Home Non Invasive Ventilation (NIV) Treatment for COPD-patients After a NIV-treated Exacerbation

• Hospitalization frequency [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  Measured by Kaplan Meier plot, logrank and absolute data. Both ITT and PP
• Health related quality of life [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  measured by the CAT and SRI questionnaires
• medication status [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  use of medication during one year's follow-up
• Dyspnea [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  The MRC dyspnea scale
• Number of contacts with ER, GP because of COPD [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Number of days admitted [ Time Frame: 1 year ] [ Designated as safety issue: No ]

• Hospitalization frequency [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  Measured by Kaplan Meier plot and logrank
• Health related quality of life [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  measured by the CAT-score system
• medication status [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  use of medication during one year's follow-up
• Dyspnea [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Dyspnea
• Number of contacts with ER, GP because of COPD [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Number of days admitted [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Chronic Obstructive Pulmonary Disease, COPD, is characterized by chronic impaired function and capacity of the lungs and airways. COPD and graded from mild to very severe COPD. Colds, inhalation of dust and pollen as well stay in the cold can cause a worsening, a so-called exacerbation in which the airways become inflamed, constricted and filled with secretions. The patient's ability to maintain adequate respiration is affected dramatically and hospitalization is required. The condition treated medically, but in severe cases, it is so critical to patient needs acute respiratory support or NIV (non invasive ventilation).

NIV is a very gentle mask respirator principle, whereby the patient's own breathing supported and does not require anesthesia. A mesh connects the mouth and nose so that the changing air pressure helps the air through the narrowed airways.

Background Normally NIV therapy is used only during hospitalization. Evidence suggests, however, that home NIV treatment of patients who have previously been admitted with a NIV-requiring exacerbation of COPD, may prevent the majority of exacerbations and admissions for this. Furthermore seem home NIV to reduce mortality among COPD patients. This technique increases both safety and quality of life for a group of very vulnerable patients. The effect is not documented. In this project the investigators want to investigate this effect.

The project in practice In practice, the investigators ask all patients admitted with an exacerbation NIV-consuming in the Capital Region, if they want to participate. If the patient wants this, pull the left as to whether he / she will receive usual care (which is internationally approved gold standard) or usual care + NIV. It is here supposed, the patient must sleep with NIV mask on every night.

Both groups attached to the same follow-up in outpatient clinic and a telephone hotline and receive exactly the same care and attention - except for the NIV. Thereby all the differences in the two groups such as the quality of life, functioning, hospitalization frequency, medication use, and especially mortality are certain to be due to the NIV treatment.

The above mentioned are the end points of this study

Noninvasive positive-pressure ventilation (NIV) has been shown to improve survival significantly (1) in patients with chronic obstructive pulmonary disease (COPD), hospitalized for acute exacerbation and complicated with acute hypercapnic respiratory failure (AHRF). Similarly, NIV reduces complications such as pneumonia, compared with invasive ventilation. NIV is recommended as first-line treatment in these patients (GOLD guidelines). However, the risk of re-hospitalization after an acute NIV-treated exacerbation is 80% within the first year, the risk of a second life threatening event is 63% and the risk of death is 49% (2).

In univariate analyzes, survival of chronic hypercapnic COPD patients treated with NIV at home correlates with age, BMI, hemoglobin, FEV1, specific airway resistance, hyperinflation (RV / TLC), pH, Base Excess; and in multivariate analysis significantly with age, BMI , hyperinflation (RV / TLC) and Base Excess (3).

No previous studies of home NIV in COPD patients - except one (4) - have used previous acute NIV treatment as an inclusion criterion, and the results have been conflicting. The largest randomized, controlled trial of home NIV found a small but significant reduction in mortality - apparently at the expense of worsening of the quality of life (5). This study included stable hypercapnic COPD patients treated with Long Term Oxygen Treatment (LTOT) without previous NIV treatment. One possible explanation for the reduced quality of life may be that the patients had not previously experienced a severe acute NIV-dependent exacerbation in COPD with associated anxiety and loss of quality of life. This was also reflected in a high patient dropout in the group receiving home NIV.

