401) where there was an incidence of 32% (18) that was compared to 23 patients (Study TAHRS) with an incidence of 78% (18). The sponsor offered possibilities, but was unable to explain the difference.
List of questionsThe evaluator made recommendations to the Delegate regarding the PI but these are beyond the scope of this AusPAR. Clinical summary and conclusionsFirst round benefit-risk assessmentBenefitsThere are two propositions supporting the benefit of HRS reversal:
Study 0401 failed to show a difference in transplant free survival. While for the Terlipressin group, transplant free survival was statistically greater to Day 180 in patients who had Treatment Success and HRS reversal compared to the other patients given terlipressin. For patients given placebo who had treatment success and reversal of HRS, differences in survival at Day 180 compared to other patients given placebo were also observed. Seven terlipressin-treated and 5 placebo-treated patients who had not received liver transplants were alive at Day 180. Thus the major clinical benefit of terlipressin would be from extending the duration of survival prior to transplant. Demonstrating a survival benefit from treating the HRS-1 component amidst other concomitant life-threatening pathologies presents a challenging task. This was only partially met in the data submitted. It seems likely that for approximately 20% of patients terlipressin results in a few additional days to weeks of survival without a liver transplant. The clinical benefit of such a small increase in survival time depends on whether this additional time is likely to result in a clinically significant increase in the availability of a liver for transplant. Therefore the clinical benefit of terlipressin will vary with the availability of livers for transplant and it is thus not possible to estimate how many patients will receive transplants (and have increased probability of longer term survival) because of the use of terlipressin. Where few livers are available the benefit would be negligible.
Neither study could show a significant difference in survival, although the Cochrane review did (unfortunately it included Yang 200131 who did not specify the HRS type of the patients and Pomier 200332 which related to the use of octreotide.) Again in Study OT-0401for the terlipressin group the survival was statistically greater to Day 90 in the Treatment Success and HRS reversal patients compared to the other terlipressin patients without these; but there were no differences in survival for HRS reversal or Treatment Success in the placebo group. There was no difference in Dialysis rates in Study OT-0401 between the treatment groups and ICU/hospital stay was not reported. In TAHRS, there was no significant difference in hospital stay while dialysis rates and ICU stay were not reported. The Study OT-0401 showed significant differences in HRS reversal and change in SCr with minimal overlap of CIs. The interpretation of the abandoned Study TAHRS and the submitted literature do not refute these results but the numbers are small. RisksThe survival of patients who were on terlipressin and did not have HRS reversal was comparable to patients on placebo who did not achieve HRS reversal. Overall there was no difference in survival between the terlipressin and placebo groups but those on terlipressin who achieved HRS reversal had better survival than those on terlipressin who did not. The studies submitted had relatively small numbers exposed to terlipressin but showed considerable treatment related AEs; in Study OT-0401 where there was an incidence of 32% (18) that was compared to study TAHRS with an incidence of 78% (18). More concerning was the incidence of treatment related deaths reported in the literature 7 among 1433 patients (0.5%) where the incidence of AEs was given. Of particular concern was the incidence of cardiac and respiratory treatment related AEs in patients already with liver and renal dysfunction and the occurrence of skin and intestinal events (for example, necrosis) the increased the possibility of infection – given that infection affects survival in liver transplantation.33 Benefit-risk balanceThe benefit-risk balance of terlipressin given the proposed usage was considered unfavourable. Recommendation regarding authorisationIt was not recommended that terlipressin be registered for the Indication proposed. Yüklə 238,6 Kb. Dostları ilə paylaş:
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