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11 October 2011
The REALIZE trial (n = 663) found that the addition of oral telaprevir▼to standard therapy with peginterferon alfa-ribavirin was significantly more effective than standard treatment alone in patients with previously treated genotype 1 hepatitis C infection. Patients were randomised to one of three groups and results were reported separately for different levels of previous response to standard therapy. For example, in patients with a previous relapse, 83% of patients who were given peginterferon alfa-ribavirin plus telaprevir for 12 weeks followed by placebo plus peginterferon alfa-ribavirin for 4 weeks and then peginterferon alfa-ribavirin alone for 32 weeks had a sustained virologic response, compared to 24% of patients on standard therapy for 48 weeks.
Anaemia (defined as a haemoglobin level < 10 g/dl) occurred in 33% of patients who received telaprevir compared to 15% in the standard treatment group and rash in 37% and 19%, respectively.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
Telaprevir (Incivo▼) has recently been marketed and local decision-making bodies may need to consider its managed introduction, bearing in mind that NICE guidance is anticipated in June 2012. The Scottish Medicines Consortium (SMC) telaprevir appraisals are also underway, with advice potentially due mid-December 2011. Factors to take into account are the number of patients who may be eligible for treatment and the incidence of adverse events, such as anaemia.
This study represents the best available evidence relating to this new medicine. These data, together with its limitations, should be taken into account by local decision-makers when managing the entry of this new medicine and planning the commissioning of appropriate services. Local decision-makers may need to consider additional published data about this product as it emerges.
Telaprevir is licensed in combination with peginterferon alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis) who are treatment‑naïve or who have previously been treated with interferon alfa alone or in combination with ribavirin, including prior relapsers, partial responders and null responders.
What is the background to this?
The blood-borne hepatitis C virus (HCV) predominantly infects the cells of the liver. The virus is usually acquired through parenteral exposure to contaminated blood. Infected needles used for injecting drugs are the most common means of transmission. Six major genotypes of HCV are known, with genotype 1 being the most common in England and Wales. Genotype is a key predictor of the effectiveness of anti-viral treatment and people with genotype 1 have HCV that is the most resistant to treatment.
In approximately 80% of people who are infected, the virus is not cleared and they go on to develop chronic hepatitis C. The Health Protection Agency estimates that around 216,000 individuals in the UK are chronically infected with hepatitis C with many currently undiagnosed and therefore untreated. Standard therapy is with peginterferon alfa and ribavirin and information on the appropriate use of these drugs is available from NICE guidance.
Telaprevir is an oral protease inhibitor. It has recently been marketed at a price of £7,466.0 (exclusive of VAT) for a pack of 168 x 375 mg tablets (4 weeks supply). Telaprevir is indicated, in combination with peginterferon alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis):
- who are treatment‑naïve;
- who have previously been treated with interferon alfa (pegylated or non‑pegylated) alone or in combination with ribavirin, including relapsers, partial responders and null responders.
Further information on the management of hepatitis can be found on NHS Evidence.
What does this study claim?
In patients with genotype 1 HCV who did not have a sustained virologic response to previous treatment, the addition of telaprevir to peginterferon alfa-ribavirin was compared to standard treatment alone. The control group (n = 132) received standard treatment for 48 weeks with placebo for the first 16 weeks (PR 48). Two groups received standard treatment plus telaprevir, one with and one without a lead-in period. The group with the lead-in period (n = 264) received placebo plus peginterferon alfa-ribavirin for 4 weeks, followed by telaprevir and peginterferon alfa-ribavirin for 12 weeks and then peginterferon alfa-ribavirin alone for 32 weeks (lead-in T12 PR 48). The group without a lead-in period (n = 266) received telaprevir with peginterferon alfa-ribavirin for 12 weeks, followed by placebo plus standard therapy for 4 weeks and then standard therapy for 32 weeks (T12 PR 48).
