Date: 2011-12-20
Type of information:
phase: 3
Announcement: termination of the study
Company: Novartis (Switzerland)
Product: Rasilez®/Tekturna® (aliskiren)
Action mechanism:
Disease: hypertension in a specific population of patients with type 2 diabetes and renal impairment.
Therapeutic area: Cardiovascular diseases
Country:
Trial
details: ALTITUDE was a multinational study in 8,606 patients from 36 countries evaluating the potential benefits of Rasilez®/Tekturna® to reduce the risk of cardiovascular and renal events in this patient population. ALTITUDE was the first randomized, double-blind, placebo-controlled study to investigate Rasilez/Tekturna for more than one year in a specific population of patients with type 2 diabetes and renal impairment. These patients are known to be at high risk of cardiovascular and renal events. In the study, Rasilez®/Tekturna® was given in addition to optimal cardiovascular treatment including an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).
Latest
news: Novartis announced that following the seventh interim review of data from the ALTITUDE study with Rasilez®/Tekturna® (aliskiren), a decision to terminate the trial has been taken on the recommendation of the independent Data Monitoring Committee (DMC) overseeing the trial. * On December 22, 2011, European Medicines Agency (EMA) announced it has started review of aliskiren-containing medicines following termination of ALTITUDE study.
The DMC concluded that patients were unlikely to benefit from treatment added on top of standard anti-hypertensives, and identified higher adverse events in patients receiving Rasilez®/Tekturna® in addition to standard of care in the trial. Specifically, in the trial arm in which Rasilez®/Tekturna® was added to the standard of care there was an increased incidence after 18-24 months of non-fatal stroke, renal complications, hyperkalemia and hypotension in this high-risk study population.
The placebo-controlled Phase III ALTITUDE study is the first trial to investigate Rasilez®/Tekturna® for more than one year in a specific population of patients with type 2 diabetes and renal impairment. These patients are known to be at high risk of cardiovascular and renal events. In the study, Rasilez®/Tekturna® was given in addition to optimal cardiovascular treatment including an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).
Novartis is in ongoing discussions with health authorities worldwide about the implications of the findings from ALTITUDE for patients. As a precautionary measure Novartis will cease promotion of Rasilez®/Tekturna®-based products for use in combination with an ACE-inhibitor or ARB. Novartis is recommending that ALTITUDE investigators remove Rasilez®/Tekturna® -based products from their patients\'treatment regimen and review their high blood pressure medication. Novartis is also reviewing the findings with DMCs of other clinical studies involving Rasilez®/Tekturna®-based products and combination therapies.
The agency is assessing the impact of data coming from this study on the balance of benefits and risks of these medicines in their approved indication. (Aliskiren-containing medicines are approved for the treatment of essential hypertension). The Committee for Medicinal Products for Human Use (CHMP) started the review after it was informed on 19 December 2011 by the marketing authorisation holder of the decision to terminate the ALTITUDE study early. Termination of the placebo-controlled phase III trial was recommended by the independent Data Monitoring Committee overseeing the study, because the results showed that there was no benefit with aliskiren and that there were more cases of stroke, renal complications, hyperkalemia and hypotension in patients who received aliskiren compared with patients who received a placebo.
* On February 17, 2012, the EMA announced that it has finalised a review of aliskiren-containing medicines, recommending that these medicines should be contraindicated in patients with diabetes or moderate to severe renal impairment who take angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). In addition, the Agency recommended the inclusion of a warning that the combination of aliskiren and ACE inhibitor or ARB is not recommended in all other patients because adverse outcomes cannot be excluded.
Aliskiren-containing medicines are approved for the treatment of essential hypertension. ‘Essential’ means that there is no obvious cause for high blood pressure.
The EMA announced that doctors should stop prescribing aliskiren-containing medicines to patients with diabetes (type 1 or type 2) or with moderate to severe kidney impairment who are also taking an ACE inhibitor or ARB, and should consider alternative antihypertensive treatment as necessary. For all other patients receiving aliskiren-containing medicines in combination with an ACE inhibitor or an ARB, the balance of benefits and risks of continuing treatment should be considered carefully. Patients should discuss their treatment with their doctor at their next scheduled (non-urgent) appointment. They should not stop any of their treatment before speaking to their doctor, because stopping anti-hypertensive medication without medical supervision can put them at risk. Patients in clinical trials with aliskiren should contact their study site for guidance on their medication.
* On April 19, 2012, Novartis announced that the Tekturna® labels have been updated in the US, following the FDA review of the preliminary findings from the ALTITUDE study.
The label change includes a contraindication against combined use of aliskiren-based products with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with diabetes. The FDA has also requested the inclusion of a warning against the use of aliskiren-based products in patients with moderate renal (kidney) impairment (eGFR < 60 ml/min) who are also taking an ACE inhibitor or an ARB. Aliskiren-based products will continue to be available in the US for the treatment of high blood pressure in appropriate patients.
Furthermore, and in consultation with the FDA, Novartis has decided to voluntarily cease marketing in the US of Valturna® (aliskiren and valsartan, USP), a single pill combination of aliskiren and the ARB valsartan. Valturna sales in the US represented less than 10% of Aliskiren sales in 2011. Novartis advises US patients to seek guidance from their prescribing healthcare provider at their next (non-urgent) visit to determine appropriate alternate therapy. Novartis has also decided to voluntarily withdraw marketing authorization of the same combination pill in Switzerland, Rasival® (aliskiren and valsartan), which received marketing approval for export but was not launched.
The US Prescribing Information has been updated for Tekturna®, Tekturna HCT® (aliskiren and hydrochlorothiazide), Tekamlo® (aliskiren and amlodipine) and Amturnide® (aliskiren, amlodipine and hydrochlorothiazide). In view of the importance of controlling high blood pressure and to enable physicians to transition patients to alternate therapies, Novartis will make Valturna® available in the US until July 20, 2012. Novartis advises patients in the US to seek guidance from their prescribing healthcare provider at their next (non-urgent) visit, prior to July 20, 2012, to determine appropriate alternate therapy. Novartis will communicate to US physicians informing them of the above actions.
