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GSK announces interim US Serevent study results

Company reinforces asthma guidelines

Philadelphia, PA, January 23, 2003 - GlaxoSmithKline [NYSE: GSK] is announcing the results from an interim analysis of data from a US safety study of Serevent® (salmeterol xinafoate), a long-acting ß2-agonist used in the treatment of asthma, and as a follow-up to these data, reinforcing advice to physicians on appropriate prescribing of Serevent.

"We are recommending to US doctors that asthma patients taking Serevent should also be prescribed asthma controllers, preferably inhaled corticosteroids," said Dr. Kathy Rickard, VP Respiratory, Clinical Development and Medical Affairs, North America. "This is consistent with both national guidelines for optimal asthma treatment, and with the trends we've seen in our interim analysis of the study data."

National Asthma Education and Prevention Program (NAEPP) guidelines recommend that patients requiring more than "as-needed" short-acting ß2-agonists should be prescribed regular and adequate doses of an inhaled anti-inflammatory asthma medication, such as inhaled corticosteroids, for optimal asthma management.1

SMART (Serevent Multi-center Asthma Research Trial) was designed to compare Serevent to placebo, in addition to regular asthma therapy, in terms of respiratory-related deaths or life-threatening experiences such as intubations and mechanical ventilation (the primary endpoint) or asthma-related deaths (a secondary endpoint). SMART was started in 1996 to further study the safety of Serevent.

Because of the small number of events, no conclusions can be drawn from the interim analysis of the data. While this analysis showed no significant difference for the primary endpoint, a higher though not statistically significant number of asthma related life-threatening experiences, including asthma-related deaths, occurred in the Serevent-treated patients.

While there were no significant differences between the Serevent and placebo treatment groups among Caucasian patients (71% of the study population), African American patients (17% of the study population) on Serevent experienced a statistically significant greater number of respiratory and asthma-related events, including deaths, than those on placebo. It is important to note that less than 1% of all African American patients enrolled in the study experienced such events in the 28-week trial. Again, no conclusions can be drawn from the data.

Differences between the African American and Caucasian patients recruited into the study may have contributed to a higher rate of asthma-related events among African Americans. African American patients had more severe asthma at study entry than Caucasian patients, as measured by frequency of symptoms, peak expiratory flow at study entry, and history of prior intubations, emergency-room visits, and hospitalizations.

The interim analysis also suggested that the use of inhaled corticosteroids may have impacted on the outcome for patients taking Serevent. In the interim analysis, patients on Serevent who did not receive inhaled corticosteroids as part of their usual therapy at the start of the study experienced a statistically significant greater number of asthma-related deaths compared to those taking placebo. There were no significant differences between the Serevent and placebo treatment groups among patients who were receiving inhaled corticosteroids at the start of the study.

Whether or not a patient used inhaled corticosteroids as part of their asthma treatment was determined by their physician, not by the SMART design. At the start of the study, only 47% of the overall study population used inhaled corticosteroids. Only 50% of Caucasian patients and 38% of African American patients were receiving treatment with inhaled corticosteroids. As with the other analyses, no conclusions can be based on these data, however.

For the above reasons, and since the SMART study was not designed to obtain robust results within or between sub-populations, continuing the study would be unlikely to answer questions raised by the interim analysis. GSK has therefore decided to discontinue the study. The company is discussing the design of other investigations with the FDA to provide meaningful conclusions about the appropriate use of Serevent in patients with asthma, particularly African Americans.

In light of the SMART study data, GSK and the FDA agree on the need to reinforce advice for the management of patients, including African Americans, as established in the Serevent prescribing information and national asthma management guidelines.

