Lessons learnt
| |
▪ Thus far, there are no definitive specific curative or preventative therapies available for vestibular migraine (VM). ▪ This is the first pragmatic phase III, double-blind, randomized placebo-controlled superiority trial in adults with definite or probable VM comparing metoprolol as a prophylactic medication against placebo. ▪ There are important implications for the planning stage of future randomized controlled trials in VM with respect to placebo or nonspecific and drug-specific effects. ▪ The PROVEMIG trial was prematurely ended due to insufficient recruitment. Reasons for the poor participant accrual were multifactorial and included lowered patient acceptability, unwillingness to accept the underlying intervention (being on antihypertensive therapy), comorbidities being contraindications for metoprolol, or uncertainties in diagnosis. ▪ For VM, there is a strong need to develop and validate clinically meaningful, consensus-based patient-centred core outcome measures considering both the vestibular- and headache-related disease burden and to assess their psychometric performance. |
Background
Methods
Study oversight
Study population and procedures
Study procedures
Event-driven diary documentation
Randomization, concealment and blinding
Study treatments
Statistical methodology and planned analyses
Protocol-defined efficacy outcomes and changes after trial commencement
Statistical efficacy analyses (including changes to protocol-specified analyses)
Safety and tolerability
Sample size considerations
Results
Premature termination of the trial
Patient disposition and baseline characteristics
Characteristics | Placebo (n = 65) | Metoprolol (n = 65) |
---|---|---|
Demographics | ||
Age (years) | ||
Mean (SD) | 42.8 (14.3) | 44.4 (14.2) |
Median (range) | 44.0 (19–70) | 45.0 (19–75) |
Male sex | ||
n (%) | 29 (44.6) | 22 (33.8) |
VM diagnostic criteria | ||
Probable VM, n (%) | 27 (41.5) | 23 (35.4) |
Definite VM, n (%) | 38 (58.5) | 42 (64.6) |
General physical examination | ||
Body mass index (kg/m2) | ||
Mean (SD) | 26.4 (5.5) | 25.9 (3.9) |
Median (range) | 25.3 (17.6–46.6) | 26.0 (17.5–38.1) |
Missing, n (%) | 5 (7.7) | 6 (9.2) |
Systolic blood pressure (mmHg) | ||
Mean (SD) | 134.1 (18.6) | 136.8 (16.3) |
Median (range) | 130.0 (100.0–188.0) | 136.0 (109.0–180.0) |
Missing, n (%) | 9 (13.8) | 6 (9.2) |
Diastolic blood pressure (mmHg) | ||
Mean (SD) | 85.8 (10.1) | 85.5 (9.7) |
Median (range) | 86.0 (66.0–108.0) | 84.0 (68.0–107.0) |
Missing, n (%) | 9 (13.8) | 6 (9.2) |
Heart rate (bpm) | ||
Mean (SD) | 74.8 (10.0) | 72.4 (10.3) |
Median (range) | 73.0 (60.0–100.0) | 73.0 (54.0–100.0) |
Missing, n (%) | 8 (12.3) | 6 (9.2) |
DHI total scorea | ||
Mean (SD) | 1.7 (0.8) | 1.6 (0.7) |
Median (range) | 1.7 (0.4–3.5) | 1.5 (0.4–3.1) |
Missing, n (%) | 1 (1.5) | 2 (3.1) |
Physical examination | ||
Cranial nerves: head-shaking nystagmus | ||
Patients with nystagmus, n (%) | 4 (6.2) | 4 (6.2) |
Missing, n (%) | 5 (7.7) | 6 (9.2) |
Coordination: Romberg’s test | ||
Patients with instability, n (%) | 3 (4.6) | 4 (6.2) |
Missing, n (%) | 2 (3.1) | 0 (0.0) |
Neuro-orthoptic examinations | ||
Smooth pursuit eye movement | ||
Saccaded, n (%) | 25 (41.5) | 29 (44.6) |
Missing, n (%) | 2 (1.5) | 0 (0.0) |
Absolute SVV deviation (°) | ||