The only randomized study in which an inclusion criterion was a previous acute NIV-treated exacerbation of COPD, it was found that home NIV reduced the number of hospitalizations and exacerbations (4). But the study was small (23 + 24 patients), and quality of life was not investigated. Chronic high CO2 was not an inclusion criterion.

Home NIV treatment of COPD aims at a normalization of PaCO2 and Base Excess, and both randomized and observational studies have shown that this can happen with high levels of Inspiratory Positive Airway Pressure (IPAP) up to 28 cm of water and Expiratory Positive Airway Pressure (EPAP) 5 cm of water(6).

We retrospectively evaluated our patients who received NIV at home, based on more than three NIV-treated acute exacerbations and found a significantly reduced number of readmissions and hospital days per se in the previous year. We found a high tolerability using NIV in these highly selected patients.

The purpose of this randomized controlled trial is to investigate whether home NIV

- As an exacerbation prophylactic treatment - may reduce mortality in COPD patients after first acute NIV treatment and secondarily reduce both exacerbations and hospitalizations and improve the quality of life.

We find that sham NIV or CPAP in the control group could have a negative effect on quality of life and thus favor the NIV treatment group. Likewise, we believe that by offering the same outpatient monitoring in the two arms, and as our primary outcome is mortality, the risk of bias in an open trial will be minimal.

In order to reduce dropout rates in the NIV group, we evaluate the effect of the home NIV treatment after one month. Here, some patients will be permitted to pause the treatment. Below are listed a number of criteria for permissible pausation, as well as resume of the NIV therapy.

Inclusion criteria

• Admitted with a NIV-requiring exacerbation of COPD
• COPD with a FEV1/FVC <0.7 after bronchodilatation.
• ≥ 1 hypercapnic acute respiratory failure (AHRF *).
• Optimal medical treatment of COPD, ie. inhaled steroids, long-acting β2-agonists Tiotropium and according to GOLD guidelines.
• Address in the Capital Region

• Patients must be able to give a verbal consent and sign a written consent form and understand Danish

  • AHRF with pH <7.35 and PaCO2> 6 kPa.

Exclusion Criteria

• Severely depressed level of consciousness / confusion / non-cooperative.
• Respiratory rate <12/min
• Severe hypoxia requiring more than 15L O2/min.
• Large quantities of sputum.
• Vomiting and high risk of aspiration.
• Inability to accept NIV.
• Recent abdominal, facial or upper airway surgery.
• Malignancy or life expectancy <6 months because of disease other than COPD
• Known obstructive sleep apnea syndrome (OSAS)
• Metabolic acidotic component - Standard bicarbonate StHCO3-<20 mM

By readmissions, patients who have previously entered into the study will not be re-randomized. They continue in the study, and, if the patient is in the intervention group, home NIV is resumed if stopped.

Design The study is a randomized, controlled, open-label study with an intervention group (NIV) and a control group without NIV (usual care) Patients are included during admission. Patients receive home visits by a nurse after 1 week and the possibility of acute telephone by a nurse during the day Monday to Friday.

Outpatient follow-up visits are scheduled 1, 3, 6, 9 and 12 months after discharge. A total of 150 COPD patients will be included from the 5 regional departments of pulmonary medicine - ie. Hvidovre Hospital, Bispebjerg Hospital, Herlev Hospital, Hillerød Hospital and Gentofte Hospital. Patients are randomized in a 1:1 ratio in the NIV or usual care group. Each center should have at least 15 patients.

Randomization is carried out using a computer-generated block randomization list for each center. Equal numbers = NIV, odd numbers = usual care. The randomization list is stored at Gentofte Hospital in a sealed envelope. 50 sealed envelopes are prepared for each. center, each containing an individual code.

Sample size / power calculation Mortality during the first year among COPD patients with NIV treatment of AHRF is 49% (2), but mortality is greatest during the first 3 months (ca. 30%) (2) Since COPD patients with a life expectancy of less than 6 months due to other diseases than COPD are excluded from this study, we expect the 1-year mortality in the control group to be around 40%. Minimum relevant difference (MIREDIF) after 12 months is set at 40% reduction in mortality (ie mortality in the control group = 0.40 and the NIV group = 0.24). Type 1 error (α) is set to 0.05 and type 2 error (β) is set to 0.9. The required sample size is then computed to 37, but in order to ensure that the strength to detect the difference in the quality of life, 75 patients are included in each arm.

