Ghrelin Treatment of Cachectic Patients with Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND: Pulmonary cachexia is common in advanced chronic obstructive pulmonary disease (COPD), culminating in exercise intolerance and a poor prognosis. Ghrelin is a novel growth hormone (GH)-releasing peptide with GH-independent effects. The efficacy and safety of adding ghrelin to pulmonary rehabilitation (PR) in cachectic COPD patients were investigated. METHODOLOGY/PRINCIPAL FINDINGS: In a multicenter, randomized, double-blind, placebo-controlled trial, 33 cachectic COPD patients were randomly assigned PR with intravenous ghrelin (2 µg/kg) or placebo twice daily for 3 weeks in hospital. The primary outcomes were changes in 6-min walk distance (6-MWD) and the St. George Respiratory Questionnaire (SGRQ) score. Secondary outcomes included changes in the Medical Research Council (MRC) scale, and respiratory muscle strength. At pre-treatment, serum GH levels were increased from baseline levels by a single dose of ghrelin (mean change, +46.5 ng/ml; between-group p<0.0001), the effect of which continued during the 3-week treatment. In the ghrelin group, the mean change from pre-treatment in 6-MWD was improved at Week 3 (+40 m, within-group p = 0.033) and was maintained at Week 7 (+47 m, within-group p = 0.017), although the difference between ghrelin and placebo was not significant. At Week 7, the mean changes in SGRQ symptoms (between-group p = 0.026), in MRC (between-group p = 0.030), and in maximal expiratory pressure (MEP; between-group p = 0.015) were better in the ghrelin group than in the placebo group. Additionally, repeated-measures analysis of variance (ANOVA) indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (p = 0.049) and MEP (p = 0.021). Ghrelin treatment was well tolerated. CONCLUSIONS/SIGNIFICANCE: In cachectic COPD patients, with the safety profile, ghrelin administration provided improvements in symptoms and respiratory strength, despite the lack of a significant between-group difference in 6-MWD. TRIAL REGISTRATION: UMIN Clinical Trial Registry C000000061

Adverse events.

<p>Values are presented as n (% of group). * One patient developed lung cancer 2 years and 9 months after study treatment.</p

Patients’ baseline characteristics. ^*

<p>Data are presented as means (SD), and the minimum and maximum values unless otherwise stated. BMI = body mass index; FEV₁ = forced expiratory volume in one second; FVC = forced vital capacity; ICPET = incremental cardiopulmonary exercise testing; ICS = inhaled corticosteroids; LABA = long-acting β₂-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting β₂-agonist; SAMA = short-acting muscarinic antagonist; VC = vital capacity.</p>*<p>The groups shown represent only patients analyzed for efficacy. Medications are not mutually exclusive, and data are presented separately.</p>†<p>Analyzed using a Wilcoxon rank sum test.</p>‡<p>Analyzed using a Fisher’s exact test.</p

Change from pre-treatment in 6-min walk distance (6-MWD), Medical Research Council (MRC) score, and maximal expiratory pressure (MEP) over time.

<p>Open circles, ghrelin; closed circles, placebo. Data are presented as mean differences±SE. * p<0.05: change between pre- and post-treatment (within-group difference). ^† p<0.05: change between pre-treatment and post-treatment (between ghrelin and placebo group difference). ^‡ p<0.05: time course effect of ghrelin versus placebo by repeated-measures ANOVA. A) In both groups, 6-MWD increases significantly to a similar level from pre-treatment at Week 3. Prolonged effects can be seen in the ghrelin group at Week 7, though the improvement in 6-MWD declined in the placebo group. B) Though the MRC score became progressively worse in the placebo group, the maintained effects in the MRC score can be seen in the ghrelin group at Week 7. C) Repeated-measures ANOVA indicated significant time course effects of ghrelin versus placebo in MEP (F (2, 51) = 4.17, p = 0.021).</p

Changes in pre-treatment exercise capacity, pulmonary function and other parameters during pulmonary rehabilitation with ghrelin or placebo.

<p>Data are means (SE), or mean effect (95% CI; p value) unless otherwise indicated. BP = blood pressure; FEV₁ = forced expiratory volume in one second; FVC = forced vital capacity; IL = interleukin; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MRC = medical research council; ND = not done; NE = norepinephrine; PFT = pulmonary function test; VC = vital capacity.</p>*<p>p<0.05,</p>**<p>p<0.01: change between pre-treatment and post-treatment within-group difference.</p

Change from pre-treatment in St. George Respiratory Questionnaire (SGRQ) scores over time.

<p>Open circles, ghrelin; closed circles, placebo. Data are presented as mean differences±SE. * p<0.05: change between pre- and post-treatment (within-group difference). ^† p<0.05: change between pre-treatment and post-treatment (between ghrelin and placebo group difference). ^‡ p<0.05: time course effect of ghrelin versus placebo by repeated-measures ANOVA. At Week 3, marked improvements in SGRQ scores are not seen in both groups. However, SGRQ scores, especially SGRQ symptom scores, are significantly improved in the ghrelin group at Week 7. B) Repeated-measures ANOVA indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (F (2, 51) = 3.19, p = 0.049).</p

Changes in pre-treatment scores of health-related quality of life during pulmonary rehabilitation with ghrelin or placebo

<p>Data are means (SE), or mean effect (95% CI; p value) unless otherwise indicated. SGRQ = St. George Respiratory Questionnaire; SF 36 = short-Form 36.</p>*<p>p<0.05,</p>**<p>p<0.01: change between pre-treatment and post-treatment within-group difference.</p

Trial profile.

<p>Trial profile.</p