Periodic Salbutamol in Facioscapulohumeral Muscular Dystrophy: A Randomized Controlled Trial

Article Outline

• Abstract
• Methods
  • Patient Selection
  • Design
  • Study Medication
  • Assessments and Outcome Measures
  • Testing Muscle Strength
  • Statistical Analysis
• Results
  • Patient Description
  • Efficacy
  • Safety
  • Drug Assays
• Discussion
  • Methodological Issues
  • Study Limitations
• Conclusion
• Acknowledgments
• References
• Copyright

Abstract 

Payan CA, Hogrel JY, Hammouda EH, Lacomblez L, Ollivier G, Doppler V, Eymard B, Attarian S, Pouget J, Desnuelle C, Laforêt P. Periodic salbutamol in facioscapulohumeral muscular dystrophy: a randomized controlled trial.

Objective

To evaluate the effects on muscle strength of salbutamol administered for 6 months using a periodic regimen in patients presenting with facioscapulohumeral muscular dystrophy (FSHD).

Design

Placebo-controlled double-blind randomized study.

Setting

Three clinical centers involved in neuromuscular disorders.

Participants

Ambulatory patients (N=112), 56 per group, with genetically confirmed FSHD, age 18 to 60 years.

Interventions

Salbutamol (sustained released formulation) administered orally at a daily dose of 16mg using a periodic dosage regimen (3wks on, 1wk off).

Main Outcome Measures

Muscle strength was assessed with quantitative muscle testing (QMT), manual muscle testing (MMT), and timed motor tests. Patients were evaluated at baseline, and 3 and 6 months later. Plasma drug assays were carried out at each visit.

Results

There was no significant change with periodic use of salbutamol in the total composite QMT z-score, MMT score, or timed motor tests. Salbutamol was well tolerated. Lack of efficacy did not seem to be related to plasma concentrations, which were within the expected range.

Conclusions

Results from this study and previous controlled trials preclude at present the use of salbutamol as routine treatment for FSHD, even if we cannot exclude improvement from anabolic effects with a longer duration of treatment.

Key Words: Clinical trial, Phase III, Facioscapulohumeral muscular dystrophy, Pharmacokinetics, Rehabilitation, Salbutamol

List of Abbreviations: ECG, electrocardiogram, FSHD, facioscapulohumeral muscular dystrophy, MMT, manual muscle testing, MVIC, maximum voluntary isometric contractions, QMT, quantitative muscle testing, VAS, visual analog scale

FACIOSCAPULOHUMERAL muscular dystrophy is one of the most common inherited neuromuscular diseases, with autosomal transmission and specific pattern of muscle weakness initially affecting the facial and shoulder girdle muscles. The decline in strength/rate of progression of the disease is highly variable, with generally slow progression and frequent occurrence of walking difficulties, 20% of patients becoming wheelchair-bound.¹ Genetic analysis shows a contraction of the D4Z4 repeat on the subtelomere of chromosome 4 (4q35) in 95% of cases,² but precise pathogenetic mechanism remains unidentified. At present, there is no therapy which modifies the progress of the disease. Preclinical and clinical data have shown that beta2-adrenergic agonists such as albuterol (salbutamol) or clenbuterol increase muscle strength and muscle mass.³, ⁴, ⁵, ⁶ A clinical pilot study⁷ conducted on 15 FSHD patients treated for 12 weeks with albuterol (16 mg/day) showed an increase in muscle strength. Two controlled studies⁸, ⁹ comparing albuterol with placebo showed nonsignificant improvement after 6 months of treatment along with increases in lean body mass. After 1 year, improvement in muscle strength was no longer observed, suggesting that any anabolic effect may be transient.⁸ We hypothesized that desensitization of beta2-adrenoreceptors with chronic use would weaken the effects of agonists and mask any effect on muscle strength.¹⁰ To test this hypothesis we conducted a controlled study using a periodic regimen of salbutamol administration consisting of 3 weeks of drug administration followed by 7 days without treatment, for 6 months.

