216 subjects who have been diagnosed with NLC, were recruited from hospital wards and outpatient clinics and entered the screening period of the trial. 28 subjects were subsequently excluded due to having less than 4 NLC episodes during the 2-week screening period. 2 additional subjects were excluded due to meeting other exclusion criteria and 2 subjects withdrew their consent. 184 were randomized into the placebo (N = 89) and MOMH (N = 95) groups. After treatment initiation, 2 subjects were excluded due to meeting exclusion criteria and 7 subjects withdrew their consent. 175 subjects, 87 in the placebo group and 88 in the MOMH group, completed the study. The study flow diagram, per CONSORT guidelines, is presented in Fig. 1. The study was conducted from February 2018 to September 2018.
The NLC frequency of two subjects in the MOMH group numerically exceeded the cumulative NLC duration throughout all visits, namely, the accumulated NLC duration (in seconds) was shorter than the total number of NLC episodes. Their data were therefore, excluded from all the analyses except for safety. Baseline characteristics per group are presented in Table 1. The groups were similar with respect to gender distribution, age, height, weight and body mass index (BMI). Physiological parameters that included systolic and diastolic blood pressure (SBP and DBP, respectively) and heart rate, were similar between the groups as well. Importantly, there were no between-group differences in NLC frequency, duration and pain, sleep quality and the quality of life evaluations at Baseline.
Table 1
Baseline characteristics by group
|
MOMH group N = 86
|
Placebo group N = 87
|
P Value
|
Demographics
|
Gender Female n (%)
|
65 (75.6)
|
64 (73.6)
|
0.862
|
Age (years) mean (± SD)
|
57.3 (± 10.7)
|
57.1 (± 10.2)
|
0.955*
|
Weight (kg) mean (± SD)
|
74.9 (± 13.0)
|
74.9 (± 13.9)
|
0.995
|
Height (cm) mean (± SD)
|
167.4 (± 9.6)
|
167.4 (± 9.3)
|
0.991
|
BMI (kg/m2) mean (± SD)
|
26.7 (± 4.0)
|
26.7 (± 4.5)
|
0.791*
|
Physiological parameters
|
Systolic blood pressure (mmHg)
mean (± SD)
|
128.6 (± 11.5)
|
130.0 (± 10.3)
|
0.519*
|
Diastolic blood pressure (mmHg)
mean (± SD)
|
80.0 (± 6.9)
|
79.0 (± 6.2)
|
0.246*
|
Heart rate (beats/min) mean (± SD)
|
71.5 (± 6.5)
|
71.6 (± 6.2)
|
0.934*
|
Baseline efficacy parameters
|
NLC frequency (num/week) mean (± SD)
|
5.4 (± 5.0)
|
6.4 (± 8.4)
|
0.523*
|
NLC duration (sec/week) mean (± SD)
|
244.5 (± 238.6)
|
266.5 (± 248.9)
|
0.562*
|
NLC pain (mean VAS/week) mean (± SD)
|
6.6 (± 1.4)
|
6.7 (± 1.4)
|
0.584
|
Sleep quality (mean cumulative score/week) mean (± SD)
|
13.1 (± 3.4)
|
12.5 (± 3.7)
|
0.327
|
Quality of life subscales:
|
- Physical functioning
|
63.6 (± 25.4)
|
64.8 (± 27.5)
|
0.904*
|
- Role limitation due to physical health
|
44.5 (± 45.3)
|
46.6 (± 42.7)
|
0.686*
|
- Role limitation due to emotional problems
|
40.7 (± 45.0)
|
40.6 (± 43.6)
|
0.993*
|
- Vitality
|
45.9 (± 14.5)
|
45.9 (± 12.3)
|
0.746*
|
- Mental health
|
50.1 (± 13.6)
|
49.9 (± 11.6)
|
0.944*
|
- Social functioning
|
61.9 (± 16.8)
|
60.1 (± 16.3)
|
0.572*
|
- Body Pain
|
47.9 (± 17.3)
|
49.9 (± 18.9)
|
0.640*
|
- General health
|
44.9 (± 12.1)
|
45.9 (± 9.3)
|
0.551*
|
BMI – body mass index; MOMH – magnesium oxide monohydrate; NLC – nocturnal leg cramps; SD – standard deviation; VAS – visual analogue scale. |
