Prucalopride, tablets (film-coated), 1 mg and 2 mg (as succinate), Resotrans® - November 2011
Page last updated: 16 March 2012
Public Summary Document
Product: Prucalopride, tablets (film-coated), 1 mg
and 2 mg (as succinate), Resotrans®
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
The submission requested a Restricted Benefit listing for the
treatment of moderate to severe chronic constipation in adults who
are intolerant to or are not adequately controlled with both bulk
forming agents and osmotic laxatives.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Prucalopride tablets were registered by the TGA on 18 November 2011
for:
Treatment of chronic functional constipation in adults in whom
laxatives fail to provide adequate relief.
- Before prucalopride is considered patients must have tried at least two different types of laxatives from different classes (at the highest tolerated recommended doses) for at least 6 months, but have not had adequate relief from constipation.
- If treatment with prucalopride is not effective within 4 weeks, the benefit of continuing treatment should be reconsidered.
4. Listing Requested and PBAC’s View
Restricted Benefit
For the treatment of moderate to severe chronic constipation in
adults who are intolerant to or are not adequately controlled with
both:
- bulk forming agents, and
- osmotic laxatives
Note:
If the intake of 2 mg RESOTRANS once daily is not effective after 4
weeks of treatment, the patient should be re-examined and the
benefit of continuing treatment with prucalopride
reconsidered.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Chronic constipation is a common condition in the Australian
population. The prevalence of chronic constipation is higher in
women, the elderly and in individuals of lower socioeconomic class.
Complications of chronic constipation are infrequent, but if poorly
managed, constipation can lead to serious and severe complications
such as faecal impaction, bowel perforation and ulceration,
intestinal obstruction and bleeding.
Chronic constipation is largely self managed by most patients using
over the counter laxatives and herbal remedies.
The submission proposed that the place in therapy of prucalopride
is third line therapy after bulk forming agents and osmotic
laxatives in patients who are not adequately controlled by or are
unable to tolerate bulk forming agents and osmotic laxatives.
6. Comparator
The submission nominated best supportive care as the comparator
(BSC). BSC constituted stimulant laxatives and/or enemas as rescue
interventions in those patients who had failed or were intolerant
to bulk forming and osmotic laxatives.
The PBAC did not agree that best supportive care (BSC) was the
appropriate comparator. The PBAC considered that bisacodyl or
possibly docusate sodium would be a more appropriate choice of
comparator, as they are likely to be used after bulk forming agents
and osmotic laxatives have failed.
7. Clinical Trials
The submission presented a meta-analysis of four randomised placebo
controlled trials (over 4 and 12 weeks) comparing prucalopride plus
best supportive care with placebo plus best supportive care
(PRU-INT-6, PRU-USA-11, PRU-USA-13 and PRU-INT-12), two related
extension safety studies (PRU-INT-10 and PRU-USA-22) and four
supportive randomised phase II dosing trials.
The submission also presented a post-hoc pooled subgroup analysis
of female and male patients in the pivotal 12 week trials with
baseline bowel function of at least one complete bowel motion (CBM)
per week. The proportion of male patients enrolled in the four
randomised placebo controlled studies was low (14%).
Details of the studies published at the time of submission are
shown in the table below:
| Trial ID | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Direct randomised trials | ||
| PRU-INT-6 | ||
| Tack et al 2009 | Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. | Gut. 2009, 58(3):357-65. |
| PRU-USA-11 | ||
| Camilleri et al 2008 | A placebo-controlled trial of prucalopride for severe chronic constipation. | N Engl J Med 2008, 358:2344-54. |
| PRU-USA-13 | ||
| Quigley et al 2009 | Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation – a 12-week, randomised, double-blind, placebo-controlled study. | Aliment Pharmacol Ther. 2009, 29;315–328. |
| PRU-INT-12 | ||
| Müller-Lissner et al 2010 | A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation. | Neurogastroenterol Motil. 2010, 22(9):991-8. |
8. Results of Trials
In all four pivotal trials “best supportive care” (i.e.
use of rescue agents bisacodyl and enemas) was allowed in both the
prucalopride and placebo trial arms after patients failed to
experience a bowel motion for three consecutive days. Bowel motions
reported within 24 hours of the use of a rescue agent were not
included in the primary analyses of efficacy.
Efficacy was measured using data derived from patient diaries.
However, there were concerns regarding missing data as the primary
analyses were based on weekly frequencies and scores. Patients with
missing diary entries had their data inputed using the last 7 days
of data recorded after week 1 (at least 14 days of data
required).
The primary efficacy measure was the proportion of patients with
three or more spontaneous complete bowel motions (SCBM) per week
over 1-12 weeks. A bowel movement was defined as spontaneous if no
laxatives were taken in the 24 hours preceding that bowel
movement.
The PBAC noted that the results of the trials for the primary
outcome suggested that the response to prucalopride was modest,
with fewer than 30% of prucalopride treated patients in Trials
PRU-INT-6, PRU-USA-11 and PRU-USA-13 achieving relief of symptoms.
The differences between the prucalopride and placebo arms were
small and statistically significant in all three 12 week trials
(rates 10%-16%) and in the meta-analysis (12%).