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Methods 

Patient Selection 

Patients with a genetically confirmed diagnosis of FSHD (D4Z4 deletion at 4q35 with number of repeats lower than 10) were included between November 2001 and June 2003 at 3 French centers. Patients aged 18 to 60 years showing typical FSHD symptomatology with shoulder involvement (Brooke grade ≥2) who remained ambulant were included. Contraceptive use was required in woman of childbearing age. Patients were not included if they had contra-indications to beta-agonist treatment (hypertension, arrhythmia, diabetes, hypokalemia), used beta-blockers, steroids, sympathomimetics, or antidepressants, or presented any locomotor disease that could interfere with strength assessment. Patients had blood tests, an ECG and 24-hour ambulatory ECG monitoring, and were not included in case of significant arrhythmias or high-degree atrioventricular block. Physiotherapy initiated more than 3 months before inclusion could be maintained unchanged. Patients gave written informed consent before participation.

Design 

Patients were randomly and equally allocated to either salbutamol or placebo (fig 1). Randomization was stratified by center. The active treatment and placebo were identical in appearance, and were provided as individual numbered sealed boxes at each visit by the site pharmacy. Evaluations of muscle strength were performed by physiotherapists at entry and at 3 and 6 months after the start of treatment. Patients were examined by a cardiologist at month 1 to confirm participation in the trial. Patients stopped treatment at month 6 and were reassessed 3 months later for muscle strength and late side-effects. Patients, investigators, and physiotherapists were blind to group assignment.

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• Fig 1. 

  Study flowchart.

Study Medication 

Treatment provided was 4-mg sustained-release salbutamol tablets. In each cycle of 4 weeks, active medication or placebo was given for 3 weeks then no treatment for 1 week. During the treatment weeks, the dose was increased from 1 tablet bid (8mg salbutamol daily in the active group) in the first week, to 2 tablets bid (16mg daily) for the next 2 weeks. Six of these 4-week cycles made up a study duration of 24 weeks. Patients were seen at the end of week 11 and in week 23 before stopping treatment. In case of side-effects, dosage was flexible and could be reduced to a minimum of 2 tablets.

Assessments and Outcome Measures 

Table 1 presents the measurements performed at each visit. The primary criterion was MVIC measured by QMT in 11 functional muscle groups bilaterally (internal and external shoulder rotation, shoulder flexion and extension, shoulder abduction, elbow flexion and extension, knee flexion and extension, ankle dorsiflexion, and handgrip). Data were summarized as a total composite z-score. Secondary criteria were upper (16 muscle groups) and lower limb (8 muscle groups) composite QMT subscores, mean score of the 23 muscles tested bilaterally with manual muscle testing (MMT, mean of ratings 0 to 5 of 12 upper limb or scapular muscles, and 11 lower limb muscles), timed motor tests, and scores of the 8 dimensions of the SF36 quality-of-life scale. Differences calculated between baseline and final visit were compared between groups. Plasma concentrations of salbutamol were analyzed to check for the absence of its administration before the trial and for correlation with change in muscle strength measures.

Table 1. Measurements Performed at Each Visit

	Baseline	Week 3	Week 11	Week 23
Medical history	X
Physical examination (weight, heart rate, BP)	X	X	X	X
Blood tests
K, glucose	X	X	X	X
CK, Creatinine	X			X
Pregnancy test	X
ECG	X	X		X
Ambulatory ECG	X	X
Muscle strength (quantitative & manual muscle testing)	X		X	X
Timed motor tests	X			X
SF36	X			X
Plasma salbutamol concentrations	X		X⁎	X†
Side effects		X	X	X
Compliance		X	X	X
Overall assessments by patient and investigator (efficacy, safety)‡				X

Abbreviation: BP, blood pressure.