Concomitant illnesses assessed included hypertension, coronary artery disease, cardiosclerosis, osteochondrosis, heart failure, angina pectoris, chronic tonsillitis, chronic cholecystitis, arthrosis, chronic pancreatitis, chronic prostatitis, diabetes mellitus, stomach ulcer, hypertensive heart, chronic sinusitis in remission stage, chronic gastritis, chronic pyelonephritis, chronic cystitis in remission stage, adenoma of prostate, bronchial asthma, varicose disease of the lower extremities, tension headache, dizziness, insomnia, migraine, myopia, neurocirculatory dystonia of the cardiac type, cataract, anxiety disorder, fibroscopic mastopathy, Parkinson’s disease, chronic bronchitis, chronic gastroduodenitis, chronic glomerulonephritis (remission stage), chronic tonsillopharyngitis (remission stage), cerebral atherosclerosis, post-onset (ischemic stroke in 2005) encephalopathy, kidney cyst, climacteric vegetative disorders, constitutional-exogenous obesity (I degree), breast myoma, pre-diabetes (impaired glucose tolerance), reactive arthritis, urinogenic diathesis, chronic dyshidrotic eczema, chronic dyscirculatory brain insufficiency and chronic cholecystopancreatitis. Analysis of concomitant illnesses revealed no between-group differences (Supplementary Table 1).
Concomitant medications assessed included angiotensin converting enzyme inhibitor, diuretics, anti-aggregants, beta-blockers, blockers of AT1 receptors, calcium channel blockers, polyferment drugs, sugar-lowering drugs, homeopathic remedies, metabolic drugs, antagonists of alpha 1 adrenergic receptors, antidepressants, anti-migraine medications, ophthalmic drugs, gastrointestinal medications, nonsteroidal anti-inflammatory drugs, nitrates, nootropic drugs, acid-dependent diseases medications, drugs used in the treatment of cough and colds, sleep and sedative medications, phytotherapeutics, anti-prostate hyperplasia drugs, drugs used in the treatment of musculoskeletal system diseases and drugs for vascular therapy. Analysis of concomitant illnesses revealed no between-group differences (Supplementary Table 2).
Primary Outcome
The primary efficacy analysis was performed on the number of NLC episodes per week calculated at each study visit. The dynamics of the mean number of NLC episodes per week over the study period are presented in Fig. 2.
A significant change in the number of NLC episodes per week was observed for both groups at Visit 2 as compared to Baseline (means for the placebo group: 6.4 vs 3.6, p < 0.001; means for MOMH group: 5.4 vs 3.2, p < 0.001) and at Visit 3 as compared to Baseline (means for the placebo group: 6.4 vs 3.7, p < 0.001; means for MOMH group: 5.4 vs 1.9, p < 0.001). The magnitude of the reduction in NLC frequency was compared between the groups using ANOVA on ranks and contrasts. There was no significant between-group difference in the magnitude of NLC frequency reduction 30 days after treatment initiation (Visit 2, p = 0.099). However, when assessed 60 days after treatment initiation, a significant between-group difference in the magnitude of NLC frequency reduction was revealed (Visit 3, p = 0.005), indicating a larger effect in the MOMH group.
Secondary Outcomes
The duration of the NLC episodes, the severity of NLC-induced pain, the quality of sleep and the quality of life were studied as part of the secondary efficacy analysis. The dynamics of these parameters as measured at each of the study visits are presented in Fig. 3.
A significant reduction in the NLC episode duration was found for both groups at Visit 2 as compared to Baseline (means for the placebo group: 137.4 vs 266.5, p < 0.001; means for MOMH group: 99.9 vs 244.5, p < 0.001) and at Visit 3 as compared to Baseline (means for the placebo group:127.2 vs 266.5 p < 0.001; means for MOMH group: 67.9 vs 244.5, p < 0.001). A marginally significant between-group difference in the magnitude of reduction in the NLC episode duration from Baseline to Visit 2 (p = 0.057) and a significant between-group difference from Baseline to Visit 3 (p = 0.004) were identified, indicating a larger reduction in the mean NLC episode duration in MOMH group.