Mean (SD) | 0.5 (1.2) | 0.4 (1.2) |
Median (range) | 0.0 (0.0–5.0) | 0.0 (0.0–6.0) |
Missing, n (%) | 3 (4.6) | 0 (0.0) |
Gaze-evoked nystagmus | ||
n (%) | 7 (10.8) | 14 (21.5) |
Missing, n (%) | 2 (3.1) | 0 (0.0) |
Nystagmus in the scanning laser ophthalmoscope | ||
n (%) | 8 (12.3) | 3 (4.6) |
Missing, n (%) | 12 (18.5) | 9 (13.8) |
Disturbed fixation suppression | ||
n (%) | 6 (9.2) | 3 (4.6) |
Missing, n (%) | 4 (6.2) | 1 (1.5) |
Oculography | ||
Spontaneous nystagmus (°/s) | ||
Velocity = 0, n (%) | 47 (72.3) | 48 (73.8) |
Velocity ≥1, n (%) | 16 (24.5) | 16 (24.5) |
Velocity ≥3, n (%) | 1 (1.5) | 1 (1.5) |
Missing, n (%) | 2 (3.1) | 1 (1.5) |
Gaze-evoked nystagmus (°/s) | ||
Velocity = 0, n (%) | 14 (21.5) | 7 (10.8) |
Velocity ≥1, n (%) | 43 (66.1) | 49 (75.3) |
Velocity ≥3, n (%) | 6 (9.2) | 10 (15.3) |
Missing, n (%) | 8 (12.3) | 9 (13.8) |
Bithermal caloric testing (normalized right–left difference (%) according to Jongkees’ formulab) | ||
Mean (SD) | −8.5 (20.5) | −6.9 (21.9) |
Median (range) | −10.8 (−58.3 to 73.0) | −5.9 (−82.9 to 71.4) |
Missing, n (%) | 6 (9.2) | 5 (7.7) |
Dosing and adherence to initial treatments
Primary and key secondary efficacy analyses
Na | Placebo | Metoprolol | |
---|---|---|---|
Primary end point | |||
Vertigo attacks, monthlyb incidence rates (95% CI)a | 114 | ||
Month 4 | 4.499 (3.295–5.704) | 4.202 (3.138–5.267) | |
Month 5 | 3.733 (2.527–4.939) | 3.428 (2.384–4.471) | |
Month 6 | 3.097 (1.914–4.281) | 2.796 (1.792–3.800) | |
Decay rate (95% CI), P value | 0.830 (0.776–0.887), <0.001 | ||
IRR (95% CI), P value | 0.983 (0.902–1.071), 0.696 | ||
Secondary end points | |||
Vertigo days, monthlyb incidence rates (95% CI)a | 114 | ||
Month 4 | 6.757 (5.067–8.447) | 5.278 (3.999–6.557) | |
Month 5 | 5.881 (4.126–7.637) | 4.319 (3.070–5.569) | |
Month 6 | 5.119 (3.326–6.912) | 3.534 (2.334–4.735) | |
Decay rate (95% CI), P value | 0.870 (0.821–0.923), <0.001 | ||
IRR (95% CI), P value | 0.940 (0.869–1.017), 0.125 | ||
Mean monthlyb MHDsc | 91 | ||
Months 4–6 | 2.400 (1.410–4.410) | 2.505 (1.488–4.215) | |
IRR (95% CI), P value | 1.048 (0.482–2.250), 0.904 |
Secondary End points | Nb | Placebo | Metoprolol |
---|---|---|---|
DHI mean total score | 91 | ||
LS mean changec (95% CI) | 0.159 (−0.252 to 0.570) | 0.080 (−0.310 to 0.470) | |
Difference vs. placebo (95% CI) | −0.079 (−0.360 to 0.201) | ||
P value | 0.577 | ||
Pursuit eye movement | 92 | ||
Patients achieving responsed, n (%) | 5 (11.6) | 8 (16.3) | |
OR (95% CI) | 0.132 (0.045–0.305) | 0.195 (0.092–0.416) | |
Difference vs. placebo, OR (95% CI) | 1.483 (0.454–5.277) | ||
P value | 0.520 | ||
SVV | 90 | ||
Patients achieving responsed, n (%) | 4 (9.5) | 2 (4.2) | |
OR (95% CI) | 0.105 (0.032–0.262) | 0.043 (0.012–0.179) | |
Difference vs. placebo, OR (95% CI) | 0.413 (0.055–2.235) | ||
P value | 0.322 |
Safety and tolerability
Safety assessment | Placebo (n = 59) | Metoprolol (n = 62) |
---|---|---|
Deaths, n | 0 | 0 |
Patients with SUSARs, n | 0 | 0 |
Patients with early termination from the study due to SAEsa, n (%) | 2 (3.4) | 1 (1.6) |
Treatment-related SAEs, n (%) | 1 (1.7) | 1 (1.6) |
Patients with at least one SAE, n (%); total number of SAEs | 8 (13.5); 10 | 6 (9.7); 7 |
Patients with early termination due to adverse eventsa, n (%) | 4 (6.7) | 8 (12.9) |