Primary outcome The primary outcome is the decrease in 1-year mortality in the home NIV group compared with the control group. Analyzed as an Intention-To-Treat analysis and calculated by the Kaplan-Meier plot and logrank.

Secondary outcomes

• Admissions with exacerbation of COPD in a year after initiation
• Total admissions in a year after initiation
• Emergency room visits for one year after initiation
• Number of visits to GP and emergency physician in one year
• Number of prednisolone and / or antibiotic-treated exacerbations of one year
• Changes in BMI
• Changes in FEV1
• Cost efficiency
• Quality of life measured by COPD Assessment Test (CAT) and Severe Respiratory Insufficience Questionnaire (SRI).
• Sleep quality measured by the Epworth Sleepiness Scale (ESS)
• Apnoea / hypopnea index (AHI) recorded on the NIV-device SIM card
• Medical Research Council's Dyspnea scale (MRCD)

Intervention

Standard care in both intervention and control group:

During hospitalization:

• Acute NIV treatment of AHRF
• Informed consent and randomization, when the patient is stabilized and able to complete the acute NIV treatment
• Medical standard treatment of COPD exacerbation according to GOLD
• Start of standard medical treatment, including smoking cessation program according to GOLD and in relation to the severity of COPD.
• Patients are offered COPD rehabilitation in outpatient visits, typically after 6 months.
• Home visits by NIV-nurse 1 week after discharge.
• Outpatient visits (or home, if necessary) after 1, 3, 6, 9 and 12 months.
• Associated nurse and emergency telephone hotline weekdays. 8 - 15

Only the intervention group = Home-NIV-treated

• Home NIV initiated as a direct continuation of the acute NIV treatment during hospitalization
• Home NIV optimized and IPAP is increased to the maximum value, the patient can accept.
• Patients and caregivers are trained in handling and cleaning of the NIV apparatus, tubes, masks, etc.
• Patients are encouraged to a minimum of 6 hours of daily use of NIV.
• At the home visits and outpatient visits, NIV is optimized for patient requests / complaints. IPAP is set to the maximum level acceptable to the patient
• At the first outpatient visit at one month, patients are evaluated by the nurse. Patients who have had only this one NIV-treated exacerbation and who do not feel a subjective improvement after one month of NIV are offered to pause the NIV therapy - provided, however, they have not had any of the following in the first month:

Exacerbation Need for antibiotics or increased steroid or inhaled medicine Hospitalization, emergency room visits, or emergency doctor visits due to COPD Fever > 38˚C > 1 day More or more viscous / purulent expectoration > 1 day Increasing dyspnea > 1 day If it is agreed to pause the daily NIV therapy, the patient is instructed to resume NIV at one or more of the above symptoms

Measurements at startup. NB! These measurements are done as a standard at the acute hospitalization and NOT as part of the protocol.

• Arterial blood gasses with PaCO2, PaO2, pH and StHCO3- during acute NIV treatment procedure.
• Blood Tests
• Electrocardiogram (ECG)
• Chest x-ray

Measurements at discharge:

• Lung function, ie: FEV1, FVC, FIVC
• Oxygen saturation in the blood
• Arterial blood gasses with PaCO2, PaO2, pH and StHCO3-
• Oxygen supply
• Height and weight
• Dyspnea score (MRCD)
• CAT, and SRI
• ESS
• NIV-device SIM card read with regards to compliance (hours used per day) and apnea-hypopnea index (AHI)
• Medication Status

Measurements at outpatient visits 1, 3, 6, 9 and 12 months after discharge (see protocol):

• Lung function, ie: FEV1, FVC, FIVC
• Oxygen saturation in the blood
• Arterial blood gasses with PaCO2, PaO2, pH and StHCO3-
• Oxygen supply
• Weight
• Dyspnea score (MRCD)
• CAT and SRI
• NIV-device SIM card read with regards to compliance (hours used per day) and apnea-hypopnea index (AHI)
• Medication Status
• Sleep Quality for the ESS
• Tobacco Status + CO-assessment
• Medication Status
• Data are collected on mortality, hospital admissions, emergency room visits each outpatient visit and at the end of the study after 12 months
• IPAP, EPAP and BPM are optimized in order to normalize the PaO2, and Base Excess.