A significant reduction in pain was observed for both groups at Visit 2 as compared to Baseline (means for the placebo group: 5.3 vs 6.7, p < 0.001; means for MOMH group: 5.3 vs 6.6, p < 0.001) and at Visit 3 as compared to Baseline (means for the placebo group: 4.5 vs 6.7, p < 0.001; means for MOMH group: 4.4 vs 6.6, p < 0.001). Between-group comparisons of the magnitude of change in the pain scores revealed no significant between-group differences (p = 0.954), indicating that treatment with MOMH and treatment with placebo had similar impact on pain.
Sleep quality was assessed, and a significant improvement was identified for both groups at Visit 2 as compared to Baseline (means for the placebo group: 8.0 vs 12.5, p < 0.001; means for MOMH group: 7.2 vs 13.1, p < 0.001) and at Visit 3 as compared to Baseline (means for the placebo group: 7.1 vs 12.5, p < 0.001; means for MOMH group: 5.0 vs 13.0, p < 0.001). The magnitude of improvement from Baseline to Visit 2 was significantly different between the groups (p = 0.049), as was the magnitude of improvement from Baseline to Visit 3 (p < 0.001), indicating larger improvement in MOMH group.
The quality-of-life parameters significantly improved for both groups at Visit 2 and Visit 3 as compared to Baseline (p < 0.045 for all). The magnitude of improvement in all parameters was compared between the groups. Role limitation due to physical health (RP) and Role limitation due to emotional problems (RE) were the only parameters for which a significant between-group difference was observed (RP (from Baseline to Visit 3): p = 0.017; RE (from Baseline to Visit 2): p = 0.021). This difference indicated larger improvement in MOMH group.
One subject from the placebo group and 6 subjects from the MOMH group withdrew their consent during the study period, indicating a relatively low dropout rate and high tolerability.
Safety/Tolerability and Adverse Effects
177 subjects (placebo group N = 88; MOMH group N = 89) received at least 1 dose of the study treatment and were included in the analysis of safety and tolerability. There were no deaths or serious adverse events during the study. 4 subjects from the placebo group reported of having adverse events that included fatigue, headache, nausea, diarrhea, and muscle twitching. No adverse events were reported in the MOMH group.
Post-hoc Analyses
Following the database lock, a by-site post-hock analysis of the efficacy variables was carried out to assess site-specific outcomes. It was discovered that the results obtained from Site 1 demonstrated opposite dynamics (placebo superior to MOMH) as compared to all other sites. To learn about the potential sources for this difference, the collected data were divided into two subsets. Subset 1 included the data obtained from Site 1; Subset 2 included the data obtained from all the other sites. Baseline characteristics were compared between the two subsets of results and are presented in Table 2. Significant between-group differences were found in gender distribution, which indicated that Subset 1 was more equally gender-distributed whereas female participants constituted the majority of Subset 2 subjects. In addition, Subset 1 participants were younger, taller and had significantly higher SBP and DBP (Table 2).
Table 2
Baseline Characteristics by Subset
|
Subset 1
(N = 44)
|
Subset 2
(N = 129)
|
P Value
|
Demographics
|
Gender Female n (%)
|
26 (59.1)
|
103 (79.8)
|
0.009
|
Age (years) mean (± SD)
|
50.0 (± 6.1)
|
59.7 (± 10.5)
|
< 0.001
|
Weight (kg) mean (± SD)
|
75.6 (± 16.1)
|
74.7 (± 12.4)
|
0.638
|
Height (cm) mean (± SD)
|
171.4 (± 12.5)
|
166.1 (± 7.7)
|
0.001
|
BMI (kg/m2) mean (± SD)
|
25.5 (± 3.4)
|
27.1 (± 4.4)
|
0.108
|
Physiological parameters
|
Systolic blood pressure (mmHg)
mean (± SD)
|
134.2 (± 11.4)
|
127.7 (± 10.2)
|
< 0.001
|
Diastolic blood pressure (mmHg)
mean (± SD)
|
83.4 (± 5.2)
|
78.2 (± 6.5)
|
< 0.001
|
Heart rate (beats/min) mean (± SD)
|
70.6 (± 5.0)
|
71.8 (± 6.7)
|
0.429
|
Baseline efficacy parameters
|
NLC frequency (num/week) mean (± SD)
|
3.9 (± 0.8)
|
6.6 (± 7.9)
|
0.003
|
NLC duration (sec/week) mean (± SD)
|
48.7 (± 12.9)
|
326.1 (± 244.5)
|
< 0.001
|
NLC pain (mean VAS/week) mean (± SD)
|
6.7 (± 0.9)
|
6.6 (± 1.6)
|
0.686
|
Sleep quality (mean cumulative score/week) mean (± SD)
|
13.0 (± 2.9)
|
12.7 (± 3.7)
|
0.627
|
BMI – body mass index; NLC – nocturnal leg cramps; SD – standard deviation; VAS – visual analogue scale. |
In terms of the baseline efficacy parameters, Subset 1 subjects experienced significantly fewer NLC episodes which, overall, persisted substantially less time as compared to Subset 2 subjects.