Testing Muscle Strength 

All centers used the same QMT system, including a wall-mounted frame,^a a load cell that utilizes strain gauge technology for measuring force,^b straps to attach the load cell to the frame and to the patient,^c a mobile examination table,^d a grip dynamometer,^e and a computer for feedback and recording by Quantitative Muscle Assessment.^f Detailed experimental procedures have been published elsewhere.¹¹ The examination lasted 45–60 minutes on average.

Statistical Analysis 

Estimation of the number of subjects to be included was made from a previous trial of salbutamol versus placebo.⁸ With a power of 90% and α risk set to 5%, 60 patients per group were required to demonstrate a difference of 0.6 between groups, corresponding to an increase in muscle force of 0.3 in the QMT z-score in the treated group and an equivalent decrease in the placebo group. The QMT z-score for each muscle function was computed using a normative database established in a previous study.¹¹ Composite scores were calculated when missing data within a score did not exceed 50% (ie, at least 8 functions tested for the upper limbs and 3 for the lower limbs). Differences of mean change of scores (between baseline and final visit for QMT, MMT, and timed motor tests) were submitted to covariance factor analysis, including “treatment” and “center” as between factors, the interaction “treatment by center,” and as covariates, age at inclusion and baseline score. Initial characteristics and final overall assessments of efficacy and safety were compared between groups of treatment using Student's t test for continuous variables or the Mann-Whitney test when relevant, and the chi-square test for categorical variables (or Fisher's exact probability tests when appropriate). Reported side effects were compared using the chi-square test (with Fisher's exact probability test if necessary). A P value <0.05 was considered significant. Data are presented as means ±SD, ranges for continuous parameters and relative frequencies for categorical variables. Correlations were calculated using the Spearman rank coefficient. Statistical analysis was performed using BMDP software.^g

This protocol was approved by the Ethical Committee of the Pitié-Salpêtrière Hospital, Paris.

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Results 

Patient Description 

One hundred and twelve patients were randomized, 56 per treatment group (61 at Center 1, 39 at Center 2 and 12 at Center 3). One patient in the salbutamol group was lost to follow-up after 1 month. Three patients (2 in the salbutamol group) withdrew from the study in the first or second months because of side effects. Only 1 of these patients (in the placebo group) was not reassessed for muscle strength after inclusion, and thus was not included in the efficacy analysis (see fig 1). Patient characteristics are presented in table 2. No significant difference, other than age, was observed; patients were on average younger in the placebo (37.7y) than in the salbutamol group (42.3y). Clinical presentation of patients was variable, with time since diagnosis ranging from less than 1 year to 42 years (mean 10.3y) and duration of upper limb weakness between 1 and 44 years (mean 16.2y). Impairment of upper limb strength was rated by patients as severe to very severe in 41% of cases. Although all patients were ambulatory, 40% also rated impairment of lower limb strength as severe to very severe. Distribution of strength in the 11 muscle groups tested bilaterally with QMT at baseline, expressed as percentages of predicted values (fig 2), showed that on average, all functions were impaired with some patients presenting above-normal values.

Table 2. Patient Characteristics at Baseline

	Placebo (n=56)	Salbutamol (n=56)	P
Age (y)	37.7±11.1(18–60)	42.3±10.7(22–60)	0.02
Gender (% women)	39%	25%	0.11
Heart rate (beats/min)	70.1±12.3	69.7±12.8	0.86
Systolic BP (mm Hg)	125.8±12.9	125.2±12.8	0.81
Diastolic BP (mm Hg)	74.1±10.9	72.3±7.3	0.32
Vital capacity (liters)	4.3±1.0	4.4±0.9	0.52
Vital capacity (% predicted)	99.9±13.1	101.2±13.6	0.67
Dyspnea reported	29%	21%	0.35
Time since diagnosis (y)	10.6±7.5(1–28)	8.9±7.7(1–42)	0.12
Duration of upper limb weakness (y)	14.8±9.7(1–42)	17.6±11.5(2–44)	0.28
Duration of lower limb weakness (y)	9.6±6.5(1–27)	11.3±9.7(0–41)	0.79
Functional impairment (patient evaluation)
Upper limb			0.65
Mild	14%	9%
Moderate	45%	50%
Severe/very severe	41%	41%
Lower limb			0.99
Absent	16%	16%
Mild	23%	23%
Moderate	20%	21%
Severe/very severe	41%	39%
Physiotherapy	46%	41%	0.57

Note. Values are mean ±SD − (range) unless otherwise noted.

