Chronic Obstructive Pulmonary Disease Clinical Trial
— CENTR(AR)Official title:
CENTR(AR): Lungs Moving
Verified date | January 2024 |
Source | Aveiro University |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
Chronic Respiratory Diseases (CRDs) are associated with substantial morbidity and mortality, ranking as the third leading cause of death worldwide. Pulmonary rehabilitation (PR) is a fundamental evidence-based intervention for the management of a variety of CRDs, such as Chronic Obstructive Pulmonary Disease (COPD) and Interstitial Lung Diseases (ILDs). However, the benefits of PR tend to decline over time and there is currently no strong evidence that patients translate those benefits into a more active lifestyle. There is an urgent need for evidence-based interventions to promote physical activity (PA) participation, whilst maintaining PR positive effects in the long-term. Community-based PA interventions adjusted to the local context, as well as patients' needs and preferences, might be a key strategy to meet this target. CENTR(AR) will be a sustainable response to support healthy lifestyles and enhance long-term PR benefits, by providing access to PR within Primary Healthcare Centres (PHC), followed by the inclusion in a community-based PA program, which embraces urban facilities and available resources.
Status | Completed |
Enrollment | 80 |
Est. completion date | December 31, 2023 |
Est. primary completion date | June 1, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: - Clinical diagnosis of a chronic respiratory disease; - Stable clinical condition (defined as no acute exacerbation or hospitalization in the previous month). Exclusion Criteria: - Signs of cognitive impairment; - Neoplasic/Immunologic disease or an unstable/significant cardiac (e.g., exertional angina, valvular heart disease, congestive heart failure, etc.), musculoskeletal/orthopaedic, neuromuscular or psychiatric condition limiting ability to exercise or co-operate. |
Country | Name | City | State |
---|---|---|---|
Portugal | School of Health Sciences of the University of Aveiro (ESSUA) | Aveiro |
Lead Sponsor | Collaborator |
---|---|
Aveiro University | Administração Regional de Saúde do Centro, IP (ARS Centro), Aveiro Institute of Biomedicine (iBiMED), Centro Hospitalar do Baixo Vouga (CHBV), E.P.E., City Council/Municipality: a) Aveiro; b) Estarreja; c) Oliveira do Bairro; d) Montemor-o-Velho, Portuguese National Funding Agency for Science, Research and Technology (FCT), Programa Operacional Competitividade e Internacionalização (POCI) - Compete2020, Programa Operacional Inclusão Social e Emprego (POISE), School of Health Sciences, University of Aveiro (ESSUA) |
Portugal,
Arbillaga-Etxarri A, Gimeno-Santos E, Barberan-Garcia A, Balcells E, Benet M, Borrell E, Celorrio N, Delgado A, Jane C, Marin A, Martin-Cantera C, Monteagudo M, Montella N, Munoz L, Ortega P, Rodriguez DA, Rodriguez-Roisin R, Simonet P, Toran-Monserrat P, Torrent-Pallicer J, Vall-Casas P, Vilaro J, Garcia-Aymerich J. Long-term efficacy and effectiveness of a behavioural and community-based exercise intervention (Urban Training) to increase physical activity in patients with COPD: a randomised controlled trial. Eur Respir J. 2018 Oct 18;52(4):1800063. doi: 10.1183/13993003.00063-2018. Print 2018 Oct. — View Citation
Burge AT, Cox NS, Abramson MJ, Holland AE. Interventions for promoting physical activity in people with chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2020 Apr 16;4(4):CD012626. doi: 10.1002/14651858.CD012626.pub2. — View Citation
