Salmeterol and Fluticasone Salmeterol and Fluticasone Propionate and Survival in COPD: Propionate and Survival in COPD:

a TORCH triala TORCH trialNEJM, Feb 2007NEJM, Feb 2007

Silpa Kilaru, MDSilpa Kilaru, MD

Georgetown University HospitalGeorgetown University Hospital

3/27/20073/27/2007

COPDCOPD

Characterized by components of chronic Characterized by components of chronic bronchitis and emphysemabronchitis and emphysema

http://www.healthline.com/adamimage?contentId=1-000091&id=19376&tab=images&series=0&images=7&slide=0

COPDCOPD Causes approximately 2.75 million deaths annuallyCauses approximately 2.75 million deaths annually Chronic bronchitis: “blue bloaters”, absence of dyspnea at rest, Chronic bronchitis: “blue bloaters”, absence of dyspnea at rest,

associated obesity and cyanosis, coarse rhonchiassociated obesity and cyanosis, coarse rhonchi Emphysema: “pink puffers:, dyspnea at rest, prolonged Emphysema: “pink puffers:, dyspnea at rest, prolonged

expiratory phase, decreased breath soundsexpiratory phase, decreased breath sounds FEV1 is a predictor of mortality in patients with COPD: 0.75-FEV1 is a predictor of mortality in patients with COPD: 0.75-

1.25L: 5 year survival 66%, less than 0.75L: 33%1.25L: 5 year survival 66%, less than 0.75L: 33% Thus far, only treatments shown to reduce mortality are home Thus far, only treatments shown to reduce mortality are home

oxygen treatment for hypoxemia, smoking cessation for early oxygen treatment for hypoxemia, smoking cessation for early disease, and lung volume reduction surgery in patients with disease, and lung volume reduction surgery in patients with emphysemaemphysema

Current treatments focus on improving symptoms and Current treatments focus on improving symptoms and preventing exacerbationspreventing exacerbations

Current TreatmentsCurrent Treatments

Include anticholinergics, beta-agonists, Include anticholinergics, beta-agonists, methylxanthinesmethylxanthines

Due to the large amount of pulmonary Due to the large amount of pulmonary inflammation, inhaled steroids are also usedinflammation, inhaled steroids are also used

However, while previous studies (ISOLDE) However, while previous studies (ISOLDE) trial have shown a decrease in frequency of trial have shown a decrease in frequency of exacerbations and improvement in health exacerbations and improvement in health status, they have not been shown to status, they have not been shown to significantly reduce mortality. significantly reduce mortality.

ObjectiveObjective

Would the combination of a long-acting beta Would the combination of a long-acting beta agonist salmeterol and an inhaled agonist salmeterol and an inhaled corticosteroid fluticasone propionate reduce corticosteroid fluticasone propionate reduce mortality among patients with COPD?mortality among patients with COPD?

Study ParticipantsStudy Participants

Ages 40-80, M or FAges 40-80, M or F Baseline FEV1 < 60%Baseline FEV1 < 60% Clinical hx of COPDClinical hx of COPD Current or ex-smokers Current or ex-smokers

(with at least a 10 pack (with at least a 10 pack year history)year history)

Poor reversibility of Poor reversibility of airflow obstructionairflow obstruction

Pre-bronchodilator Pre-bronchodilator FEV1/FVC ratio FEV1/FVC ratio < < 70% 70%

For females: non-child For females: non-child bearing potential, or neg bearing potential, or neg preg. test plus no preg. test plus no possibility of pregnancypossibility of pregnancy

Exclusion criteriaExclusion criteria Diagnosis of asthmaDiagnosis of asthma Other resp. disorders such as Other resp. disorders such as

lung cancer, sarcoidosislung cancer, sarcoidosis Prev. lung volume reduction Prev. lung volume reduction

surgery and/or transplantationsurgery and/or transplantation Long-term oxygen therapy (> Long-term oxygen therapy (>

