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VISION-DMD

Year of Publication: 2022

Journal: JAMA Neurology

Link: https://doi.org/10.1001/jamaneurol.2022.2480

PDF: https://jamanetwork.com/journals/jamaneu...article/2795670

Clinical Question

Is vamorolone as effective as prednisone for motor function in Duchenne muscular dystrophy while sparing growth and bone morbidities?

Bottom Line

In 121 steroid-naive boys aged 4 to <7 with DMD, vamorolone 6 mg/kg/day improved 24-week time-to-stand velocity by 0.06 rise/s over placebo (95% CI 0.02-0.10; p=0.002) and met the first 4 hierarchical secondary endpoints (including 6MWT +42 m and TTRW +0.24 m/s). Unlike prednisone, vamorolone did not reduce height percentile or bone turnover markers, supporting it as a safer alternative dissociative steroid for DMD.

        Major Points
        Multicenter (33 sites, 11 countries) double-blind placebo- and prednisone-controlled phase 2b/3 RCT, June 2018 - Feb 2021 (Guglieri 2022)
N=121 randomized; 114 completed 24-week period 1
Four arms: placebo, prednisone 0.75 mg/kg/day, vamorolone 2 mg/kg/day, vamorolone 6 mg/kg/day (1:1:1:1)
Boys aged 4 to <7 years; steroid-naive; genetically confirmed DMD
Primary endpoint: TTSTAND velocity change at 24 weeks for vamorolone 6 mg/kg vs placebo — MET (p=0.002)
Hierarchical secondaries: first 4 met (TTSTAND 2 mg/kg, 6MWT 6 mg/kg, 6MWT 2 mg/kg, TTRW 6 mg/kg); fifth (TTRW 2 mg/kg) failed
Vamorolone vs prednisone for motor efficacy: similar for TTSTAND, 6MWT, NSAA; slightly less effect on TTRW and TTCLIMB
Height percentile: vamorolone 6 mg/kg +3.86 vs prednisone -1.88 (p=0.02) — no growth stunting
Bone turnover markers (osteocalcin, P1NP, CTX1) fell with prednisone but were preserved with vamorolone (all p<0.001)
Baseline ACTH stimulation showed high adrenal insufficiency prevalence in DMD; all drug arms suppressed HPA axis further
Safety profile broadly similar (TEAEs: 79% placebo, 84% prednisone, 83% vam 2 mg/kg, 89% vam 6 mg/kg); 1 prednisone withdrawal for personality change
Basis for FDA approval of vamorolone (Agamree) in October 2023 for DMD aged ≥2 years

      

Design

Study Type: Multicenter double-blind placebo- and prednisone-controlled phase 2b/3 RCT with crossover period 2 (NCT03439670)

Randomization: 1

Blinding: Double-blind, double-dummy (suspension + tablet) for 24 weeks

Follow-up Duration: 24 weeks period 1 (reported here); 24-week period 2 crossover separately

Sample Size: 133

Analyzed: 121

Analysis: Sequential hierarchical testing with 2-sided α=0.05; MMRM with fixed effects for treatment, week, baseline, age stratum, and treatment-by-week interaction

Inclusion Criteria

Boys aged 4 to <7 years at screening
Genetic confirmation of DMD (loss-of-function dystrophin variant) or absent muscle dystrophin
Steroid-naive (no prior corticosteroid use for DMD)
Able to perform time-to-stand from supine in <10 seconds
Parent/guardian provided informed consent

Exclusion Criteria

Prior corticosteroid exposure for DMD
Inability to stand from supine within 10 seconds
Concurrent systemic condition precluding motor assessment
Known adrenal insufficiency at baseline (though discovered incidentally in many)
Active infection or other exclusion per protocol