Crawford B, Monz B, Hohlfeld J, Roche N, Rubin B, Magnussen H, Nivens C, Ghafouri M, McDonald J, Tetzlaff K. Development and validation of a cough and sputum assessment questionnaire. Respir Med. 2008 Nov;102(11):1545-55. doi: 10.1016/j.rmed.2008.06.009. Epub 2008 Jul 27. — View Citation
Cruz J, Brooks D, Marques A. Walk2Bactive: A randomised controlled trial of a physical activity-focused behavioural intervention beyond pulmonary rehabilitation in chronic obstructive pulmonary disease. Chron Respir Dis. 2016 Feb;13(1):57-66. doi: 10.1177/1479972315619574. Epub 2015 Dec 23. — View Citation
Dowman L, Hill CJ, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2014 Oct 6;(10):CD006322. doi: 10.1002/14651858.CD006322.pub3. — View Citation
GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020 Jun;8(6):585-596. doi: 10.1016/S2213-2600(20)30105-3. — View Citation
Gimeno-Santos E, Frei A, Steurer-Stey C, de Batlle J, Rabinovich RA, Raste Y, Hopkinson NS, Polkey MI, van Remoortel H, Troosters T, Kulich K, Karlsson N, Puhan MA, Garcia-Aymerich J; PROactive consortium. Determinants and outcomes of physical activity in patients with COPD: a systematic review. Thorax. 2014 Aug;69(8):731-9. doi: 10.1136/thoraxjnl-2013-204763. Epub 2014 Feb 20. Erratum In: Thorax. 2014 Sep;69(9):810. multiple investigator names added. — View Citation
Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, McCormack MC, Carlin BW, Sciurba FC, Pitta F, Wanger J, MacIntyre N, Kaminsky DA, Culver BH, Revill SM, Hernandes NA, Andrianopoulos V, Camillo CA, Mitchell KE, Lee AL, Hill CJ, Singh SJ. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014 Dec;44(6):1428-46. doi: 10.1183/09031936.00150314. Epub 2014 Oct 30. — View Citation
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009 Sep;34(3):648-54. doi: 10.1183/09031936.00102509. — View Citation
Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir Med. 1991 Sep;85 Suppl B:25-31; discussion 33-7. doi: 10.1016/s0954-6111(06)80166-6. — View Citation
Mantoani LC, Rubio N, McKinstry B, MacNee W, Rabinovich RA. Interventions to modify physical activity in patients with COPD: a systematic review. Eur Respir J. 2016 Jul;48(1):69-81. doi: 10.1183/13993003.01744-2015. Epub 2016 Apr 21. — View Citation
Markland, D. and V. Tobin, A Modification to the Behavioural Regulation in Exercise Questionnaire to Include an Assessment of Amotivation. 2004. 26(2): p. 191.
McCarthy B, Casey D, Devane D, Murphy K, Murphy E, Lacasse Y. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015 Feb 23;2015(2):CD003793. doi: 10.1002/14651858.CD003793.pub3. — View Citation
O'Shea SD, Taylor NF, Paratz JD. Measuring muscle strength for people with chronic obstructive pulmonary disease: retest reliability of hand-held dynamometry. Arch Phys Med Rehabil. 2007 Jan;88(1):32-6. doi: 10.1016/j.apmr.2006.10.002. — View Citation
Ozalevli S, Ozden A, Itil O, Akkoclu A. Comparison of the Sit-to-Stand Test with 6 min walk test in patients with chronic obstructive pulmonary disease. Respir Med. 2007 Feb;101(2):286-93. doi: 10.1016/j.rmed.2006.05.007. Epub 2006 Jun 27. — View Citation
Reuben DB, Siu AL. An objective measure of physical function of elderly outpatients. The Physical Performance Test. J Am Geriatr Soc. 1990 Oct;38(10):1105-12. doi: 10.1111/j.1532-5415.1990.tb01373.x. — View Citation
Robinson H, Williams V, Curtis F, Bridle C, Jones AW. Facilitators and barriers to physical activity following pulmonary rehabilitation in COPD: a systematic review of qualitative studies. NPJ Prim Care Respir Med. 2018 Jun 4;28(1):19. doi: 10.1038/s41533-018-0085-7. — View Citation
Sarason, I.G., et al., A Brief Measure of Social Support: Practical and Theoretical Implications. Journal of Social and Personal Relationships, 1987. 4(4): p. 497-510.