12h/day)12h/day) Evidence of alcohol, drug, or Evidence of alcohol, drug, or

solvent usesolvent use Serious uncontrolled disease Serious uncontrolled disease

likely to cause death within 3 likely to cause death within 3 yr periodyr period

Known/suspected Known/suspected hypersensitivity to any of hypersensitivity to any of study medicationsstudy medications

Alpha-1 anti-trypsin Alpha-1 anti-trypsin deficiencydeficiency

Use of oral corticosteroid Use of oral corticosteroid therapy ( > 6wks)therapy ( > 6wks)

Received any Received any investigational drugs in investigational drugs in previous 4 weeksprevious 4 weeks

Exacerbation during run-in Exacerbation during run-in periodperiod

Study DesignStudy Design

Multicenter, randomized, double-blinded, parallel Multicenter, randomized, double-blinded, parallel group study over a 3 year periodgroup study over a 3 year period

2 week run-in period and 2 week follow-up period 2 week run-in period and 2 week follow-up period (including withdrawals from study)(including withdrawals from study)

Stratified according to country and smoking statusStratified according to country and smoking status Randomly assigned to placebo, salmeterol alone, Randomly assigned to placebo, salmeterol alone,

fluticasone alone, or salmeterol plus fluticasonefluticasone alone, or salmeterol plus fluticasone During run-in period, patients could continue use of During run-in period, patients could continue use of

other medications for COPD (theophyllines, anti-other medications for COPD (theophyllines, anti-cholinergics, short acting beta-agonists)cholinergics, short acting beta-agonists)

Study DesignStudy Design

Calverly et al. NEJM 2007

Analysis PopulationsAnalysis Populations

Intent to treat-Efficacy populationIntent to treat-Efficacy population Safety population: examined the development of Safety population: examined the development of

fractures (using DEXA at lumbar spine and hip) as fractures (using DEXA at lumbar spine and hip) as well as development of cataracts and pneumoniawell as development of cataracts and pneumonia

Health-Outcomes population: subset of efficacy Health-Outcomes population: subset of efficacy population, included patients who completed SGRQpopulation, included patients who completed SGRQ

Ophthalmic and Skeletal Safety population: subset of Ophthalmic and Skeletal Safety population: subset of safety population, subjects with any safety population, subjects with any ophthalmic/skeletal data (as not collected at all sites)ophthalmic/skeletal data (as not collected at all sites)

OutcomesOutcomes

Primary: Primary: Time to death from any Time to death from any

cause by 3 yearscause by 3 years Esp. COPD related Esp. COPD related

deathsdeaths

Secondary: Secondary: Frequency of Frequency of

exacerbations - exacerbations - moderate vs. severe moderate vs. severe (req. hospitalization)(req. hospitalization)

Health Status (assessed Health Status (assessed by St. George’s by St. George’s Respiratory Respiratory Questionnaire)Questionnaire)

St.George’s Respiratory St.George’s Respiratory QuestionnaireQuestionnaire

Disease-specific questionnaire to measure Disease-specific questionnaire to measure impact of COPD on quality of lifeimpact of COPD on quality of life

Includes impact of COPD on daily activities Includes impact of COPD on daily activities such as getting dressed, exercise, travelsuch as getting dressed, exercise, travel

Scores based on scale of 0 to 100, with lower Scores based on scale of 0 to 100, with lower scores indicating better functioning;scores indicating better functioning;

Change of 4 units is considered clinically Change of 4 units is considered clinically relevantrelevant

Sample Size DeterminationSample Size Determination

Based on ISOLDE studyBased on ISOLDE study Showed all-cause mortality rates of 16% with fluticasone Showed all-cause mortality rates of 16% with fluticasone

and 21% with placebo among randomized patientsand 21% with placebo among randomized patients 18% vs. 27% among subjects with FEV1 < 60% predicted18% vs. 27% among subjects with FEV1 < 60% predicted Predicted that survival rates for combo should be at least Predicted that survival rates for combo should be at least

that of fluticasone, and true treatment difference for combo that of fluticasone, and true treatment difference for combo vs. placebo should be at least as great as fluticasone vs. vs. placebo should be at least as great as fluticasone vs. placeboplacebo

