A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy

Abstract

Objective: To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD).

Methods: Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg^-1·d^-1, tadalafil 0.6 mg·kg^-1·d^-1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome.

Results: Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state.

Conclusions: Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age.

Clinicaltrialsgov identifier: NCT01865084.

Classification of evidence: This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy.

Figure 1. Patient disposition

Figure 2. Mean change in efficacy measures

(A) Mean change from baseline to week 48 in 6MWD. (B) Mean change from baseline to week 48 in NSAA (linearized score on scale of 0–100). (C) Mean 6MWD (meters), baseline to week 48. (D) Mean percent of predicted 6MWD, baseline to week 48. *Primary efficacy endpoint. Analyses for each efficacy parameter included all patients with nonmissing baseline and at least 1 nonmissing postbaseline value (for 6MWD: n = 113 in placebo, 101 in tadalafil 0.3 mg/kg, and 111 for tadalafil 0.6 mg/kg; for NSAA: n = 116 in placebo, 102 in tadalafil 0.3 mg/kg, and 112 for tadalafil 0.6 mg/kg). LS = least squares; NSAA = North Star Ambulatory Assessment; 6MWD = 6-minute walk distance.

Figure 3. Mean change in total and shoulder level PUL score

(A) Total PUL score in the total population (n = 114 in placebo, 99 in tadalafil 0.3 mg/kg, and 107 in tadalafil 0.6 mg/kg). (B) Total PUL score in patients ≤10 years of age (n = 95 in placebo, 68 in tadalafil 0.3 mg/kg, and 85 in tadalafil 0.6 mg/kg). (C) Total PUL score in patients >10 years of age (n = 19 in placebo, 31 in tadalafil 0.3 mg/kg, and 22 in tadalafil 0.6 mg/kg). (D) Shoulder-level PUL subscore in the total population (n = 116 in placebo, 101 in tadalafil 0.3 mg/kg, and 111 in tadalafil 0.6 mg/kg). (E) Shoulder-level PUL subscore in patients ≤10 years of age (n = 96 in placebo, 69 in tadalafil 0.3 mg/kg, and 89 in tadalafil 0.6 mg/kg). (F) Shoulder-level PUL subscore in patients >10 years of age (n = 20 in placebo, 32 in tadalafil 0.3 mg/kg, and 22 in tadalafil 0.6 mg/kg). Changes in total PUL score are from a total score range of 0 to 72; changes in shoulder-level PUL are from a total score range of 0 to 16. Higher score represents better function. Analyses for each efficacy parameter included all patients with nonmissing baseline and at least 1 nonmissing postbaseline value. *p < 0.05. LS = least squares; PUL = Performance of Upper Limb.