Between-subset comparison of concomitant medications revealed that higher proportion of Subset 1 subjects were treated with anti-aggregants (36.4% in Subset 1 vs 14.0% in Subset 2, p = 0.002), polyferment drugs (11.4% in Subset 1 vs 0.8% in Subset 2, p = 0.004) and medications for gastrointestinal disorders (6.8% in Subset 1 vs 0% in Subset 2, p = 0.016), whereas the proportion of subjects treated with angiotensin converting enzyme inhibitor was higher in Subset 2 (45.7% in Subset 2 vs 27.3% in Subset 1, p = 0.002). Other concomitant medications assessed included betablockers, diuretics, angiotensin II receptor blockers, medications used in cough and colds, homeopathic products, anti-prostate hyperplasia medications, acid-dependent disease remedies, antagonists of alpha 1 adrenergic receptors, antidepressants, anti-migraine remedies, medications used in the treatment of musculoskeletal system diseases, medications used in gynecology, ophthalmic medications, metabolic medications, nonsteroidal anti-inflammatory medications, nitrates, nootropics, medications for vascular therapy, sedative-hypnotic drugs, phyto-therapeutics and sugar lowering medications. No significant differences were observed.
Comparison of comorbidities showed higher proportion of heart failure (27.3% in Subset 1 vs 0% in Subset 2, p < 0.0001), chronic prostatitis (15.9% in Subset 1 vs 0.8% in Subset 2, p < 0.0001), chronic pancreatitis (11.4% in Subset 1 vs 1.6% in Subset 2, p = 0.012), chronic gastritis (11.4% in Subset 1 vs 0.8% in Subset 2, p = 0.004), chronic tonsillitis (13.6% in Subset 1 vs 0.8% in Subset 2, p = 0.001), chronic cystitis (9.1% in Subset 1 vs 0% in Subset 2, p = 0.004) and myopia (6.8% in Subset 1 vs 0% in Subset 2, p = 0.015) in Subset 1 subjects. Cardiosclerosis (10.9% in Subset 2 vs 0% in Subset 1, p = 0.022) and chronic cholecystitis (9.3% in Subset 2 vs 0% in Subset 1, p < 0.039) were diagnosed in higher proportion of Subset 2 subjects as compared to Subset 1. Other comorbidities assessed included hypertension, ischemic heart disease, osteochondrosis, arthrosis, chronic bronchitis, diabetes mellitus, angina pectoris, stomach ulcer, chronic pyelonephritis, hypertensive heart, neurocirculatory dystonia of the cardiac type, mastopathy, chronic cholecystopancreatitis, adenoma of prostate, arthritis, cerebral atherosclerosis, bronchial asthma, varicose disease of the lower extremities, tension headache, eczema, dizziness, insomnia, history of ischemic stroke, kidney cyst, climacteric vegetative disorders, migraine, breast myoma, pre-diabetes (impaired glucose tolerance), cataract, urinogenic diathesis, anxiety disorder, Parkinson’s disease, chronic dyscirculatory brain insufficiency, chronic gastroduodenitis, cerebral atherosclerosis, chronic tonsillopharyngitis, chronic sinusitis and chronic glomerulonephritis. No significant differences were observed.
These results indicate that Subset 1 subjects had a somewhat more severe profile in terms of concomitant medications and comorbidities as compared to Subset 2 subjects.
To assess the impact of Site 1 data on the outcomes we reanalyzed the results with Subset 1 data entirely excluded.