Spruit MA, Pitta F, McAuley E, ZuWallack RL, Nici L. Pulmonary Rehabilitation and Physical Activity in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2015 Oct 15;192(8):924-33. doi: 10.1164/rccm.201505-0929CI. — View Citation
Spruit MA, Singh SJ, Garvey C, ZuWallack R, Nici L, Rochester C, Hill K, Holland AE, Lareau SC, Man WD, Pitta F, Sewell L, Raskin J, Bourbeau J, Crouch R, Franssen FM, Casaburi R, Vercoulen JH, Vogiatzis I, Gosselink R, Clini EM, Effing TW, Maltais F, van der Palen J, Troosters T, Janssen DJ, Collins E, Garcia-Aymerich J, Brooks D, Fahy BF, Puhan MA, Hoogendoorn M, Garrod R, Schols AM, Carlin B, Benzo R, Meek P, Morgan M, Rutten-van Molken MP, Ries AL, Make B, Goldstein RS, Dowson CA, Brozek JL, Donner CF, Wouters EF; ATS/ERS Task Force on Pulmonary Rehabilitation. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013 Oct 15;188(8):e13-64. doi: 10.1164/rccm.201309-1634ST. Erratum In: Am J Respir Crit Care Med. 2014 Jun 15;189(12):1570. — View Citation
Wootton SL, Hill K, Alison JA, Ng LWC, Jenkins S, Eastwood PR, Hillman DR, Jenkins C, Spencer LM, Cecins N, McKeough ZJ. Effects of Ongoing Feedback During a 12-Month Maintenance Walking Program on Daily Physical Activity in People with COPD. Lung. 2019 Jun;197(3):315-319. doi: 10.1007/s00408-019-00216-5. Epub 2019 Apr 15. — View Citation
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage. 1997 Feb;13(2):63-74. doi: 10.1016/s0885-3924(96)00274-6. — View Citation
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983 Jun;67(6):361-70. doi: 10.1111/j.1600-0447.1983.tb09716.x. — View Citation
* Note: There are 23 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Change in PA levels (time spent in moderate to vigorous physical activity (MVPA)) | Time spent in MVPA will be collected with the ActiGraph accelerometry-based activity monitors (wGT3X-BT) during for week. Raw data will be downloaded, summed and filtered by the ActiLife software (Version 6.13.4) to determine the average MVPA (min/wk). | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in PA levels (time spent in sedentary behaviour) | Time spent in sedentary behaviour will be collected with the ActiGraph accelerometery-based activity monitors (wGT3X-BT) for one week. Raw data will be downloaded, summed and filtered by the ActiLife software (Version 6.13.4). | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in step count (steps/day-1) | Steps/day-1 will be collected with the ActiGraph accelerometery-based activity monitors (wGT3X-BT) for one week. Raw data will be downloaded, summed and filtered by the ActiLife software (Version 6.13.4). | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in health-related quality of life (HRQoL) - St. George Respiratory Questionnaire | The St. George Respiratory Questionnaire (SGRQ) will be used to measure disease-specific impact on overall health, daily life and perceived well-being. The SGRQ is standardized self-administered 50-item questionnaire divided into three subscales: symptoms (eight items), activity (sixteen items) and impact (twenty-six items). Scores range from 0 to 100, with higher scores indicating more limitations. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in exercise capacity/tolerance - 6-minute walk test (6MWT) | The 6MWT is a sub-maximal exercise test used to assess (aerobic) exercise capacity that entails measurement of distance walked over a total of 6 minutes (back and forth a 30-m indoor, unobstructed, flat, straight enclosed corridor.) Distance covered will be recorded in metres. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in overall functional status/physical function - Physical Performance Test | Functional status will be assessed with the Physical Performance Test, which comprises multiple domains of physical function using tasks that replicate activities of daily living (ADLs). This measure has 9-items with a total score of 36 points, with higher scores indicating better performance. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in quadriceps muscle strength - Isometric dynamometry | Quadriceps muscle strength will be measured using a hand-held dynamometer (kilogram/force). | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in handgrip strength - Isometric dynamometry | Handgrip strength will be measured with a hand-held dynamometer (kilogram) | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Healthcare utilisation - AECOPD frequency (previous year) | Number of exacerbations the year prior will be collected, since exacerbation rate/frequency is associated with accelerated lung function decline. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Healthcare utilisation - Emergency department visits (number of visits per participant) | Healthcare utilization will be assessed through the number of emergency department visits per participant the year prior. