Ig PRx in AECOPD: Pilot Study

Chronic Obstructive Pulmonary Disease Clinical Trial

Official title:

Feasibility and Safety of Immunoglobulin (Ig) Prophylactic Treatment in COPD Patients With Frequent Exacerbations: A Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02690038
• Other study ID #: 20150925 / 20160077-01H
• Status: Completed
• Phase: Phase 2
• Start date: September 2016
• Est. completion date: November 20, 2019

Study information

• Verified date: November 2019
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will look at immunoglobulin (Ig) treatment in hospitalized chronic obstructive lung disease (COPD) patients with frequent exacerbations.

This is a Phase II, pilot randomized double blind control study, meaning this study will help assess if this research can be expanded to evaluate Ig treatment in patients with COPD. Ig treatment is a sterile solution of human immunoglobulin proteins given intravenously (in the vein). Immunoglobulins are part of the immune system and help the body fight infections. Participants will be assigned to either receiving the Ig treatment or normal saline as a control product every 4 weeks for 12 months.

Participants will continue on current standard therapy as determined by their treating physician.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: November 20, 2019
• Est. primary completion date: November 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Hospitalized adult patient with AECOPD (clinically dominant AECOPD in the case of multiple co-morbidities eg. absence of overt lobar pneumonia or acute congestive heart failure or alternate diagnosis such as acute coronary syndrome or pulmonary embolism)

• Diagnosis of severe COPD (post bronchodilator FEV1 <50%, FEV1/FVC ratio <0.7) made by standard spirometry within previous 12 months or within three days of admission if previous PFT data is not available

• Age >40 years

• >10 pack year smoking history

• At least one COPD exacerbation in the previous 12 months before enrollment, defined by having had documented inpatient or outpatient treatment by physician with antibiotics and/or prednisone for physician diagnosed COPD exacerbation

• Expected to live > 12 months

Exclusion Criteria:

• Known severe hypersensitivity to immunoglobulin or its components (anaphylaxis)

• Underlying malignancy (including chronic lymphocytic leukemia)

• History of hematopoietic stem cell transplant or solid organ transplant

• Current treatment with a biological therapy for other conditions

• Concomitant significant immunodeficiency or on immunosuppressive treatment other than for COPD

• Alpha-1 antitrypsin deficiency

• Significant proteinuria (dipstick proteinuria = 3+ or known urinary protein loss = 2 g/day or nephrotic syndrome) and/or has acute renal failure and/or severe renal impairment (creatinine more than 2.5 times the upper limit of normal and/or on dialysis)

• IgA deficiency (IgA <0.1 g/L)

• Immunoglobulin therapy in the last 12 months or on current Ig therapy or have a clinical indication for Ig replacement therapy (www.nacblood.ca/resources/guidelines/IVIG.html)

• Obesity (BMI =35 kg/m²)

• Pregnancy

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Intravenous immunoglobulin (IVIG)
Baseline Ig < 7g/L group - Intravenous immunoglobulin (IVIG) 0.8 g/kg will be given within 12 hours after randomization. Baseline Ig > or = 7 g/L group - Intravenous immunoglobulin (IVIG) 0.5 g/kg will be given within 12 hours after randomization
• Normal Saline
Baseline Ig < 7g/L group - Normal Saline (0.9% NaCl) 8 mL/kg will be given within 12 hours after randomization. Baseline Ig > or = 7 g/L group - Normal Saline (0.9% NaCl) 5 mL/kg will be given within 12 hours after randomization

Locations

Country	Name	City	State
Canada	The Ottawa Hospital, General Campus	Ottawa	Ontario

Sponsors (3)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute	CSL Behring, Grifols Biologicals, LLC

Country where clinical trial is conducted

Canada, 

References & Publications (22)

Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011 Aug 25;365(8):689-98. doi: 10.1056/NEJMoa1104623. Erratum in: N Engl J Med. 2012 Apr 5;366(14):1356. — View Citation

Baker CL, Zou KH, Su J. Risk assessment of readmissions following an initial COPD-related hospitalization. Int J Chron Obstruct Pulmon Dis. 2013;8:551-9. doi: 10.2147/COPD.S51507. Epub 2013 Nov 12. — View Citation

Brightling CE, Bleecker ER, Panettieri RA Jr, Bafadhel M, She D, Ward CK, Xu X, Birrell C, van der Merwe R. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014 Nov;2(11):891-901. doi: 10.1016/S2213-2600(14)70187-0. Epub 2014 Sep 7. — View Citation

Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009 Aug 29;374(9691):685-94. doi: 10.1016/S0140-6736(09)61255-1. Erratum in: Lancet. 2010 Oct 2;376(9747):1146. — View Citation

Cowan J, Gaudet L, Mulpuru S, Corrales-Medina V, Hawken S, Cameron C, Aaron SD, Cameron DW. A Retrospective Longitudinal Within-Subject Risk Interval Analysis of Immunoglobulin Treatment for Recurrent Acute Exacerbation of Chronic Obstructive Pulmonary Disease. PLoS One. 2015 Nov 11;10(11):e0142205. doi: 10.1371/journal.pone.0142205. eCollection 2015. — View Citation

Fedor ME, Rubinstein A. Effects of long-term low-dose corticosteroid therapy on humoral immunity. Ann Allergy Asthma Immunol. 2006 Jul;97(1):113-6. — View Citation

Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012 Nov 22;367(21):2015-25. doi: 10.1056/NEJMra1009433. Review. — View Citation

Gilardin L, Bayry J, Kaveri SV. Intravenous immunoglobulin as clinical immune-modulating therapy. CMAJ. 2015 Mar 3;187(4):257-264. doi: 10.1503/cmaj.130375. Epub 2015 Feb 9. Review. — View Citation