Abbreviation: BP, blood pressure.

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• Fig 2. 

  Box-plots of QMT muscle functions at baseline expressed as ratio of observed to predicted values according to model established with healthy volunteers. Abbreviations: RSA, right shoulder abduction; LSA, left shoulder abduction; RSER, right shoulder external rotation; LSER, left shoulder external rotation; RSIR, right shoulder internal rotation; LSIR, left shoulder internal rotation; RSF, right shoulder flexion; LSF, left shoulder flexion; RSE, right shoulder extension; LSE, left shoulder extension; REF, right elbow flexion; LEF, left elbow flexion; REE, right elbow extension; LEE, left elbow extension; RAF, right ankle flexion; LAF, left ankle flexion; RKF, right knee flexion; LKF, left knee flexion; RKE, right knee extension; LKE, left knee extension; RHG, right handgrip; LHG, left handgrip.

Efficacy 

QMT and MMT scores at baseline, 3, and 6 months are presented in Table 3, Table 4 respectively. One center was excluded from the QMT analysis because of a high rate of data inconsistencies (more than 30% due to deviations from calibration, testing, or curve analysis procedures) resulting in missing data which made calculations of composite scores impossible. QMT data were thus available for 36 placebo patients and 35 salbutamol patients at month 6. The age difference between groups at inclusion was taken into account in the analysis of variance model as a covariate. Mean changes of total QMT z-score from baseline were small, indicating nonsignificant improvement (placebo, 0.4%; salbutamol, 2%) and not statistically significant between groups (difference 0.04, F_1,60=2.05, P=0.16). Considering the subscores, upper limb score improved slightly (3% with salbutamol), while lower limb score deteriorated slightly in both groups. Analysis of data at month 3 gave similar results. Likewise, there was no difference in total or regional MMT scores. Timed motor tests (table 5) showed large variability with little or no variation with treatment. Overall assessment of efficacy by patients confirmed the results with only a third of subjects rating the improvement good or moderate (placebo, 32%; salbutamol, 34%). The assessment by investigators was less positive, with 22% judged good/moderate responses to placebo and 15% to salbutamol. Again, no difference was observed between the groups. VAS ratings gave similar results.

Table 3. QMT Z-Scores at Baseline and Mean Change at Months 3 and 6

	Placebo	Salbutamol	P⁎
Baseline (z-scores)
Upper limb score	2.32±1.19	2.34±1.07	0.80
	n=36	n=37
Lower limb score	2.32±1.15	2.19±1.45	0.78
	n=36	n=36
Total score	2.32±1.07	2.31±1.05	0.90
	n=36	n=36
Month 3 (change from baseline)
Upper limb score	0.05±0.26(2%)	0.12±0.19(5%)	0.12
	n=34	n=37
Lower limb score	−0.05±0.53(−2%)	0.001±0.48(0.04%)	0.52
	n=34	n=36
Total change	0.03±0.27(1%)	0.09±0.23(4%)	0.24
	n=34	n=36
Month 6 (change from baseline)
Upper limb score	0.02±0.31(1%)	0.08±0.26(3%)	0.11
	n=36	n=36
Lower limb score	−0.04±0.36(−2%)	−0.01±0.49(−0.3%)	0.48
	n=36	n=35
Total change	0.01±0.27(0.4%)	0.05±0.28(2%)	0.20
	n=36	n=35

NOTE. Values are mean ± SD unless otherwise noted.