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in healthcare utilization - Hospital (re)admissions (number of hospital admissions per participant) | Healthcare utilization will be assessed through the number of hospital admissions each participant had in the previous year. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in healthcare utilization - Hospital (re)admissions (length of stay per hospital admission) | Healthcare utilization will be assessed by the average of days that patients spent in the hospital (length of stay), per admission, in the previous year. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in motivation to exercise - The Behavioural Regulation Exercise Scale-2 (BREQ-2) | The Behavioural Regulation Exercise Scale-2 (BREQ-2) will be used to assess behavioural regulation according to self-determination theory (SDT) relative to exercise participation. A 5-point Likert scale, ranging from 0 = "Not True" to 4 = "Very true", is used to rate each of its 18 items. The items are grouped into six subscales (amotivation, external regulation, introjected regulation, identified regulation, integrated regulation and intrinsic motivation), which reflect the motivational continuum of SDT. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in PA levels - Brief Physical Activity Questionnaire | The Brief Physical Activity Questionnaire will be used to assess patients' PA. The Brief PA-tool consists of 2 questions assessing the frequency and duration of time spent in moderate to vigorous PA (MVPA) in a 'usual' week. A total score is calculated (0-8). If the sum of the 2-item scores is above or equal to 4 the subject will be considered physically active. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in impact of symptoms - COPD Assessment Test (CAT) | COPD Assessment Test (CAT) consists of 8 items assessing various manifestations/symptoms of COPD (cough, sputum, dyspnoea, chest tightness, confidence, activity, sleep and energy levels) aiming to provide quantified measure of health status. CAT scores range from 0-40; higher scores denote a more severe impact of COPD on patients' lives. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in emotional status - Hospital Anxiety and Depression Scale (HADS) | Hospital Anxiety and Depression Scale (HADS) will be used to assess symptoms of anxiety and depression. It is a 14-item questionnaire that can be subdivided in two subscales: anxiety and depression. Scores are provided for each subscale and range from 0 to 21, with higher scores meaning more symptoms of anxiety and depression. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in subjective experience of fatigue - Checklist of Individual Strength - Fatigue subscale | The Checklist of Individual Strength (CIS-FS) - Fatigue subscale will be used to assess subjective experience of fatigue. The CIS-FS consists of 8 items with a 7 point-Likert scale scoring. A total score is derived by summation of the item scores. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in impact of fatigue - Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) | The Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F) is a 13-item measure that assesses self-reported fatigue and its impact upon daily activities and function. A 5-point Likert-type scale is used to rate each of the 13 items. The score range is 0 to 52, with 0 being the worst possible score and 52 being the best possible score indicating no fatigue. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in impact of cough and sputum - Cough and Sputum Assessment Questionnaire (CASA-Q) | The CASA-Questionnaire will be used to assess the impact of cough and sputum on patients' lives. The CASA-Q is a 20-item, 5-point rating scale, composed of 4 domains (cough symptoms; cough impact; sputum symptoms; sputum impact) - three (items) per each symptom domain, and eight and six in the cough and sputum impact domains, respectively. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in exercise tolerance/capacity and (lower limb) functional capacity - 1-minute sit-to-stand test | The patient is seated upright on a chair of standard height of 46 cm, without arm rests, positioned against a wall. The patient sat with the knees and hips flexed to 90°, feet placed flat on the floor hip-width apart, and hands placed on the hips. Subjects are asked to perform repetitions of standing upright and sitting down, as many times as possible at a self-paced speed for one minute, without using their arms for support while rising or sitting. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in perceived social support - six-item Social Support Questionnaire (SSQ6) | A Portuguese-version of the Social Support Questionnaire - Short-Form (SSQ-6), a brief 6-question/item version of the original 27-item questionnaire, will be used to assess the availability and satisfaction of a person's social support. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Change in peripheral muscle strength (one- (1RM) or ten- (10RM) repetition maximum) | The one-repetition maximum (1RM) method, defined as the maximal weight that can be lifted once with correct lifting technique, will be used to a) measure/determine (peripheral) muscle strength and b) derive strength/resistance training intensity. In alternative to 1RM, the result of multiple repetition testing (10RM) will be used to predict/estimate the one-repetition maximum. | before PR (T0), immediately after PR (T1), and after a 3, 6 and 12 month-period. | |