In addition the PBAC noted that a statistically significantly
larger proportion of patients treated with prucalopride 1 mg per
day in PRU-INT-12 (elderly subjects) achieved three or more SCBMs
per week in weeks 1-4; however response rates were less than 40% in
prucalopride treated patients. There was no evidence of additional
benefit from a 2 mg/day dose in elderly patients.
The submission also presented results for the less stringent
secondary outcome of proportion of patients with an average
increase of one or more SCBMs per week over 1-12 weeks. The results
showed higher proportions of patients achieving this secondary
outcome, but response rates in prucalopride treated patients were
generally less than 50%.
The PBAC noted that the pivotal trials only included small
proportions of men (8-15%). However, the submission presented a
pooled subgroup analysis of the pivotal trials by gender for the
less stringent secondary outcome of one or more SCBMs per week
(weeks 1-12).
The small number of male patients in the trials showed lower rates
of response to prucalopride at doses up to and including 2 mg per
day for the secondary outcome. A larger proportion of males taking
the higher dose of 4 mg per day achieved one or more SCBMs per
week, however the 4 mg dose was not included in the requested
listing. The PBAC noted that the requested PBS listing was
for both males and females and that the European Medicines Agency
approved use of prucalopride is for women only.
A post-hoc subgroup analysis of male and female patients reporting
greater than nil complete bowel motions (CBMs) per week at baseline
and achieving the outcome at least one or more SCBMs per week in
the pivotal trials suggested that response rates were higher in
males than females for both placebo and the two dose regimens of
prucalopride. However the clinical relevance of this analysis was
unclear as patients with CBM greater than nil at baseline will be
patients with the least severe symptoms and may not reflect the
population for whom PBS listing is requested.
The four studies included in the meta-analysis assessed two quality
of life measures: PAC-QOL, a disease based measure, and SF-36.
PAC-QOL scores were averaged to a score between 0 and 4, where a
change of 1 point represented the MCID (minimum clinically
important difference, Dubois et al., 2010). Over weeks 1-12, around
40% of prucalopride-treated patients and 20% of placebo-treated
patients reported clinically relevant improvements in PAC-QOL
scores. The one statistically significant change in SF-36 scores
associated with prucalopride therapy was in the summary score for
the physical health component at week 4 in study PRU-INT-6. There
were no statistically significant differences between treatments at
week 12.
The submission also presented the results of a post hoc analysis of
individual patient assessment of constipation severity, with
response defined as an improvement in constipation severity. The
submission claimed that improvement in a patient’s global
assessment of constipation severity was likely to be indicative of
their willingness to continue therapy. The results of the post-hoc
analysis of responders (improved severity of constipation)
suggested more positive outcomes with prucalopride treatment than
implied in the PAC-QOL and SF-36 results.
For PBAC’s view of these results, see Recommendation and
Reasons.
The results for the meta-analysis of adverse events in the
randomised controlled trials showed statistically significantly
larger proportions of patients treated with prucalopride reported
events compared to patients taking placebo, but noted that these
events were generally transient and occurred mainly on the first
day of dosing. Also, a larger proportion of patients treated with
prucalopride reported severe adverse events compared to patients
taking placebo.
The adverse events most frequently reported by patients treated
with prucalopride were headache, nausea, diarrhoea, flatulence,
dizziness and upper respiratory tract infections.
The Post Marketing Safety Update (14 October 2010), reporting on
the post-marketing exposure of prucalopride in the European Union
identified no change in the character or frequency of reported
adverse events.
There are limited long-term safety data for prucalopride. The
submission suggested that the selectivity of prucalopride
differentiated it from the older systemically acting
5-HT4 inhibitors cisapride and tegaserod. Supportive
pharmacokinetic studies (PRU-GBR-9, PRU-GBR-10 and M0001-C102)
which found no evidence of clinically relevant QT interval
prolongation in healthy individuals taking prucalopride at doses up
to 10 times those included in the requested listing.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The submission described prucalopride plus best supportive care as
superior in terms of comparative effectiveness and inferior in
terms of comparative safety over placebo plus best supportive
care.
The PBAC considered that the submission’s claim of
superiority of prucalopride plus BSC in terms of comparative
effectiveness over placebo plus BSC was probably reasonable based
on the clinical trials, but the Committee considered that the
population included in the pivotal trials was not sufficiently
representative of the population in the requested PBS listing. The
PBAC accepted that prucalopride plus BSC was inferior in terms of
comparative safety over placebo plus BSC.
10. Economic Analysis
The submission presented a stepped modelled evaluation based on the
proportion of responders to prucalopride at 4 and 12 weeks,
extrapolated to 52 weeks. The only cost included in the model was
the cost of prucalopride; there were no costs included for adverse
events, complications of chronic constipation or
investigations.
Three algorithms to map the SF-36 individual patient data from the
pivotal trials to the AQoL were investigated. The utilities derived
using the AQoL (Item) model were used in the base case
evaluation.