Baseline Characteristics

Characteristic	Control	Active
N	30	30
Age	5.4 years (mean)	5.4 years (mean)
6MWT baseline	313 m (SD 56) placebo / 316 m prednisone	343 m (vam 2 mg/kg) / 355 m (vam 6 mg/kg)
TTSTAND baseline	Mean rise/s across groups similar	Similar across arms
NSAA baseline	18.9 (placebo) / 17.2 (prednisone)	21.2 (vam 2) / 18.9 (vam 6)
Baseline adrenal insufficiency by ACTH	~20% of participants
TTRW baseline		1.9 / 1.7 m/s

Arms

Field	Control	Prednisone 0.75 mg/kg/day	Vamorolone 2 mg/kg/day	Vamorolone 6 mg/kg/day
N	30	31	30	30
Intervention	Placebo suspension + placebo tablet daily	Prednisone tablet + placebo suspension daily	Vamorolone 2 mg/kg/day suspension + placebo tablet daily	Vamorolone 6 mg/kg/day suspension + placebo tablet daily
Duration	24 weeks (then crossover to vamorolone in period 2)	24 weeks (then crossover to vamorolone in period 2)	24 weeks (continued in period 2)	24 weeks (continued in period 2)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change from baseline to week 24 in TTSTAND velocity (rises per second), vamorolone 6 mg/kg vs placebo	Primary	-0.01 rise/s (SD 0.06, n=28)	0.05 rise/s (SD 0.07, n=27)		p=0.002
TTSTAND velocity vamorolone 2 mg/kg vs placebo (1st secondary)	Secondary	-0.01 rise/s	0.04 rise/s	LSM diff 0.05 (95% CI 0.01-0.08)	p=0.02
6MWT vamorolone 6 mg/kg vs placebo (2nd secondary)	Secondary	-23.9 m	28.8 m	LSM diff 41.6 m (95% CI 14.2-68.9)	p=0.003
6MWT vamorolone 2 mg/kg vs placebo (3rd secondary)	Secondary	-23.9 m	31.0 m	LSM diff 37.1 m (95% CI 9.6-64.7)	p=0.009
TTRW velocity vamorolone 6 mg/kg vs placebo (4th secondary)	Secondary	0.02 m/s	0.28 m/s	LSM diff 0.24 (95% CI 0.09-0.39)	p=0.002
TTRW velocity vamorolone 2 mg/kg vs placebo (5th secondary)	Secondary	0.02 m/s	0.16 m/s	LSM diff 0.13 (95% CI -0.03 to 0.28)	p>0.05 (FAILED, ended hierarchy)
NSAA total score vamorolone 6 mg/kg vs placebo (exploratory)	Secondary	-0.73	2.85	LSM diff 3.57 (95% CI 1.90-5.25)	p<0.001
Height percentile vamorolone 6 mg/kg vs prednisone	Secondary	-1.88 (prednisone)	+3.86 (vam 6 mg/kg)	LSM diff 4.98 (95% CI 0.75-9.21)	p=0.02
Osteocalcin change (bone formation) vamorolone 6 mg/kg vs prednisone	Secondary	-15.5 ng/mL (prednisone)	-0.17 ng/mL (vam 6 mg/kg)	LSM diff 17.1 (95% CI 9.3-24.9)	p<0.001
Any TEAE	Adverse	23/29 (79%)	25/28 (89%) vam 6 mg/kg; 25/30 (83%) vam 2 mg/kg; 26/31 (84%) prednisone		Similar across arms
Serious AE	Adverse	0	1 viral gastroenteritis (vam 2 mg/kg), unrelated		Rare
Discontinuation for AE	Adverse	0	1 on prednisone (personality change)		Only prednisone
Height percentile decline	Adverse	NA	Seen with prednisone not vamorolone		p=0.02
Adrenal suppression (low cortisol post-ACTH)	Adverse	4/20 (20%)	All drug arms >85%		Expected class effect
Cushingoid features / weight gain	Adverse	Rare	More with prednisone than vamorolone (qualitative)		Qualitative
Bone biomarker declines	Adverse	None	Prednisone only (osteocalcin, P1NP, CTX1 all fell)		p<0.001 vs vamorolone
Vertebral fractures (incident)	Adverse	1 (placebo)	1 (prednisone, total 4 fractures in that patient)		Small numbers

