Of the 33 randomized patients, 31completed the 3-week study; 2 patients in the ghrelin group discontinued study medications due to pneumonia and depression, respectively. Of the 31 patients who completed the randomized 3-week study, in the ghrelin group, one patient had infective enteritis after 3 weeks of medications, and one had low back pain due to lumbar spondylosis before and throughout the 3 weeks of medications. Two patients in the placebo group were lost to follow-up after the Week 3 measurements. Therefore, 29 patients (ghrelin, n
14; placebo, n
15) were included in the study analyses to ensure adequate efficacy evaluation using pre-protocol analysis. The mean BMI in the enrolled patients (n
29) was very low (mean±SD, 18.3±2.1 kg/m2
). The treatment groups were generally well-matched with regard to demographics and baseline characteristics ().
Exercise Tolerance and Gas Exchange Measurements
At both Week 3 and Week 7, there were no significant differences between the ghrelin and placebo groups in 6-MWD. In each group, at Week 3, a similar significant increase from pre-treatment in 6-MWD was observed (mean difference: ghrelin group +40 m, within group p
0.033 versus placebo group +35 m, within group p
0.013). The effect remained at Week 7 in the ghrelin group, whereas in the placebo group, the improvement in 6-MWD was reduced at Week 7 (mean difference: ghrelin group within group +47 m, p
0.017 versus placebo group +18 m, within group p
0.14) ( and ). To assess the time course efficacy of ghrelin versus placebo in 6-MWD, a repeated-measures ANOVA was performed. There was no significant time course effect of ghrelin versus placebo in 6-MWD (F (2, 51)
Changes in pre-treatment exercise capacity, pulmonary function and other parameters during pulmonary rehabilitation with ghrelin or placebo.
Change from pre-treatment in 6-min walk distance (6-MWD), Medical Research Council (MRC) score, and maximal expiratory pressure (MEP) over time.
In the ghrelin group, the peak
/HR were significantly increased by 1.2 ml/kg/min and 0.5 ml/beats, respectively, from pre-treatment (within-group p
0.019, respectively) (). However, there was no significant difference between the two groups in the peak
/HR. In the ghrelin group, the ventilatory equivalents for oxygen (
) was relatively improved by −3.9 from pre-treatment (within group p
Respiratory and Peripheral Muscle Strength
In the ghrelin group, at Week 3, the post-treatment increase in respiratory muscle strength, as indicated by MEP and MIP, was not significantly different from that in the placebo group, but at Week 7, the mean increase from pre-treatment in MEP (+15.6 cmH2
O) was significantly different from that in the placebo group (between group p
0.015) (). Furthermore, there was a significant time course effect of ghrelin versus placebo in MEP (repeated-measures ANOVA, F (2, 51)
At Week 3 and Week 7, there was no significant treatment effect between the two groups in grip strength ().
The present study is the first multicenter, randomized, double-blind, placebo-controlled study to assess the effect and safety of repeated ghrelin administration to very severe cachectic patients with COPD. The main results of this study can be summarized as follows. In the ghrelin group, single administration of ghrelin was accompanied by a significant increase in serum GH levels during 3-week treatment, and there was no significant difference in 6-MWD between ghrelin and placebo at Week 3 and at Week 7. With ghrelin, symptomatic improvements in SGRQ symptoms and MRC score were not obtained at Week 3, but significant differences between ghrelin and placebo were seen at Week 7. In the ghrelin group, no significant within-group improvement from pre-treatment was seen in respiratory muscle strength, as indicated by MEP and MIP, at Week 3, but there was a significant difference in MEP between ghrelin and placebo at Week 7. Repeated-measures ANOVA showed significant time course effects of ghrelin versus placebo in SGRQ symptoms and MEP. Finally, ghrelin treatment was well tolerated.