Thus, placebo mortality rate should be at least 17% over 3 Thus, placebo mortality rate should be at least 17% over 3 years, and combo should reduce mortality 25% relative to years, and combo should reduce mortality 25% relative to this (i.e 4.3%)this (i.e 4.3%)

Sample Size CalculationSample Size Calculation

Used a Group Sequential Design-allows one to look Used a Group Sequential Design-allows one to look at data at a particular time based on formulated at data at a particular time based on formulated stopping rulestopping rule

Needed 6040 subjects (1510 to each group), and 440 Needed 6040 subjects (1510 to each group), and 440 deaths per group to provide 90% power to detect a deaths per group to provide 90% power to detect a mortality difference of 4.3%mortality difference of 4.3%

2 interim analyses: first at 300 deaths, second 2 interim analyses: first at 300 deaths, second midway between first and final analysismidway between first and final analysis

Adjusted p-values for planned interim analyses using Adjusted p-values for planned interim analyses using discrete stagewise orderingdiscrete stagewise ordering

Ordered HeirarchyOrdered Heirarchy

1.1. All cause mortality within 3 yrs: combo vs. All cause mortality within 3 yrs: combo vs. placeboplacebo

2.2. Rate of moderate and severe COPD Rate of moderate and severe COPD exacerbations: combo vs. placebo, combo vs. exacerbations: combo vs. placebo, combo vs. salmeterolsalmeterol

3.3. Quality of life based on SGRQ: combo vs. Quality of life based on SGRQ: combo vs. placebo, combo vs. salmeterolplacebo, combo vs. salmeterol

*Remaining combinations are only exploratory*Remaining combinations are only exploratory..

ResultsResults

Calverly et al. NEJM 2007

Mortality Analysis/ExacerbationsMortality Analysis/Exacerbations

Calverly et al. NEJM 2007

*Lack of statistical significance in COPD- related deaths across all groups comparing treatment to placebo

Log-rank analysis of time to all-cause mortality at 3 years Log-rank analysis of time to all-cause mortality at 3 years stratified by smoking status and countrystratified by smoking status and country

Placebo Placebo (N=1524)(N=1524)

Salmeterol Salmeterol (N=1521)(N=1521)

FP (N=1534)FP (N=1534) SFC (N=1533)SFC (N=1533)

Number of Number of deathsdeaths

231231 205205 246246 193193

Probability of Probability of death by 3 yrs, death by 3 yrs, % (95% CI)% (95% CI)

15.2 (13.4-15.2 (13.4-17.0)17.0)

13.5 (11.8-13.5 (11.8-15.2)15.2)

16.0(14.2-17.9)16.0(14.2-17.9) 12.6 (10.9-12.6 (10.9-14.3)14.3)

Column txt vs. Column txt vs. placeboplacebo

Hazard ratio Hazard ratio (95% CI)(95% CI)

pvaluepvalue

0.891 (0.738-0.891 (0.738-1.076)1.076)

0.230.23

1.058(0.883-1.058(0.883-1.267)1.267)

0.540.54

0.815(0.673-0.815(0.673-0.987)0.987)

0.040.04

SFC vs. SFC vs. Column txtColumn txt

Hazard ratio Hazard ratio (95% CI)(95% CI)

pvaluepvalue

0.929 (0.763-0.929 (0.763-1.132)1.132)

0.470.47

0.775 (0.641-0.775 (0.641-0.936)0.936)

0.0080.008

Calverly et al. NEJM 2007

Secondary OutcomesSecondary Outcomes

Calverly et al. NEJM 2007

Secondary OutcomesSecondary Outcomes

Reduced number of exacerbations and Reduced number of exacerbations and hospitalizations in combination group vs. placebohospitalizations in combination group vs. placebo