Secondary | Quality trail experience | Participants outdoor experience will be assessed in a small group of patients. They will be asked to participate in an interview whilst taking one of the urban/rural trails adapted to people with chronic lung disease, to collect, for example, user's perception of the trail environment and recreation experience and make adjustments informed by their perceptions. | Immediately after PR | |
Secondary | Adherence to the physical activity programme | Participants from the EG adherence to the physical activity programme will be registered by the sports professional responsible for each physical activity and by participants' using a diary | Adherence will be collected in each session of physical activity throughout the 6 months. | |
Secondary | Occurrence of adverse events | The occurrence of adverse events in the EG during the physical activity programme will be registered by the sports professional responsible for each physical activity and by participants' in their diaries. | Occurrence of an adverse event will be collected in each session of physical activity throughout the 6 months |
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT05102305 -
A Multi-center,Prospective, OS to Evaluate the Effectiveness of 'NAC' Nebulizer Therapy in COPD (NEWEST)
|
||
Completed |
NCT01867762 -
An Effectiveness and Safety Study of Inhaled JNJ 49095397 (RV568) in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease
|
Phase 2 | |
Recruiting |
NCT05562037 -
Stepped Care vs Center-based Cardiopulmonary Rehabilitation for Older Frail Adults Living in Rural MA
|
N/A | |
Terminated |
NCT04921332 -
Bright Light Therapy for Depression Symptoms in Adults With Cystic Fibrosis (CF) and COPD
|
N/A | |
Completed |
NCT03089515 -
Small Airway Chronic Obstructive Disease Syndrome Following Exposure to WTC Dust
|
N/A | |
Completed |
NCT02787863 -
Clinical and Immunological Efficiency of Bacterial Vaccines at Adult Patients With Bronchopulmonary Pathology
|
Phase 4 | |
Recruiting |
NCT05552833 -
Pulmonary Adaptive Responses to HIIT in COPD
|
N/A | |
Recruiting |
NCT05835492 -
A Pragmatic Real-world Multicentre Observational Research Study to Explore the Clinical and Health Economic Impact of myCOPD
|
||
Recruiting |
NCT05631132 -
May Noninvasive Mechanical Ventilation (NIV) and/or Continuous Positive Airway Pressure (CPAP) Increase the Bronchoalveolar Lavage (BAL) Salvage in Patients With Pulmonary Diseases?
|
N/A | |
Completed |
NCT03244137 -
Effects of Pulmonary Rehabilitation on Cognitive Function in Patients With Severe to Very Severe Chronic Obstructive Pulmonary Disease
|
||
Not yet recruiting |
NCT03282526 -
Volume Parameters vs Flow Parameters in Assessment of Reversibility in Chronic Obstructive Pulmonary Disease
|
N/A | |
Completed |
NCT02546700 -
A Study to Evaluate Safety and Efficacy of Lebrikizumab in Participants With Chronic Obstructive Pulmonary Disease (COPD)
|
Phase 2 | |
Withdrawn |
NCT04446637 -
Acute Bronchodilator Effects of Ipratropium/Levosalbutamol 20/50 mcg Fixed Dose Combination vs Salbutamol 100 mcg Inhaler Plus Ipratropium 20 mcg Inhalation Aerosol Free Combination in Patients With Stable COPD
|
Phase 3 | |
Completed |
NCT04535986 -
A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD
|
Phase 3 | |
Recruiting |
NCT05865184 -
Evaluation of Home-based Sensor System to Detect Health Decompensation in Elderly Patients With History of CHF or COPD
|
||
Completed |
NCT03256695 -
Evaluate the Relationship Between Use of Albuterol Multidose Dry Powder Inhaler With an eModule (eMDPI) and Exacerbations in Participants With Chronic Obstructive Pulmonary Disease (COPD)
|
Phase 3 | |
Completed |
NCT03295474 -
Telemonitoring in Pulmonary Rehabilitation: Feasibility and Acceptability of a Remote Pulse Oxymetry System.
|
||
Withdrawn |
NCT04042168 -
Implications of Appropriate Use of Inhalers in Chronic Obstructive Pulmonary Disease (COPD)
|
Phase 4 | |
Completed |
NCT03414541 -
Safety And Efficacy Study Of Orally Administered DS102 In Patients With Chronic Obstructive Pulmonary Disease
|
Phase 2 | |
Completed |
NCT02552160 -
DETECT-Register DocumEnTation and Evaluation of a COPD Combination Therapy
|