Effects of Infliximab (Remicade) on Fat Free Mass in Patients With Moderate to Severe COPD Suffering From Cachexia
Information source: Center for Integrated Rehabilitation and Organ Failure Horn
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: COPD; Cachexia
Intervention: infliximab (Remicade) (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: Center for Integrated Rehabilitation and Organ Failure Horn Official(s) and/or principal investigator(s): Emiel FM Wouters, PhD, MD, Principal Investigator, Affiliation: University Hospital Maastricht, Department of Respiratory Medicine
Summary
The purpose of this study is to determine whether infliximab is effective on fat-free mass
in the treatment of patients with moderate to severe COPD suffering from cachexia.
Clinical Details
Official title: A Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Effects of Infliximab (Remicade) on Fat Free Mass in Patients With Moderate to Severe COPD Suffering From Cachexia
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
Primary outcome: Fat-free mass
Secondary outcome: Major Secondary Efficacy Endpoints in order of importance:a. Change in body weight at 8 weeks b. Change from baseline in functional capacity assessed by the incremental shuttle walk test (ISWT) at 8 weeks c. Change from baseline in muscle strength (quadriceps, sniff nasal pressure, hand grip strength) at 8 weeks d. Change from baseline in St George’s Respiratory Disease Questionnaire (SGRQ) at 8 weeks Other Secondary Efficacy Endpoints: change from baseline at 8 weeks and other timepoints in: a. Fat-Free Mass (FFM) as measured by DEXA scan b. Body Mass Index (BMI) c. Spirometry (FEV1, FVC, PEF25-75) d. Quality of life as measured by the Short-Form 36-Item (SF-36) e. Transitional Dyspnoea Index (TDI) f. Muscle cell histology: muscle biopsy is optional g. Sputum inflammatory cell count: sputum induction is optional h. Exacerbation frequency and severity Other objectives of this trial are to evaluate pharmacokinetics (PK) and pharmacodynamics (PD) in the treatment of patients with COPD-related cachexia.
Detailed description:
COPD is a multicomponent disease characterized by abnormal inflammatory response of the
lungs to noxious particles that accompanied by systemic effects like weight loss, muscle
wasting, reduced functional capacity and health status. A persistent systemic inflammatory
response reflected by enhanced levels of acute phase proteins like C-reactive protein (CRP)
or pro-inflammatory cytokines such as tumor necrosis factor (TNF) - α, is present in COPD.
There are several studies that indicate that an increased systemic inflammator response is
associated with weight loss, cachexia (loss of fat-free muscle mass), physical functioning
and health status.
Cachexia associated with systemivc inflammation can not always readily be overcome by
nutritional intervention alone.
The hypothesis of this study is that infliximab therapy (3 infusions with 5 mg/kg infliximab
or placebo 1: 1 on week 0, 2 and 6) will increase fat-free mass relatively to placebo by
decreasing inflammation. Secondary endpoints are: lung function, muscle function, exercise
capacity and health status. On week 8, 12 and 26 follow-up measurements will be done.
Eligibility
Minimum age: 40 Years.
Maximum age: 80 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. COPD acording GOLD with FEV1/FVC ratio < 70%, and post-bronchodilator FEV1 > 20% but <
80% of predicted and an FEV1 of >500ml.
2. Fat Free Mass Index : <17. 5 kg/m2 in males, <15 kg/m2 in females. 3. Symptomatic (eg,
chronic cough, sputum production, shortness of breath) for at least 2 months 4. >= 40
years of age and ≤ 80 years of age 5. History of >=10 pack years of smoking 6. Men and
women of childbearing potential must use adequate birth control measures at least one
month prior to screening and for the duration of the study and should continue such
precautions for 6 months after receiving the last infusion.
7. Ability to adhere to the study visit schedule and other protocol requirements 8.
Provide signed, written informed consent prior to participation in the study 9. Be
adequately immunized against S. pneumoniae. Patients enrolling in the study in autumn and
winter months should be immunized against influenza 10. The screening laboratory test
results must meet the following criteria:
1. Hemoglobin >= 8. 5 g/dL
2. WBC >= 3. 5 x 109/L
3. Neutrophils >= 1. 5 x 109/L
4. Platelets >= 100 x 109/L
5. SGOT (AST) and alkaline phosphatase levels must be within 3 times the upper limit of
normal range for the laboratory conducting the test.