NNT of 4 to prevent one exacerbation/yearNNT of 4 to prevent one exacerbation/year NNT of 32 to prevent one hospitalization/year NNT of 32 to prevent one hospitalization/year Greatest reduction (mean-3 units) in SGRQ in Greatest reduction (mean-3 units) in SGRQ in

combination therapy groupcombination therapy group Mean baseline FEV1 in combination group was Mean baseline FEV1 in combination group was

1.236L with increase of 0.029L vs. placebo (baseline 1.236L with increase of 0.029L vs. placebo (baseline of 1.257L and decrease of 0.062L)of 1.257L and decrease of 0.062L)

Adverse EventsAdverse Events

COPD exacerbation most COPD exacerbation most frequentfrequent

Increased incidence of PNA Increased incidence of PNA in patients receiving in patients receiving fluticasonefluticasone

Causes of death: Causes of death: cardiovascular (27%), cardiovascular (27%), pulmonary (35%), cancer pulmonary (35%), cancer (21%)(21%)

Other causes include GI Other causes include GI hemorrhage, trauma, sepsishemorrhage, trauma, sepsis

Cause of death determined Cause of death determined by physician, autopsy by physician, autopsy findingsfindings

Calverly et al. NEJM 2007

Safety StudySafety Study

No significant differences in bone mineral No significant differences in bone mineral density or cataract developmentdensity or cataract development

No significant differences in probability of No significant differences in probability of fracturesfractures

However, three years may not be long enough However, three years may not be long enough to assess for development.to assess for development.

DiscussionDiscussion

Reduction in mortality (2.3%) did not meet the pre-Reduction in mortality (2.3%) did not meet the pre-determined level of statistical significance (i.e. determined level of statistical significance (i.e. sample size calculations were made to provide at least sample size calculations were made to provide at least 90% power for a true difference of 4.3% in mortality 90% power for a true difference of 4.3% in mortality between combination and placebo)between combination and placebo)

However, combination therapy resulted in fewer However, combination therapy resulted in fewer exacerbations and an improvement in health status exacerbations and an improvement in health status and lung function overall.and lung function overall.

Study LimitationsStudy Limitations

Study underpowered: fewer deaths in placebo group Study underpowered: fewer deaths in placebo group than anticipated -> thus, could not detect a significant than anticipated -> thus, could not detect a significant decrease in mortalitydecrease in mortality

High withdrawal rate: highest in placebo groupHigh withdrawal rate: highest in placebo group Performance of second interim analysis so close to Performance of second interim analysis so close to

final analysis -> increased threshold for significancefinal analysis -> increased threshold for significance As patients were allowed to take other medications, As patients were allowed to take other medications,

no standardization for these medications across no standardization for these medications across groupsgroups

ConclusionsConclusions

Although this study did not show significant Although this study did not show significant reduction in mortality, it did result in fewer reduction in mortality, it did result in fewer exacerbations along with improved quality of exacerbations along with improved quality of life and lung function.life and lung function.

Side effects, although present, were minimal.Side effects, although present, were minimal. Thus, it supports the use of a long acting beta-Thus, it supports the use of a long acting beta-

agonist and inhaled corticosteroid for use in agonist and inhaled corticosteroid for use in COPD patients.COPD patients.

ReferencesReferences Burge PS, Calverly PM et al. Randomized, double-blind, placebo controlled study Burge PS, Calverly PM et al. Randomized, double-blind, placebo controlled study

of fluticasone propionate in patients with moderate to severe chronic obstructive of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297-303pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297-303

Young, V et al. Blueprints Medicine. Blackwell Publishing, 2004.Young, V et al. Blueprints Medicine. Blackwell Publishing, 2004. Barr J. et al. The St. George’s Respiratory Questionnaire-American Translation. Barr J. et al. The St. George’s Respiratory Questionnaire-American Translation.

Clin Therapeutics 2000: 22: 1121-1145Clin Therapeutics 2000: 22: 1121-1145