Subgroup Analysis

Motor efficacy of vamorolone 6 mg/kg and 2 mg/kg was broadly similar to prednisone 0.75 mg/kg on TTSTAND, 6MWT, and NSAA, while 2 mg/kg vamorolone showed slightly smaller effect on TTRW and TTCLIMB than prednisone. Height percentile, bone biomarkers (osteocalcin, P1NP, CTX1), and some psychosocial measures (PARS III anxiety/depression) favored vamorolone over prednisone. Baseline ACTH stimulation test flagged ~20% of boys as adrenally insufficient pre-treatment — an unexpected finding suggesting DMD itself may impact HPA axis, and raising the possibility that some efficacy of both drugs includes treatment of latent adrenal insufficiency.

Criticisms

Short 24-week primary endpoint; long-term motor and safety outcomes (bone, cognition, cardiac) require period 2 and extension data
Narrow age range (4 to <7 y) and steroid-naive — does not generalize to older boys or those already on steroids
Single daily dose of each drug studied — no dose-titration or alternative prednisone regimens (weekend-only, deflazacort) compared
Vamorolone 6 mg/kg showed greater cortisol suppression than prednisone — long-term adrenal consequences unclear
COVID-19 pandemic necessitated remote assessments; 9.6% of TTSTAND at 24 weeks done remotely, with possible measurement variability
Primarily White (83%) cohort — racial/ethnic generalizability limited

Funding

ReveraGen BioPharma, Santhera Pharmaceuticals, NIH, and EU Horizon 2020 (BIND)

Based on: VISION-DMD (JAMA Neurology, 2022)

Content summarized and formatted by NeuroTrials.ai.

VISION-DMD

(2022)

Objective

Vamorolone 2 or 6 mg/kg/day vs prednisone 0.75 mg/kg/day vs placebo — to test whether a dissociative steroidal anti-inflammatory retains efficacy while reducing corticosteroid safety concerns in boys aged 4 to <7 with Duchenne muscular dystrophy.

Study Summary

• Vamorolone 6 mg/kg/day improved time-to-stand velocity by 0.06 rise/s over placebo at 24 weeks (p=0.002).
• First four hierarchical secondary endpoints all met; fifth (TTRW for 2 mg/kg dose) failed.
• 6-minute walk distance improved by 42 m (6 mg/kg) and 37 m (2 mg/kg) versus placebo (both p<0.01).
• Unlike prednisone, vamorolone did not reduce height percentile (+3.86 vs -1.88; p=0.02) or bone turnover markers.
• Efficacy across a 3-fold dose range (2-6 mg/kg) was similar to prednisone for TTSTAND, 6MWT and NSAA.
• Supports vamorolone as a safer alternative to prednisone for DMD — basis for FDA approval 2023.

Intervention

Randomized 1:1:1:1 to placebo, prednisone 0.75 mg/kg/day, vamorolone 2 mg/kg/day, or vamorolone 6 mg/kg/day for 24 weeks, followed by crossover period 2 where placebo and prednisone patients switched to vamorolone.

Inclusion Criteria

Steroid-naive boys aged 4 to <7 years with genetically confirmed DMD (loss-of-function variant or absent dystrophin) who could stand from supine in <10 seconds at screening.

Study Design

Arms: Placebo vs Prednisone 0.75 mg/kg/day vs Vamorolone 2 mg/kg/day vs Vamorolone 6 mg/kg/day

Patients per Arm: Placebo 30; Prednisone 31; Vamorolone 2 mg/kg 30; Vamorolone 6 mg/kg 30