Measurements at the nurse visit 1 week after discharge:

• FEV1, FVC, FIVC
• Oxygen saturation
• Check that the NIV machine and the hose is ok
• Ensure that the patient is well informed and use the machine properly

Data Processing:

The primary outcome is the decrease in 1-year mortality in the home NIV group compared with the control group. Analyzed as an Intention-To-Treat analysis and calculated by the Kaplan-Meier plot and logrank.

Differences between active NIV treatment (intervention) and usual care (control) are measured during the intervention period (1 year). These differences in trends over time between intervention and control group are analyzed by analysis of variance (ANOVA) for repeated measures with a significance level of p <0.05. Statistically significant differences as analyzed using the t test for normal data

Publications:

Study results will be published in national and international journals. This applies to both positive and negative results. Similarly, the results will be published in relevant conferences, symposia, etc..

If negative results can not be published in journals, they will be published in other ways, such as on congresses.

Ethics:

The study was approved by the Research Ethics Committee, Data Protection, Clinical Trial and Drug Authority

Consent:

Informed consent is obtained after written and verbal information given by one of the attending physicians at the department. Once the acute situation is stable and the patient is ready, he/she is asked if he/she is interested in participating. This is typically 2 days after admission, although this is individual. The patient is informed about the possibility of bringing companion to the actual information interview. Desired effect confirmed or disproved orally.

The information interview is conducted in a single room with a physician who has devoted time to do so and thus not disturbed. There will be time allocated for informed consent and to ask questions and then signed consent form by both parties. If the participant wishes time for consideration, a new interview will be planned 1-2 days later. Consent sought for the discharge.

Biological material:

In the study, only sampled biological material in the form of general biochemistry and arterial gasses and this only at startup and at outpatient visits. This is the default for hospitalization and outpatient visits. Samples are handled by the Department of Clinical Biochemistry according to current guidelines, then they are destroyed. No biological material will be stored for further use.

Arterial gasses measure approx. 1mL of arterial blood, taken from the artery in the wrist.

Biochemistry measure in 10-15 ml of venous blood, typically taken from the elbow.

Risks:

There are few side effects of NIV treatment:

Some people feel uncomfortable by having the mask on, as it fits tightly to the face and some will experience dryness of the eyes, nose and mouth, because the airflow. The mask can, if not seated properly, give pressure ulcers, especially over the nose. Due the high pressure from the machine, one can get a sense of flatulence. NIV should not be used by the tendency to vomiting because of the risk of aspiration and patients are thoroughly instructed orally and in writing to use the NIV in a semi-sitting position (45 degrees).

Risks of blood samples are minimal and limited to the risk of hematoma at the injection site.

There are no risks in the study.

Budget

The following expenses are expected:

PhD scholarship: DKK 1,156,977 Employment of a nurse in each center who work ¼ of the time on the project in its first year and 1/8 of the time in other years: DKK 750,000 Transportation of patients and home care nurses: DKK 230,000 Thus a total of DKK 2,136,977

NIV equipment sponsored by Philips: Synchrony sets, masks, hoses and SIM cards. In total approx. 3,500,000 DKK

Gentofte Hospital's Pulmonary Medicine Department. Y stands behind the idea and the protocol behind the studio.

Philips has paid for the delivered NIV devices, masks and tubing for a total of nearly 3,500,000 Danish Kroner. In addition, Philips is neither involved in the study of design or performance adaptation.

Nobody involved physicians paid by Philips or have interests in the company.

Schedule January 2011 to 1 in March. 2011: Final protocol February 2011: Case Record File, informed consent forms and patient information leaflet developed.