Ghrelin treatment may have beneficial, continuing effects after treatment on HRQoL and MRC measures in this population. Though this study was conducted to determine the effectiveness of ghrelin in cachectic COPD patients, considering a synergistic interaction between ghrelin and PR, the data of this study need to be interpreted with caution, because, especially in advanced stage patients, excessive exercise training may partially worsen the anabolic and catabolic balance 
. In the present study, which included patients with a lower exercise capacity and pulmonary function than those in the pilot study 
and more cachectic patients than those in other studies on PR 
, the 6-MWD after 3-week PR in the placebo group was decreased in 3 (20%) of the 15 patients. Since 5 patients (33%) in the placebo group found the initial training work rate intolerable, the initial training work rate remained at its initial setting. In addition, at Week 3, outcome measurements showed no improvements with ghrelin compared with placebo. These findings may represent patients’ variable responses to PR, which might have an influence on the effects of ghrelin. Of note, however, there were significant treatment effects of ghrelin in both SGRQ symptoms and MRC score. In addition, the treatment tended to improve the total SGRQ score by more than 4 points; a clinically meaningful improvement. These effects were not observed soon after the 3 week-treatment, but were seen 4 weeks after treatment, maintaining the improvement obtained in 6-MWD at Week 3. Similarly, 4 weeks after treatment, the effect of ghrelin on respiratory muscle strength was confirmed, though it has been reported that GH alone does not increase strength in healthy elderly 
. Furthermore, repeated-measures ANOVA indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms and MEP. Our data suggest that improving of the respiratory muscle strength, the O2
pulse, and the ventilatory equivalents for oxygen may serve as a mechanism by which ghrelin-PR combination treatment improved symptoms, though further examination is needed to understand the precise mechanism. These findings suggest that repeated ghrelin administration may have beneficial, sustained effects after administration on symptoms through GH-dependent and/or -independent mechanisms.
Cachectic elderly patients with COPD who were given intravenous ghrelin showed a continuous increase of pulsatile GH secretion in the present study. There is evidence that insufficiency of sarcopenia-related hormones, such as GH and IGF-1, may contribute to cachexia 
. Observational studies in cachectic COPD patients have found decreased levels of these hormones 
. In the present study, despite significant increases in GH secretion levels throughout the 3-week treatment and respiratory muscle strength, ghrelin provided only a significant within-group increase in exercise performance, and a relative within-group increase in IGF-1 levels and body weight. Furthermore, ghrelin did not affect food intake, grip strength or plasma norepinephrine levels at rest in the present study. Although DEXA should be performed a greater number of times during the trial, at Week 3 ghrelin did not show any effects on whole lean body mass. Meanwhile, previous studies showed that ghrelin administration induced a positive energy balance and weight gain 
, increased food intake 
, and decreased sympathetic nervous activity 
. The discrepancy may be explained by the fact that the intensity of exercise training for some cachectic participants counteracted the effects of ghrelin, though lower extremity exercise training at higher intensity produces greater benefits than lower intensity training 
. As one of the reasons, the patients treated with both ghrelin and exercise training gained at Week 1, which was not seen in the placebo group. However, this weight gain reduced by Week 3. At Week 7, the weight was regained (). The days of attending PR in the ghrelin group was negatively correlated with the increase in body weight from Week 3 to Week 7 (r
0.003). We speculate that the unintended excessive exercise permitted by ghrelin administration with antidepressant-like effects 
might prevent the obtained results. Nevertheless, these findings suggest that clinical interventions with ghrelin may help cachectic COPD patients via inhibiting somatopause and regulating metabolic balance.
The participants in the present study tolerated daily administration of ghrelin for 3 weeks (); the most frequent ghrelin-related side effects were mild and similar to those of previous reports 
, as well as with those of GH administration by injection 
. However, given that the previous studies of the responses of ghrelin in proliferation, including tumor development, have demonstrated conflicting findings 
, more studies of the safety of ghrelin treatment are necessary before clinical application.
This study had some limitations. First, the number of participants was small, and few females were included in this trial. Second, the duration of the study was short. A more effective exercise training program, considering its intensity and frequencies, should have been conducted. Additional studies are needed to evaluate a more suitable regimen of ghrelin-PR.
In conclusion, ghrelin administration provided sustained improvements in symptoms and respiratory strength in cachectic COPD patients. Development of ghrelin administration methods may offer potential advantages over the currently approved treatment options for COPD. The lack of a significant between-group difference in exercise tolerance may result from the exercise training program conducted as the combination therapy. Careful examination is needed to develop more effective administration methods of ghrelin and combination therapy with ghrelin.