Table 4. MMT Scores at Baseline and Mean Change at Months 3 and 6^⁎

	Placebo	Salbutamol	P
Baseline (mean scores) (0–5)	n=55	n=54
Upper limb score	3.13±0.62	3.35±0.67	0.22
Lower limb score	3.74±0.79	3.94±0.87	0.44
Total score	3.42±0.61	3.63±0.66	0.28
Month 3 (change from baseline)	n=52	n=52
Upper limb score	0.02±0.19(0.6%)	0.04±0.14(1%)	0.16
Lower limb score	0.07±0.18(2%)	0.04±0.15(1%)	0.60
Total score	0.04±0.15(1%)	0.04±0.12(1%)	0.63
Month 6 (change from baseline)	n=54	n=52
Upper limb score	0.03±0.18(1%)	0.04±0.21(1%)	0.58
Lower limb score	0.04±0.19(1%)	0.05±0.20(1%)	0.78
Total score	0.03±0.16(1%)	0.04±0.18(1%)	0.69

NOTE. Values are mean ± SD unless otherwise noted.

Table 5. Functional Scores at Baseline and Mean Change at Month 6

	Placebo	Salbutamol	P⁎
Brooke grade (upper limbs) (1–7)
Baseline	2.6±0.5	2.6±0.7	0.83
Mean change	0.0±0.4	0.1±0.4	0.30
Vignos grade (lower limbs) (1–10)
Baseline	1.7±1.0	1.7±1.1	0.53
Mean change	0.1±0.6	0.1±0.5	0.65
Timed motor tests (s)
Walk 10 meters
Baseline	9.3±3.9	8.9±3.1	0.28
Mean change	−0.2±4.0	0.03±2.4	0.96
Climb 4 steps
Baseline	3.8±2.6	4.0±3.3	0.61
Mean change	−0.3±1.9	−0.1±1.3	0.68
Barré
Baseline	103.9±56.9	106.2±62.9	0.77
Mean change	−3.8±48.5	−0.1±38.1	0.54
Mingazzini
Baseline	77.5±51.7	84.8±52.0	0.27
Mean change	1.9±43.0	2.8±34.1	0.94

NOTE. Values shown are mean ±SD unless otherwise noted.

Quality of life did not show any significant difference between the treated and nontreated groups. The 8 dimensions of the SF36 scale were unchanged between baseline and month 6 for both groups, but with great variability.

Safety 

Salbutamol was, on the whole, well tolerated. Only 2 patients in the salbutamol group dropped out because of side effects (symptomatic tachycardia in both cases). One patient in the placebo group withdrew at week 4 because of hypertension. Dosage was reduced because of side effects (mainly palpitations or tachycardia) in 6 patients on placebo and 9 on salbutamol. Tremor, flushing, and depression (requiring hospitalization in 1 case) only occurred in the salbutamol group (table 6). Higher rates of hyperglycemia and hypokalemia were reported with salbutamol. There was no significant difference between groups, with only a trend for cramps in the treated group (21% vs 9%; P=0.07). The minimum, but not maximum, heart rate recorded with ambulatory ECG at month 1 was higher in the salbutamol group (50.1 vs 47.5/min; P=0.02). Mean blood pressure and heart rate were not significantly lower at month 6 in the salbutamol group. No patient was excluded following the cardiological evaluation at month 1. Overall assessment of tolerability by patients was in favor of placebo with 67% good ratings versus 51% for salbutamol. Investigators' ratings were slightly lower (65% for placebo and 45% for salbutamol).