The primary end point was sustained virologic response (undetectable plasma HCV RNA 24 weeks after the last planned dose of a study drug) in patients with a previous relapse or lack of a previous response. In patients with previous relapse, the primary end point was seen in 24% of the control group and 88% and 83% of the telaprevir groups with and without lead-in periods, respectively. In patients who had had a previous partial response the results were 15%, 54% and 59%, respectively and for those patients who had not responded previously the figures were 5%, 33% and 29%, respectively (for all groups p < 0.001 versus control).
Anaemia, defined as a haemoglobin level < 10 g/dl, occurred more frequently in the patients receiving telaprevir: 30% in the group without a lead-in period, 36% in those with a lead-in and 15% in the control group. No p-value given. Reductions in the dose of ribavirin could be made to manage the anaemia (as per ribavarin prescribing information), but the trial protocol prohibited the use of erythropoietin-stimulating agents or reductions in the dose of telaprevir. Rash was experienced by 37% of patients in the telaprevir groups compared to 19% in the control group.
How does this relate to other studies?
The use of telaprevir with standard treatment of peginterferon alfa-ribavirin in previously untreated patients was compared to standard treatment alone in the ADVANCE study and is the subject of a previous rapid review.
Another oral protease inhibitor, boceprevir▼ (Victrelis®), has recently been launched. It is licensed for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa-ribavirin, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy. A NICE appraisal is anticipated in May 2012. Data for patients with previously treated genotype 1 infection come from the HCV RESPOND-2 trial (n = 404) which found that oral boceprevir given three times a day in addition to peginterferon alfa and ribavirin significantly increased rates of sustained virologic response compared to standard therapy. Further details can be found in a previous rapid review.
So what?
As compared with peginterferon alfa-ribavirin therapy alone, the addition of telaprevir significantly increased the rate of sustained virologic response among previously treated adults infected with HCV genotype 1. The significant improvement in sustained viral response was maintained in each of the prior response subgroups: relapsed, partial response and null response. Using a lead-in period and the presence of high baseline viral load did not affect the results. A lead-in period will not be recommended in the final licence due to the findings of this study. Inclusion criteria for the REALIZE trial stated that patients had to have chronic HCV genotype 1 infection, a liver biopsy and specified levels for neutrophil and platelet counts and haemoglobin levels. This may limit generalisation to patients seen in normal clinical practice.
Potential concerns about adding protease inhibitors to standard therapy include the increasing complexity of treatment regimens, the risk of anaemia and the potential need for a reduction in the dose of ribavirin.
The licence allows non-cirrhotic prior treatment relapse patients who achieve an undetectable viral load at weeks 4 and 12 to be eligible for a shortened duration of response guided therapy. Patients eligible for this response guided therapy can stop their ongoing treatment with peginterferon and ribavirin at week 24 instead of week 48.
Results from the ILLUMINATE study, in patients infected with HCV genotype 1 who had not received treatment previously, found that a 24 week treatment regimen of peginterferon alfa-ribavirin with telaprevir, at a dose of 750 mg every 8 hours, added for the first 12 weeks was noninferior to the same regimen for 48 weeks in patients who had undetectable HCV RNA levels at weeks 4 and 12. Of the 540 patients in the study 65% met this definition for extended rapid virologic response (EVR) and were eligible for the abbreviated course of therapy. Among the 322 patients with an EVR who were assigned to a study group, 92% (149/162)who received 24 weeks treatment and 88% (140/160) who received 48 weeks had a sustained virologic response.
The Summary of Product Characteristics provides advice to physicians on the use of the response guided regimen for non-cirrhotic patients who are either treatment-naive or have relapsed on prior treatment. Guidance is available also for the 48 week regimen and this encompasses patients with cirrhosis.
The primary endpoint in this report of the REALIZE study is a disease-oriented outcome, sustained virologic response. However, the trial did include outcomes related to quality of life and fatigue but these outcomes have not been reported yet.
The telaprevir regimens were associated with a higher incidence of skin reactions than standard therapy. The Summary of Product Characteristics notes that serious skin reactions, including Stevens-Johnson syndrome have been reported rarely in trials and provides advice on patient care in such situations.