The incremental cost per quality adjusted life year (QALY) gained
was between $15,000 and $45,000. Sensitivity analyses showed the
ICER to be most sensitive to the utility mapping method used and
moderately sensitive to the prucalopride adherence rate.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost/year to the PBS was estimated by the
submission to be between $10 million and $30 million in Year 5. The
estimate was uncertain.
12. Recommendation and Reasons
The PBAC did not agree that best supportive care (BSC), consisting
of stimulant laxatives and/or enemas as rescue interventions in
patients who have failed or are intolerant to bulk forming and
osmotic laxatives, was the appropriate comparator. The PBAC
considered that bisacodyl or possibly docusate sodium would be a
more appropriate choice of comparator, as they are likely to be
used after bulk forming agents and osmotic laxatives have
failed.
The Committee considered that the patient population included in
the pivotal trials was not representative of the patient population
targeted in the requested listing. Participants in the trials were
primarily female, and included patients with mild constipation as
well as patients who had not attempted treatment with both bulk
forming agents and osmotic laxatives. In addition dose regimens of
the randomised therapies in the pivotal trials are not all within
those recommended in the draft PI for prucalopride. The PBAC also
noted that the Advisory Committee on Prescription Medicines (ACPM)
had recommended approval for prucalopride for treatment of chronic
‘functional’ constipation, consistent with the trial
populations, and considered that the PBS restriction should specify
use in patients with functional constipation.
The submission presented a meta-analysis of four randomised placebo
controlled trials comparing prucalopride plus BSC with placebo plus
BSC. Efficacy outcomes were measured using data derived from
self-reported patient diaries. The PBAC noted that a high rate of
protocol violations were reported and had concerns regarding
missing data.
The primary efficacy measure was the proportion of patients with
three or more spontaneous complete bowel motions (SCBM) per week
over 1-12 weeks. The PBAC noted that the results of the trials for
the primary outcome suggested that the response to prucalopride was
modest, with fewer than 30% of patients achieving the outcome. In
addition, the PBAC noted that a statistically significantly larger
proportion of patients treated with prucalopride 1 mg daily in
study PRU-INT-12 (in elderly patients) achieved the primary
endpoint in weeks 1-4, however response rates were less than 40%.
There was no evidence of additional benefit from a daily dose of 2
mg in elderly patients.
The submission also presented results for the secondary outcome of
proportion of patients with an average increase of one or more
SCBMs per week over 1-12 weeks. The PBAC noted that the results
showed higher proportions of patients achieving this secondary
outcome, but response rates in prucalopride treated patients were
generally less than 50%. The PBAC considered that the clinical
importance of this outcome was uncertain. The small number of male
patients in the trials showed lower rates of response to
prucalopride at doses up to and including 2 mg per day for the
secondary outcome.
In terms of safety, the PBAC noted the overall incidence of
treatment emergent adverse events was statistically significantly
higher in patients taken with prucalopride compared to placebo. The
PBAC was interested in the cardiovascular safety of prucalopride,
noting that no data were provided on cardiovascular outcomes with
longer term exposure to prucalopride. The PBAC recalled other 5HT-4
receptor agonists, cisapride (2004) and tegaserod (2007) were
withdrawn from the market as a result of cardiovascular safety
concerns. The PBAC noted that the routine pharmacovigilance plan
along with proposed studies to investigate relevant cardiovascular
events would provide more substantial evidence relating to the
potential safety issues raised.
The PBAC considered that the submission’s claim of
superiority of prucalopride plus BSC in terms of comparative
effectiveness over placebo plus BSC was probably reasonable based
on the clinical trials, but the Committee considered that the
population included in the pivotal trials was not sufficiently
representative of the population in the requested PBS listing. The
PBAC accepted that prucalopride plus BSC was inferior in terms of
comparative safety over placebo plus BSC.
The submission presented a stepped modelled evaluation based on the
proportion of responders to prucalopride at 4 and 12 weeks,
extrapolated to 52 weeks. The incremental cost per quality adjusted
life year (QALY) gained was between $15,000 and $45,000. The PBAC
noted sensitivity analyses showed the ICER to be most sensitive to
the utility mapping method used (ICER increased to between $45,000
and $75,000 using SF-6D and between $105,000 and $200,000 using
AQol (Rasch method)), and it was moderately sensitive to the
prucalopride adherence rate (ICER increased between $15,000 and
$45,000, 100% adherence rate).
The PBAC noted that three different mapping techniques to derive
utility scores from the SF-36 data were investigated, in addition
to using the SF-6D algorithm. The PBAC noted that the different
mapping techniques gave vastly different results, which impact the
results of the economic evaluation, and demonstrates considerable
uncertainty deriving from the assumed utility values.
The PBAC considered that the submission’s estimates of
patient numbers, number of prescriptions per patient and financial
implications to the PBS were likely significant underestimates. The
PBAC considered there was considerable risk of use outside the
population described in the restriction to those with milder
disease, in place of other therapies (e.g. macrogol) or
administered regularly as a chronic medication (e.g. via dose
administration aids in residential aged care facilities) and use
for different periods of time than proposed in the
submission.
The PBAC therefore rejected the submission on the basis of
uncertain clinical effectiveness in the requested PBS population
and uncertain cost-effectiveness.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor had no further comment.
