Safety
Nine cardiac events occurred during the entire treatment period, with a cumulative rate of 58.7%. Of these, three required intravenous medications [severe adverse events (SAEs)]: one for exacerbating cardiac failure due to non-steroid anti-inflammatory drug administration for pain and two for septic shock from aspiration pneumonia. Six patients changed their oral medications: one each for increased pleural effusion, asymptomatic elevation of BNP (SAE), increased arrhythmia, digitalis discontinuation due to atrioventricular block, progressive renal dysfunction due to increased diuretics administered before study entry (SAE) [17] and change in prescription dose due to miscommunication. The cumulative rates of the cardiac events are shown in Fig. 2a.
A total of 11 SAEs occurred in 8 patients: 3 deaths [2 developed sepsis due to aspiration pneumonia (as described above), and 1 choked]. Other SAEs included congestive heart failure triggered by pneumonia, hospitalization due to electrolyte abnormalities and increased arrhythmias associated with dehydration caused by heat shock, gastrostomy due to swallowing dysfunction, appendicitis, and recurrent diarrhea (as described above).
Survival rate
The 144-week survival rate in this study was 80.7%. None of the patients died of heart failure. As this was an open-label, single-arm study, no control data were available. Although bias cannot be ruled out, we compared the results with those of 35 patients with dystrophinopathy (26 with DMD, six with BMD, and three carriers), who showed BNP levels > 100 pg/mL at the NHO Osaka Toneyama Medical Center in 2019. The age and BNP levels of these patients were comparable to those of the participants, and FS was better than that of the participants (Table 1). Nonetheless, 18 patients died within 144 weeks (13 with DMD, four with BMD, one carrier, including 11 deaths due to heart failure). The log-rank test using the Kaplan–Meier method showed p = 0.039 (Fig. 2b).
Table 1. Profiles of tranilast-treated and untreated patients.
|
Tranilast treated
|
Tranilast untreated
|
p value
|
Disease
|
|
|
|
DMD
|
13 (72.2%)
|
26 (74.3%)
|
0.213
|
BMD
|
3 (16.7%)
|
6 (17.1%)
|
|
Carrier
|
0
|
3 (8.6%)
|
|
LGMD
|
2 (11.1%)
|
0
|
|
Sex: Male/Female
|
16/2
|
32/3
|
1.000
|
Age: Average ± SD
|
36.8±15.6
|
39.4±15.9
|
0.582
|
BNP: Median (IQR)
|
185 (132–260)
|
142 (109–245)
|
0.430
|
FS: Average ± SD
|
10.2±6.4
|
15.4±7.8 (n=23)
|
0.014
|
Abbreviations: SD: standard deviation, IQR: interquartile range, DMD: Duchenne muscular dystrophy, BMD: Becker muscular dystrophy, BNP: brain natriuretic peptide, FS: fractional shortening, LGMD: limb-girdle muscular dystrophy
Cardiac function
The geometric mean (GM) BNP levels were maintained for 48 weeks. Subsequently, there was an increasing trend, but the 95% CI of the rate of change from baseline was 0, except at 144 weeks (Figure 3a). The GM of hANP also maintained baseline values until 48 weeks, and then showed an increasing trend. However, the 95% CI of the rate of change from baseline was 0 for all periods (Additional file 1: Table S1). The GM of cTnT increased from 0.026 at baseline to 0.030 after the first 4 weeks of treatment but remained almost unchanged during the overall study period. The 95% CI for the rate of change from baseline included 0 for all periods except at 24 weeks (Additional file 1: Table S2).
Echocardiographic findings showed that FS exceeded baseline for up to 72 weeks after the start of treatment, which was when the trend began decreasing. However, the 95% CI for the change from baseline included zero at all time points (Figure 3b).
Holter electrocardiography showed a slight downward trend in the mean heart rate. The total number of premature ventricular contractions mildly increased for up to 48 weeks, followed by a downward trend (Additional file 1: Table S3).
TRPV2 expression in peripheral blood mononuclear cell surface
This analysis was an essential item before and after 4 weeks of treatment and an effort item after 12 weeks. Therefore, we retrieved the data of only 4–6 patients after the 12-week mark. However, all the patients maintained lower levels after treatment throughout the study (Figure 4).
Skeletal muscle indices
We evaluated the CK levels and pinch force as skeletal muscle indices. As the participants in this study had advanced diseases, the median CK level was 221 U/L (interquartile range, IQR: 152–284 U/L). Although no significant changes were observed after the treatment, a downward trend was observed after 48 weeks. The median pinch force was as low as 0.40 N (IQR: 0.2–0.6) at baseline. Although a slight decreasing trend was observed, no significant differences were detected (Additional file 1: Table S4).
Renal function
One patient showed progressive renal dysfunction in the short-term treatment period due to increased diuretics administered before study enrollment (described above). The details of this patient have been reported in a previous paper [17]. Except for this single case, no serious adverse events were associated with renal dysfunction. Although renal function values showed an increasing trend over time, the differences were not significant (Additional file 1: Table S5).
Self-questionnaire of quality of life
No MDQoL-60 items, except sex, showed obvious changes at 48 weeks (Additional file 1: Table S6). SF-12 showed no apparent changes, except for role-emotional article at 24 weeks (Additional file 1: Table S7).