Design: Phase III, randomised, double-blind, placebo-controlled trial with concealed allocation. Randomisation was stratified according to baseline HCV RNA level (< 800,000 or > 800,000 IU/ml) and previous response to peginterferon plus ribavirin (relapse, partial response or no response). No response was defined as a reduction of less than 2 log10 after 12 weeks of therapy.
Patients: Adults with chronic hepatitis C genotype 1 infection who did not have a sustained virologic response to one previous course of peginterferon plus ribavirin were included. Patients had detectable HCV RNA levels and had undergone a liver biopsy within 18 months before screening. Levels for neutrophil and platelet counts were specified. Haemoglobin levels had to be at least 12 g/dl for women and 13 g/dl for men. Included patients had a mean age of 51 years, 88% had a baseline HCV RNA level of at least 800,000 IU/ml, 53% had previous relapse, 19% a partial response and 28% no response to previous treatment. Exclusion criteria included decompensated liver disease, significant liver disease due to other causes and active cancer.
Intervention and comparison: Peginterferon alfa-2a was given subcutaneously at a dose of 180 microgram per week. Oral ribavirin was taken as 1000mg to 1200mg per day depending upon patient weight. Oral telaprevir was taken as 750mg every 8 hours. Total treatment duration was 48 weeks and patients were followed up until week 72. Patients were randomised to one of three groups as follows:
The PR 48 group (n = 132) who received peginterferon alfa-ribavirin plus placebo for 16 weeks then peginterferon alfa-ribavirin for 32 weeks
The lead-in T12 PR 48 group (n = 264) who received placebo and peginterferon alfa-ribavirin for the first 4 weeks, then telaprevir plus peginterferon alfa-ribavirin for 12 weeks followed by peginterferon alfa-ribavirin for 32 weeks
The T12 PR 48 group (n = 266) who received telaprevir plus peginterferon alfa-ribavirin for 12 weeks, then placebo plus peginterferon alfa-ribavirin for 4 weeks followed by peginterferon alfa-ribavirin for 32 weeks.
Stopping rules ensured that patients did not receive treatment unnecessarily if treatment failed. Anaemia was managed by reduction in the dose of ribavirin. No erythropoietin-stimulating agents were allowed. If reducing the dose or stopping ribavirin did not improve anaemia, telaprevir was stopped.
Outcomes and results: Outcomes were assessed on an intention-to-treat principle for all randomised patients who received at least one dose of study drug (662/663 patients). The primary outcome was the proportion of patients with previous relapse or lack of a previous response that had a sustained virologic response, defined as undetectable plasma HCV RNA levels 24 weeks after the last planned dose of study drug. In patients with previous relapse, 83% of the T12 PR 48 group and 88% of the patients in the lead-in T12 PR 48 group reached the primary outcome compared to 24% of the control group (p < 0.001 for both telaprevir groups versus control). In patients with previous partial response a sustained viral response was achieved by 59%, 54% and 15%, respectively. For patients who had had no response previously the primary endpoint was met in 29%, 33% and 5%, respectively (p < 0.001 for all comparisons).
Overall, the incidence of adverse effects was similar in the three groups. But, telaprevir was associated with a higher risk of fatigue, pruritus, rash, dysgeusia, nausea, influenza-like illness, anaemia and diarrhoea. Pruritus was reported by 51% of patients who took telaprevir compared to 27% of those in the control group. Rash was experienced by 37% of patients in the telaprevir groups compared to 19% in the control group. Grade 3 rash was seen in 3% of patients in the telaprevir groups but none of the placebo group. Anaemia was seen in 33% of patients in the telaprevir groups and 15% of the control group (no p values given).
A total of 13% of patients who received telaprevir and 3% of the control group experienced adverse events which led to discontinuation of treatment. These were mainly due to rash or anaemia.
Sponsorship
This study was sponsored by Tibotec and Vertex Pharmaceuticals.
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