Additionally, GSK and the FDA agree that:

  • Patients who are currently taking Serevent should not discontinue their treatment without first consulting a physician. Abruptly stopping medications may result in acutely deteriorating asthma control, which may be life threatening.
  • Serevent is not a replacement for inhaled corticosteroids, which should be continued at the same dose, and not stopped or reduced, when treatment with Serevent is initiated.
  • Serevent should not be initiated in patients with significantly worsening or acutely deteriorating asthma, which may be life-threatening.
  • Serevent should not be used to treat acute symptoms.
  • Patients on Serevent must also have a short-acting bronchodilator (e.g., albuterol) for use as needed for acute symptoms.
  • The increased need for using the short-acting bronchodilator is a sign of deteriorating asthma.
  • Patients should be educated to recognize the signs of deteriorating asthma control and the need to seek medical attention promptly in such circumstances.

Given the similar basic mechanisms of action of all ß2-agonists, it is possible that the findings seen in the SMART study may be relevant to the use of other medicines in the same class.

Serevent® (salmeterol xinafoate) Inhalation Aerosol is indicated for long-term, twice-daily (morning and evening) administration in the maintenance treatment of asthma and prevention of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who require regular treatment with inhaled, short-acting ß2-agonists. It should not be used in patients whose asthma can be managed by occasional use of inhaled, short-acting ß2-agonists.

Additional important information about Serevent No effect on the cardiovascular system is usually seen after treatment with Serevent Inhalation Aerosol at recommended doses. However, some patients may experience increased blood pressure, heart rate or changes in heart rhythm. Patients should tell their doctor if they have a heart condition or high blood pressure or take MAOIs or tricyclic antidepressants.

Enquiries
UK Media Martin Sutton
Siobhán Lavelle		 020 8047 5502
020 8047 5502
US Media Lisa Behrens
Nancy Pekarek 		(919) 483 2839
(215) 751 7709
European Analyst/Investor Duncan Learmouth
Philip Thomson
Anita Kidgell		 020 8047 5540
020 8047 5543
020 8047 5542
US Analyst/Investor Frank Murdolo
Tom Curry		 (215) 751 7002
(215) 751 5419

Editor's Note:

In July 1996, GSK initiated the Serevent Multi-center Asthma Research Trial (SMART), a 28-week safety study comparing Serevent and placebo in the treatment of asthma. The SMART study was designed to assess the safety of regular use of b2-agonists in the management of asthma.

The primary endpoint of the SMART study was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences, (intubations and mechanical ventilation). Other endpoints included asthma-related events including deaths, and asthma-related deaths. In addition to their usual asthma therapy, patients in one arm of the study received 42 mcg of Serevent twice a day through a metered dose inhaler (MDI), and patients in the other arm received placebo. All patients were treated according to the approved Serevent labelling. The study protocol included a planned interim analysis once half of the patients were recruited.

Well-controlled studies confirm the contribution of salmeterol when used in conjunction with inhaled corticosteroids in improving overall asthma control in patients with asthma.2-19 A meta-analysis of 9 randomized controlled trials in 3,685 patients not controlled on inhaled corticosteroids alone showed that the addition of salmeterol significantly reduced exacerbations compared with double the dose of inhaled corticosteroids.20

Serevent was introduced in the US in 1994. Worldwide, the experience with Serevent, from 1990 to 31st October 2002, is estimated to be 26 million patient years.

Please see Prescribing Information for Serevent Inhalation Aerosol for additional information.