1 April 2011:. Submission of application to the Ethics Committee, Data Protection

1 September 2011: All applications approved August 2011: First meeting of board of studies (a medical doctor (MD) and a nurse (RN) from each of all five study centers, an extra nurse from Gentofte, Kim Mikkelsen, MD (statistical consultant), Lars Henriksen and Annette Mørck (Philips), Kasper Ankjærgaard (Ph: D.student, MD), Torgny Wilcke, Philip Tonnesen ie a total of 17 persons).

May 2013 Start-up meeting and training seminar: 1 day in Copenhagen. March 15th 2013: First patient included. March 15th 2014: The last patient included. March 15th 2015: The last patient's last follow-up. April 15th 2015: Cleaned database is locked. May 2015: Results are presented at the end of the study session for the Board of Studies.

June 2015: The first manuscript draft. July 2015: Final manuscript ready and released, including poster presentations.

• Chronic Obstructive Pulmonary Disease
• Acute Exacerbation of Chronic Obstructive Airways Disease
• Chronic Hypercapnic Respiratory Failure

• Experimental: NIV group

  NIV group is given golden standard COPD care as described in GOLD-guidelines + NIV every night.

  Outpatient visits are given every three months

  Intervention: Device: Nightly NIV for at least 6 hours
• No Intervention: Control Group

  Control Group is given golden standard COPD care as described in GOLD-guidelines.

  Outpatient visits are given every three months

• Ram FS, Wellington S, Rowe BH, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD004360. Review. Update in: Cochrane Database Syst Rev. 2005;(3):CD004360.
• Chu CM, Chan VL, Lin AW, Wong IW, Leung WS, Lai CK. Readmission rates and life threatening events in COPD survivors treated with non-invasive ventilation for acute hypercapnic respiratory failure. Thorax. 2004 Dec;59(12):1020-5.
• Budweiser S, Hitzl AP, Jörres RA, Heinemann F, Arzt M, Schroll S, Pfeifer M. Impact of noninvasive home ventilation on long-term survival in chronic hypercapnic COPD: a prospective observational study. Int J Clin Pract. 2007 Sep;61(9):1516-22.
• Cheung AP, Chan VL, Liong JT, Lam JY, Leung WS, Lin A, Chu CM. A pilot trial of non-invasive home ventilation after acidotic respiratory failure in chronic obstructive pulmonary disease. Int J Tuberc Lung Dis. 2010 May;14(5):642-9.
• McEvoy RD, Pierce RJ, Hillman D, Esterman A, Ellis EE, Catcheside PG, O'Donoghue FJ, Barnes DJ, Grunstein RR; Australian trial of non-invasive Ventilation in Chronic Airflow Limitation (AVCAL) Study Group. Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial. Thorax. 2009 Jul;64(7):561-6. Epub 2009 Feb 12.
• Windisch W, Haenel M, Storre JH, Dreher M. High-intensity non-invasive positive pressure ventilation for stable hypercapnic COPD. Int J Med Sci. 2009;6(2):72-6. Epub 2009 Feb 27.
• Kolodziej MA, Jensen L, Rowe B, Sin D. Systematic review of noninvasive positive pressure ventilation in severe stable COPD. Eur Respir J. 2007 Aug;30(2):293-306. Epub 2007 Apr 25. Review.

Inclusion Criteria:

• Patient admitted with a NIV-requiring exacerbation of COPD
• COPD with a FEV1/FVC <0.7 after bronchodilatation.
• ≥ 1 acute hypercapnic respiratory failure (AHRF *).
• Optimal medical treatment of COPD, ie. inhaled steroids, long-acting β2-agonist Tiotropium, according to GOLD guidelines.
• Address in Capital Region
• Patients are able to give verbal consent and sign a written consent form and understand Danish-

Exclusion Criteria:

• Severely depressed level of consciousness / confusion / non-cooperative.
• Respiratory rate <12/min
• Severe hypoxia, such as requiring more than 15L O2/min.
• Large amounts of sputum.
• Vomiting and high risk for aspiration.
• Inability to accept NIV.
• Recent abdominal, facial or upper airway surgery.
• Malignancy or life expectancy <6 months because of disease other than COPD
• Known obstructive sleep apnea syndrome (OSA)
• Metabolic acidotic component - StHCO3- < 20 mM