MOMH and placebo groups of Subset 2 were compared for characteristics and baseline efficacy outcomes. The results are presented in Table 3.
Table 3
Baseline Characteristics of Subset 2 data by Group
|
MOMH
(N = 64)
|
Placebo
(N = 65)
|
P Value
|
Demographics
|
Gender Female n (%)
|
52 (81.3)
|
51 (78.5)
|
0.827
|
Age (years) mean (± SD)
|
60.4 (± 10.9)
|
59.1 (± 10.1)
|
0.517*
|
Weight (kg) mean (± SD)
|
75.1 (± 11.8)
|
74.3 (± 13.1)
|
0.583
|
Height (cm) mean (± SD)
|
165.9 (± 7.7)
|
166.2 (± 7.8)
|
0.278
|
BMI (kg/m2) mean (± SD)
|
27.3 (± 4.1)
|
26.9 (± 4.8)
|
0.395*
|
Physiological parameters
|
Systolic blood pressure (mmHg)
mean (± SD)
|
127.6 (± 10.9)
|
127.7 (± 9.6)
|
0.826*
|
Diastolic blood pressure (mmHg)
mean (± SD)
|
78.8 (± 6.7)
|
77.5 (± 6.2)
|
0.154*
|
Heart rate (beats/min) mean (± SD)
|
72.0 (± 6.9)
|
71.7 (± 6.6)
|
0.749*
|
Baseline efficacy parameters
|
NLC frequency (num/week) mean (± SD)
|
5.8 (± 5.7)
|
7.3 (± 9.5)
|
0.753*
|
NLC duration (sec/week) mean (± SD)
|
311.4 (± 242.9)
|
340.7 (± 247.1)
|
0.410*
|
NLC pain (mean VAS/week) mean (± SD)
|
6.5 (± 1.6)
|
6.8 (± 1.5)
|
0.252
|
Sleep quality (mean cumulative score/week) mean (± SD)
|
13.0 (± 3.7)
|
12.5 (± 3.8)
|
0.451
|
Quality of life subscales:
|
- Physical functioning
|
58.6 (± 24.2)
|
60.2 (± 26.9)
|
0.934*
|
- Role limitation due to physical health
|
38.3 (± 44.5)
|
40.8 (± 43.4)
|
0.616*
|
- Role limitation due to emotional problems
|
37.0 (± 44.9)
|
33.9 (± 43.1)
|
0.696*
|
- Vitality
|
45.4 (± 14.2)
|
45.5 (± 12.4)
|
0.783*
|
- Mental health
|
49.2 (± 13.8)
|
49.2 (± 12.0)
|
0.879*
|
- Social functioning
|
60.4 (± 15.7)
|
57.7 (± 15.3)
|
0.457*
|
- Body Pain
|
46.0 (± 18.2)
|
46.0 (± 17.7)
|
0.921*
|
- General health
|
44.3 (± 13.1)
|
45.4 (± 8.8)
|
0.580*
|
BMI – body mass index; MOMH – magnesium oxide monohydrate; NLC – nocturnal leg cramps; SD – standard deviation; VAS – visual analogue scale. |
There was no difference in the demographics and physiological parameters between the groups. Importantly, no between-group differences in any of the baseline efficacy parameters were identified.
Analysis of comorbidities revealed no difference between the groups, except for hypertension which had higher incidence in MOMH group (73.4% vs 53.9%, p = 0.028). There was no between-group difference in concomitant medications.
All efficacy parameters significantly improved in both groups from Baseline to Visit 2 (p < 0.02 for all) and from Baseline to Visit 3 (p < 0.01 for all). Between-group comparisons of the magnitude of improvement revealed a significant difference in favor of the MOMH treatment in the primary efficacy parameter of NLC episodes number per week (Baseline to Visit 2: p = 0.007; Baseline to Visit 3: p < 0.001) and in the following secondary efficacy parameters: NLC duration (Baseline to Visit 2: p = 0.003; Baseline to Visit 3: p < 0.001), NLC pain (Baseline to Visit 2: p = 0.023; Baseline to Visit 3: p < 0.001) and sleep quality (Baseline to Visit 2: p < 0.001; Baseline to Visit 3: p < 0.001). These results indicate that when Site 1 data were excluded, a more robust advantage for MOMH treatment over placebo was observed.