6. TSH within the normal range of 0. 3 to 5 mIU/L. 11. Are considered eligible according
to the tuberculosis (TB) eligibility assessment, screening, and early detection of
reactivation rules
Exclusion Criteria:
1. > 11% increase in FEV1 as % of predicted after a fixed dose of bronchodilator
(200 µg inhaled salbutamol)
2. >12% variation between screening and baseline FEV1 assessments
3. FEV1 < 500 ml
4. Patients with asthma as main component of their obstructive airways disease
5. Moderate or severe exacerbation of COPD within previous 2 months
6. History or clinical signs of severe cor pulmonale, or pulmonary hypertension,
severe right or left sided cardiac failure, serious arrhythmias, myocardial
infarction or cardiac interventions within 6 months of screening.
Exclusion criteria on echocardiogram:
Exclude patients with right–sided heart defects, as defined by any 1 of the following
3 echocardiography criteria:
1. Right ventricular size increased, with an inlet diameter of >5cm
2. Moderate-to-severe tricuspid valve regurgitation
3. Right ventricular (RV)-right atrial (RA) pressure drop of >50 mmHg Exclusion of
patients with left ventricular ejection fraction (LV EF) of <40%, as measured on
echocardiography.
Exclusion criteria on electrocardiogram:
Exclude patients with the following arrhythmias identified on electrocardiography
(ECG):
1. Fast atrial fibrillation at ventricular rate of >90/min
2. Atrial-ventricular conduction delay of grade 2 or higher : excludes 2nd and 3rd
degree heart block.
3. Left bundle branch block, with QRS complex >120msec.
4. Ventricular arrhythmias: ventricular tachycardia and trigeminy.
7. Chronic respiratory failure (PaO2 < 7. 3kPa with or without hypercapnia) and
patients requiring long term oxygen therapy.
8. Participation in the acute phase of a pulmonary rehabilitation program within 4
weeks prior to screening or planned participation in pulmonary rehabilitation during
the study 9. Stopping smoking or attending a smoking cessation class within 6 weeks
of enrollment.
10. Known a1 antitrypsin deficiency 11. Serious acute infections (eg, hepatitis,
pneumonia or pyelonephritis) in the previous 3 months 12. Major surgery in the
previous 3 months 13. Women who are pregnant, nursing, or planning pregnancy within
one year after screening (i. e., approximately 6 months following last infusion) 14.
Use of any investigational drug within 1 month prior to screening or within 5
half?lives of the investigational agent, whichever is longer 15. Treatment with any
other therapeutic agent targeted at reducing TNFa (e. g. pentoxifylline, thalidomide,
etanercept, etc.) within 3 months of screening. Treatment with immunosuppressive or
cytotoxic therapy.
16. Previous administration of infliximab 17. Known allergy to murine products 18.
Are considered ineligible according to the TB eligibility assessment, screening, and
early detection of reactivation rules defined in Section 4. 3.
19. Have or have had an opportunistic infection (eg, herpes zoster [shingles],
cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria
other than TB) within 6 months prior to screening.
20. Have a chest radiograph at screening that shows evidence of malignancy,
infection, or any abnormalities suggestive of TB 21. Have had an opportunistic
infection (e. g. herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii,
aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months of
screening.
22. Documented HIV infection. 23. Positive serology for active hepatitis B or C based
on all subjects being tested at screening. A positive result will indicate referral
to a consultant Hepatologist for further investigation and support.
24. Have current signs or symptoms of severe, progressive or uncontrolled renal,
hepatic, hematological, gastrointestinal, endocrine, cardiac, neurologic, or cerebral
disease (including demyelinating diseases such as multiple sclerosis) 25. Presence of
a transplanted organ (with the exception of a corneal transplant > 3 months prior to
screening) 26. Malignancy within the past 5 years (except for squamous or basal cell
carcinoma of the skin that has been treated with no evidence of recurrence) 27.
History of lymphoproliferative disease including lymphoma, or signs and symptoms
suggestive of possible lymphoproliferative disease, such as lymphadenopathy of
unusual size or location (such as nodes in the posterior triangle of the neck,
infra?clavicular, epitrochlear, or periaortic areas), or splenomegaly 28. Known
recent substance abuse (drug or alcohol) 29. Poor tolerability of venipuncture or
lack of adequate venous access for required blood sampling during the study period
30. Known atypical mycobacterium infection
Locations and Contacts
Center for Integrated Rehabilitation and Organ failure (CIRO) Horn, Horn 6085 NM, Netherlands
Additional Information
Related publications: van der Vaart H, Koëter GH, Postma DS, Kauffman HF, ten Hacken NH. First study of infliximab treatment in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005 Aug 15;172(4):465-9. Epub 2005 Jun 3.
Starting date: October 2003
Last updated: December 8, 2005
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