References

  1. National Heart, Lung, and Blood Institute, National Institutes of Health. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. April 1997. (NIH Publication No. 97 4051).
  2. Greening AP, Ind PW, Northfield N, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344:219-224.
  3. Woolcock A, Lundback B, Ringdal N, et al. Comparison of addition of salmeterol to inhaled steroids with doubling ot the dose of inhaled steroids. Am J Respir Crit Care Med 1996;153:1481-1488.
  4. Weinstein SF, Murray JJ, Kerwin E, et al. A comparison of adding Serevent to Beclovent versus doubling the dose of Beclovent on pulmonary function in symptomatic asthmatic patients > 18 years of age. Am J Respir Crit Care Med 1997;155(4):A347. Abstract.
  5. Stricker W, Weinstein S, Chervinsky P, et al. Additive benefits of concurrent salmeterol and fluticasone propionate therapy in asthma. J Allergy Clin Immunol 1997;99(1):S319. Abstract.
  6. Van Noord JA, Schreurs AJM, Mulder PGH, et al. Comparison of the efficacy of doubling the dose of fluticasone propionate (FP) and adding salmeterol (SLM) in patients with mild-to-moderate asthma. Am J Respir Crit Care Med 1997;155(4):A347. Abstract.
  7. Ind PW, Dal Negro R, Colman N, et al. Inhaled fluticasone propionate and salmeterol in moderate adult asthma I: Lung funtion and symptoms. Am J Respir Crit Care Med 1998;157(3):A414.
  8. Ind PW, Dal Negro R, Colman N, et al. Inhaled fluticasone propionate and salmeterol in moderate adult asthmaII: exacerbations. Am J Respir Crit Care Med 1998;157(3):A415.
  9. Matz J, Emmett A, Rickard K et al. The addition of salmeterol to low-dose fluticasone versus higher-dose fluticasone: an analysis of asthma exacerbations. J Allergy Clin Immunol 2001; 107: 783-789.
  10. Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann Allergy Asthma Immunol 1999; 82:383-389.
  11. Cook D, Srebro SH, Rogenes PR, et al. A comparison of the safety and efficacy of fluticasone, triamcinolone, and fluticasone plus salmeterol in patients with mild to moderate asthma. Am J Respir Crit Care Med 1998;157(3):A416.
  12. Johnson MC, Srebro SH, Rogenes PR, et al. A comparison of physician-rated and patient-rated outcomes in a study with fluticasone, triamcinolone, and fluticasone plus salmeterol. Am J Respir Crit Care Med 1998;157(3):A414.
  13. Creticos PS, Freidhoff LR, Bernstein DI, et al. Comparison of an inhaled corticosteroid (triamcinolone acetonide) to a long-acting bronchodilator (salmeterol), the combination, and placebo in mild-moderate adult asthmatic patients. Int Arch Allergy Immunol 1999;118:345-346.
  14. van Noord JA, Schreurs AJM, Mol FJM, et al. Addition of salmeterol versus doubling the dose of fluticasone in patients with mild to moderate asthma. Thorax 1999;54:207-212.
  15. Vermetten FAAM, Boermans AJM, Luiten WDVF, et al. Comparison of salmeterol with beclomethasone in adult patients with mild persistent asthma who are already on low-dose inhaled steroids. J Asthma 1999;36:97-106.
  16. Boskovska M, Gjorcev A, Gerovski B, et al. Combination of long-acting beta2 adrenergic agonist with a low or high doses of glucocorticoids reduce the rate of severe asthma exacerbations. Presented at the European Academy of Allergology and Clinical Immunology Meeting; Brussels, Belgium; July 3-7, 1999.
  17. Baraniuk J, Murray JJ, Nathan RA, et al. Fluticasone alone or in combination with salmeterol vs triamcinolone in asthma. Chest 1999;116:625-632.
  18. Murray JJ; Church NL; Anderson WH; Bernstein DI; Wenzel SE; Emmett A; Rickard KA. Concurrent use of salmeterol with inhaled corticosteroids is more effective than inhaled corticosteroid dose increases. ALLERGY ASTHMA PROC. 1999;20(3):173-180.
  19. Kelsen SG, Church NL, Gillman SA, Lanier BQ, Emmett AH, Rickard KA, et al. Salmeterol added to inhaled corticosteroid therapy is superior to doubling the dose of inhaled corticosteroids: A randomized clinical trial. J. ASTHMA 1999;36(8):703-715.
  20. Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). Br Med J 2000;320:1368-1373.

Updated January 23, 2003 - © 2001-2005 GlaxoSmithKline - All Rights Reserved
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