Table 6. Frequency of Side Effects

Drug Assays 

Samples were available for 53 patients in the treated group and 55 in the placebo group. At inclusion, all samples were drug-free. In the placebo group, no positive samples were found. Plasma salbutamol concentrations obtained at steady state at months 3 and 6 showed a small increase in the levels from before (C_min) to 2 hours (C_2hours) after salbutamol intake, and no difference between months 3 and 6 (table 7). At month 3, 13 samples were available 4 hours after intake and plasma concentrations were close to those obtained at month 6 on average 5 hours after intake. The small variation observed from trough to maximum (or post-dose) levels was consistent with the smooth profile expected from the sustained release formulation (9 to 12 ng/ml). Two patients on salbutamol (on 8mg and 16mg/d) had undetectable C_min and 2 (with 16mg/d) undetectable C_2hours, possibly due, but could not be ascertained, to missed tablets. No correlations were observed between plasma concentrations of salbumatol and change in strength of composite scores (MMT, QMT).

Table 7. Plasma Concentrations of Salbutamol

NOTE. Values are ng/ml.

Abbreviations: M3, month 3; M6, month 6.

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Discussion 

This is the third randomized controlled trial of β2-adrenergic agonists in FSHD, after Kissel et al⁸ and van der Kooi et al.⁹ The rationale was the same, but following the suggestion that progressive β2-receptor desensitization may have caused a loss of pharmacologic effect⁸ we used a periodic dosing regimen, with a break in drug administration for 1 week out of every 4. It had been shown in rats that a 2 days on, 2 days off regimen prevented loss of the effect on weight gain.⁴, ¹² But given the half life of the SR salbutamol in humans (9h)¹³ and for practical reasons mainly related to patient's compliance, a 4-weekly schedule was considered as optimal.

The present study did not show any effect on muscle strength with 8mg salbutamol twice daily using this periodic dosing regimen. The primary outcome measure (MVIC) was the same as for previous trials. In addition, this study was the first multicentric study of FSHD, at 3 French neuromuscular centers. This cooperation among centers permitted the recruitment of sufficient patients but resulted in methodological difficulties, particularly in the analysis of QMT results. The exclusion of one center for the primary criteria, because of testing procedure deviations, led to a reduction of power which could explain the lack of effect. However statistical power was maintained close to 80% as standard deviations were much lower than anticipated from previous studies.¹⁴ Moreover, no trend to positive effects was found in any of the other outcome measures examined. Also, the expected deterioration of 10% to 15% in the placebo group did not eventuate. On the contrary, a slight improvement was detected, reducing the effect size. A longer period of observation might be necessary to evidence a significant positive effect (or deterioration in the placebo group), but with a drug such as salbutamol, it does not seem reasonable to wait more than 6 months for this effect. Also, we cannot exclude the possibility that the periodic regimen chosen (3wk on, 1wk off) was not optimal to reveal therapeutic effects masked by continuous agonist administration.

The mean plasma concentrations before (C_min) and after (C_2hours) drug intake were in the same range as previously reported to be effective in pulmonary disorders.¹⁵, ¹⁶, ¹⁷ We found no correlation in our study between salbutamol concentration and muscle strength. Different results might be obtained at higher salbutamol doses, but presumably at the expense of increased side effects.

Using the same daily dose given continuously for 1 year, Kissel et al⁸ observed no improvement of composite QMT or MMT scores. The only significant result was a change in grip strength (assessed separately) after 1 year. Van der Kooi et al⁹ identified significant improvements in several muscle functions (5 of 12 functions) after 6 months treatment but did not calculate composite QMT or MMT scores. They also assessed fatigue, pain, functional status, psychological distress and training, and the interaction between training and strength, with still no effect of albuterol, nor interaction between training and albuterol.⁹, ¹⁸ Among individual muscle functions in our study, the single significant difference observed (right elbow flexion) may have been an artifact of multiple comparisons. In both previous studies increase of lean muscle mass was reported, using dual energy X-ray absorptiometry⁸ or stereologic computed tomography.⁹ However this effect on muscle mass has not yet been related to increased muscle function in patients with muscle impairment. Recently, in a crossover trial with Duchenne patients¹⁹ lean body mass was increased with albuterol compared to placebo, but muscle strength (knee extensors and flexors) remained unchanged. Beneficial effects on muscle strength have been shown in several other neuromuscular disorders, but only in pilot studies.²⁰, ²¹, ²² In our study, there was a nonsignificant increase of weight in the salbutamol-treated patients after 6 months (1.84 vs 0.81 kg in the placebo group). A positive effect of clenbuterol has also been reported in mdx mice but with increased fatigability.²³ Fatigability was not assessed in our study, but was not reported as a side effect.

