Wednesday, July 26, 2017

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 Ambition Study - Combination versus Monotherapy.

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AMBITION study of ambrisentan/tadalafil combination therapy versus monotherapy achieves primary endpoint of time to first clinical failure event


Comments from the President of the PHSANZ Prof. Trevor Williams.

The first cut results of the AMBITION study were recently presented at the European Respiratory Society ASM in Munich. This much-awaited study was the first to investigate systematically the effect of up front combination therapy.
The study design was a double blind event driven RCT with the plan to stop the study once 105 events of disease progression had occurred. The study was in newly diagnosed, treatment naïve incident patients. The primary endpoint was (to date) a unique Time to Clinical Failure (TtCF). This was defined as Death, Hospitalization due to worsening PAH (adjudicated), worsening (15 % fall in 6MWD and patient in NYHA/WHO FC III or IV) or unsatisfactory clinical response at 24 weeks (adjudicated). Secondary end-points were also assessed at 24 weeks.
The interventions were ambrisentan 10mg plus Tildalafil 40 mg or ambrisentan 10mg alone or Tildalafil 40 mg alone in a 2:1:1 randomisation in 610 patients. The dose of ambrisentan started at 5mg and was uptitrated to 10mg at 8 weeks. The dose of tildalafil was commenced at 20 mg and uptitrated to 40mg after 4 weeks. The uptitration occurred in both the mono and dual therapy arms primarily to reduce side effects. Almost all patients were successfully uptitrated.
The study met its primary endpoint with a 50% reduction in the number of clinical failure events in the up front combination patients compared to the monotherapy patients. The contribution of deaths was small and not different between the groups. The result was mostly driven by a marked difference in hospitalisations  (4% for combination and 12% for monotherapy) for worsening of PAH. TtCF was not different in the ambrisentan or Tildalafil arms.
A hierarchical approach was taken to analyzing the secondary end-points. The combined therapy had a greater reduction in NT pro BNP, higher rate of satisfactory clinical response and +20-25m treatment effect on 6MWD all at 6 months. Treatment effects seemed to be greater in younger WHO FC II patients.
A haemodynamics substudy showed significantly better improvements in cardiac output (+53% vs +23%) and PVR (-61% vs -40%) in the dual initial therapy group. In this group 6MWD improve 25% in the dual therapy group and 10% in the monotherapy group.
In terms of side effects these were not different in the dual vs monotherapy groups.
Comment: This study does support the notion that upfront combination with ambrisentan and tildalafil gives improved efficacy with no increased side effects compared to monotherapy. It did not however test this hypothesisrelative to early add on therapy for inadequate response. Of course how this rolls out in the Australian and New Zealand regulatory environment is another matter entirely. I was very struck however by the magnitude of the effect on the TtCF.

Click here to download a copy of the AMBITION Study press release from GSK.

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