Han MK, Martinez FJ. Pharmacotherapeutic approaches to preventing acute exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2011 Aug;8(4):356-62. doi: 10.1513/pats.201102-016RM. Review. — View Citation

Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010 Sep 16;363(12):1128-38. doi: 10.1056/NEJMoa0909883. — View Citation

Kaveri SV, Maddur MS, Hegde P, Lacroix-Desmazes S, Bayry J. Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy. Clin Exp Immunol. 2011 Jun;164 Suppl 2:2-5. doi: 10.1111/j.1365-2249.2011.04387.x. Review. — View Citation

Kawano T, Matsuse H, Obase Y, Kondo Y, Machida I, Tomari S, Mitsuta K, Fukushima C, Shimoda T, Kohno S. Hypogammaglobulinemia in steroid-dependent asthmatics correlates with the daily dose of oral prednisolone. Int Arch Allergy Immunol. 2002 Jul;128(3):240-3. — View Citation

Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001 Sep 6;345(10):747-55. Review. — View Citation

Müllerova H, Maselli DJ, Locantore N, Vestbo J, Hurst JR, Wedzicha JA, Bakke P, Agusti A, Anzueto A. Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort. Chest. 2015 Apr;147(4):999-1007. doi: 10.1378/chest.14-0655. — View Citation

Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA Jr, Korducki L, Cassino C, Kesten S. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005 Sep 6;143(5):317-26. — View Citation

Ochsenbein AF, Fehr T, Lutz C, Suter M, Brombacher F, Hengartner H, Zinkernagel RM. Control of early viral and bacterial distribution and disease by natural antibodies. Science. 1999 Dec 10;286(5447):2156-9. — View Citation

Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies. Clin Immunol. 2010 Oct;137(1):21-30. doi: 10.1016/j.clim.2010.06.012. Epub 2010 Aug 1. — View Citation

Sabroe I, Postma D, Heijink I, Dockrell DH. The yin and the yang of immunosuppression with inhaled corticosteroids. Thorax. 2013 Dec;68(12):1085-7. doi: 10.1136/thoraxjnl-2013-203773. Epub 2013 Aug 8. — View Citation

Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1418-22. — View Citation

Toy EL, Gallagher KF, Stanley EL, Swensen AR, Duh MS. The economic impact of exacerbations of chronic obstructive pulmonary disease and exacerbation definition: a review. COPD. 2010 Jun;7(3):214-28. doi: 10.3109/15412555.2010.481697. Review. — View Citation

Yip NH, Lederer DJ, Kawut SM, Wilt JS, D'Ovidio F, Wang Y, Dwyer E, Sonett JR, Arcasoy SM. Immunoglobulin G levels before and after lung transplantation. Am J Respir Crit Care Med. 2006 Apr 15;173(8):917-21. Epub 2006 Jan 6. — View Citation

Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P, Yao WZ, Ma LJ, Li X, Raiteri L, Sardina M, Gao Y, Wang BS, Zhong NS; PANTHEON study group. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014 Mar;2(3):187-94. doi: 10.1016/S2213-2600(13)70286-8. Epub 2014 Jan 30. Erratum in: Lancet Respir Med. 2014 Apr;2(4):e4. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recruitment	Average number of patients being recruited per month. The study meets primary outcome if at least 4 patients can be recruited per month on average.	52 weeks
Primary	Adherence and protocol compliance	Number and percentage of recruited patients adhere to the allocated treatment and protocol. We aim to achieve 80% adherence rate which is defined as at least 80% of patients adhere to 80% of allocated treatment and protocol	104 weeks
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE	This will be assessed by documentation of adverse events in patients treated with Ig treatment versus control	104 weeks
Secondary	Tolerability of treatment	The proportion of patients able to complete the treatment in the experimental arm during the study period versus in the control arm	104 weeks
Secondary	Efficacy trend: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) rates	AECOPD will be ascertained by monthly follow-up phone calls as well as questionnaires during study visits to detect inpatient/outpatient treatment for exacerbations.	104 weeks
Secondary	Efficacy trend: Health status	measured by the validated St. George Respiratory Questionnaire	104 weeks
Secondary	Efficacy trend: Quality of life	validated quality of life measurement tool - EuroWol EQ-5D-5L	104 weeks
Secondary	Efficacy trend: % predicted FEV1	FEV1 value will be measured using a hand held spirometer. FEV1 value will be recorded in Litres (L) and reported as a percent of their predicted value (using the NHANES III reference standards for predicted values	104 weeks
Secondary	Efficacy trend: FEV1/FVC	FVC will be measured using a hand held spirometer, and will be recorded in Litres (L). Ratio of FEV1 and FVC will be reported.	104 weeks
Secondary	Efficacy trend: Health services use	Number of non-study physician visits, emergency department (ED) and hospital admissions over the twelve-month study period.	104 weeks
Secondary	Efficacy trend: Health care system cost	we will take the perspective of healthcare system and will measure the cost of health services use and an intervention. Intervention cost includes medication, staff, and equipment cost.	104 weeks

External Links

•   Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework - Health Quality Ontario (HQO).
•   Chronic Obstructive Pulmonary Disease (COPD) Fact Sheet - American Lung Association.
•   GOLD_Pocket_2017_Feb18.pdf
•   Intravenous immunoglobulin enhances the killing activity and autophagy of neutrophils isolated from immunocompromised patients against multidrug-re...
•   Microsoft Word - OLA Final Report June 21 - document.doc.
•   WHO | Burden of COPD