Methodological Issues 

Our study, with more than 100 patients, provided an opportunity to investigate procedures for testing muscle strength in FSHD. The involvement of very specific muscles, often asymmetrically, is challenging. We chose the QMT as a primary criterion for its potential to be a more reliable measure than MMT, perhaps with greater responsiveness to change, as shown for other neuromuscular diseases such as Duchenne muscular dystrophy.²⁴ However, marked weakness of muscles, and compensation by other less impaired muscles (as is the case for FSHD patients), can render testing procedures defined for healthy volunteers difficult to apply, leading to variability within patients and between examiners.¹¹ We recommend thorough training with patients before and regularly throughout the trial, although this was not the case for our study, as the examiners had been trained in a previous study with healthy volunteers. The secondary criterion, the MMT, proved satisfactory, with no center effect and very few inconsistencies or missing data. Timed functional tests (walking 10 meters, climbing 4 steps, Mingazzini test) reflect mainly lower limb impairment, which is not a primary concern in this pathology, the predominant deficit of which is in the shoulder girdle. Great variability in results was obtained for these outcomes. The functional grades of Vignos for the lower limb and of Brooke for the upper limb are considered insensitive and showed no differences. Quality of life as assessed by the SF36 proved disappointing also, with no change on average and great inter- and intra-subject variability. Further, this generic questionnaire was poorly accepted by patients because some questions were difficult to understand, intrusive or repetitive. A more specific quality of life scale for neuromuscular conditions might be more useful, such as the INQoL recently developed by Vincent et al²⁵ which evaluates the impact of disability on quality of life.

Study Limitations 

From our results over a period of 6 months, we were not able to evince deterioration (in the placebo group) with the outcome measures chosen, but FSHD is a slowly progressive disease and a longer period of observation than 6 months is probably required. Significant results might also be obtained with larger groups of patients. However, larger trials may not be feasible, as recruiting sufficient patients in a reasonable time frame is difficult in this type of disease, especially with drugs having many contraindications and safety concerns. Another issue is the number of tests to be repeated. The fatigability of patients must be taken into account, and thus the choice of the most appropriate measures for the trial is crucial. A functional scale, the Motor Function Measure, has been recently validated for neuromuscular diseases²⁶ and could be an alternative outcome measure to assess disease progression, but the responsiveness to change of this scale remains to be determined in FSHD. However, it has the advantage of being applicable whatever the severity of the disease, unlike timed motor tests assessing ambulation, or measures of strength when retractions or pain are present. If future studies are planned, they should address alternative periodic regimens, duration of treatment, and the role of training, along with the evaluation of dynamic strength of the trained muscle.

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Conclusion 

In conclusion, the results from this study and both previous controlled trials preclude at present the use of salbutamol as a routine treatment for FSHD, even if we cannot yet exclude improvement from anabolic effects with a longer duration of treatment or alternative dosing regimens.

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Acknowledgments 

We thank H.M. Bécane, MD, for his cardiological advice; A. Verschueren, MD, and L. Richard, MD, for their participation in enrollment of patients; A. Couillandre, PhD, PT, O. Maisetti, PhD, PT, L. Frichot, PT, J. Paulus, PT (deceased), V. Tanant, PT for their participation in the assessments of patients; B. Diquet, PhD, PharmD, and G. Aymard, PharmD for analysis of drug concentrations. We also thank Denis De Castro, MD, for his kind assistance for the language revision of the manuscript.

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• a Rose & Krieger GmbH, Potsdamer Str 9, 32423 Minden , Germany.
• b SM-250; Intergace Inc, 7401 E Butherus Rd, Scottsdale, AZ 85260.
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