Outcome

• Primary: TTSTAND velocity at 24 wk — vamorolone 6 mg/kg 0.05 vs placebo -0.01 rise/s; LSM diff 0.06 (95% CI 0.02-0.10); p=0.002
• First secondary: TTSTAND velocity vamorolone 2 mg/kg vs placebo; LSM diff 0.05 (95% CI 0.01-0.08); p=0.02
• 6MWT vamorolone 6 mg/kg vs placebo +41.6 m (95% CI 14.2-68.9); p=0.003; 2 mg/kg +37.1 m (95% CI 9.6-64.7); p=0.009
• TTRW velocity 6 mg/kg: +0.24 m/s (95% CI 0.09-0.39); p=0.002; 2 mg/kg fifth-rank secondary failed (p>0.05)
• Safety: height percentile +3.86 vamorolone 6 mg/kg vs -1.88 prednisone (p=0.02); bone turnover markers preserved with vamorolone

Clinical Question

In steroid-naive boys aged 4 to <7 years with Duchenne muscular dystrophy, does vamorolone 2 or 6 mg/kg/day improve motor function compared with placebo and reduce corticosteroid-associated morbidities compared with prednisone 0.75 mg/kg/day over 24 weeks?

Bottom Line

Major Points

Multicenter (33 sites, 11 countries) double-blind placebo- and prednisone-controlled phase 2b/3 RCT, June 2018 - Feb 2021 (Guglieri 2022)
N=121 randomized; 114 completed 24-week period 1
Four arms: placebo, prednisone 0.75 mg/kg/day, vamorolone 2 mg/kg/day, vamorolone 6 mg/kg/day (1:1:1:1)
Boys aged 4 to <7 years; steroid-naive; genetically confirmed DMD
Primary endpoint: TTSTAND velocity change at 24 weeks for vamorolone 6 mg/kg vs placebo — MET (p=0.002)
Hierarchical secondaries: first 4 met (TTSTAND 2 mg/kg, 6MWT 6 mg/kg, 6MWT 2 mg/kg, TTRW 6 mg/kg); fifth (TTRW 2 mg/kg) failed
Vamorolone vs prednisone for motor efficacy: similar for TTSTAND, 6MWT, NSAA; slightly less effect on TTRW and TTCLIMB
Height percentile: vamorolone 6 mg/kg +3.86 vs prednisone -1.88 (p=0.02) — no growth stunting
Bone turnover markers (osteocalcin, P1NP, CTX1) fell with prednisone but were preserved with vamorolone (all p<0.001)
Baseline ACTH stimulation showed high adrenal insufficiency prevalence in DMD; all drug arms suppressed HPA axis further
Safety profile broadly similar (TEAEs: 79% placebo, 84% prednisone, 83% vam 2 mg/kg, 89% vam 6 mg/kg); 1 prednisone withdrawal for personality change
Basis for FDA approval of vamorolone (Agamree) in October 2023 for DMD aged ≥2 years

Study Design

Study Type: Multicenter double-blind placebo- and prednisone-controlled phase 2b/3 RCT with crossover period 2 (NCT03439670)
Randomization: Yes
Blinding: Double-blind, double-dummy (suspension + tablet) for 24 weeks
Sample Size: 133
Follow-up: 24 weeks period 1 (reported here); 24-week period 2 crossover separately

Primary Outcome

Definition: Change from baseline to week 24 in TTSTAND velocity (rises per second), vamorolone 6 mg/kg vs placebo

Control	Intervention	HR/OR	P-value
-0.01 rise/s (SD 0.06, n=28)	0.05 rise/s (SD 0.07, n=27)	- (0.02 to 0.10)	p=0.002

Limitations & Criticisms

Short 24-week primary endpoint; long-term motor and safety outcomes (bone, cognition, cardiac) require period 2 and extension data
Narrow age range (4 to <7 y) and steroid-naive — does not generalize to older boys or those already on steroids
Single daily dose of each drug studied — no dose-titration or alternative prednisone regimens (weekend-only, deflazacort) compared
Vamorolone 6 mg/kg showed greater cortisol suppression than prednisone — long-term adrenal consequences unclear
COVID-19 pandemic necessitated remote assessments; 9.6% of TTSTAND at 24 weeks done remotely, with possible measurement variability
Primarily White (83%) cohort — racial/ethnic generalizability limited

Citation

View Original Publication →

VISION-DMD

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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