Patient flow
370 patients who had signed the informed consent were assessed for eligibility criteria (Figure 1). 61 patients were withdrawn at screening visit as they didn’t completely meet the inclusion criteria or met the exclusion criteria. 309 patients were randomized into two groups (n=151, Kolofort group; n = 158, Placebo group).
282 patients (n=140, Kolofort group; n=142, Placebo group) completed therapy per protocol. 27 cases (n=11, Kolofort group; n=16, Placebo group) were excluded from PP analysis due to some deviations from protocol requirements.
Patient demographics
The mean patients’ age in Kolofort group was 30.5±7.7 [30.6±7.7] years and in Placebo group 29.7±7.9 [29.9±7.8] years (p=0.3035 [р=0.4033]). Females predominated in both groups (69.5 [69.3] % and 69.6 [67.6] %). Males proportions were 30.5 [30.7] % and 30.4 [32.4] %, respectively (p=0.9872 [р=0.7615]). There were no other significant differences in demographic characteristics between the two groups. At the screening visit all the patients had negative results of H. pylori test. The initial GIS score had no significant difference between the groups, reaching a total of 10.4±3.5 [10.4±3.4] points in Kolofort group and 10.1±4.0 [10.0±4.0] points in Placebo group (p=0.1209 [p=0.0763]).
47.7% [47.1%] of patients in Kolofort group and 48.1% [47.9%] in Placebo group had various comorbidities (р=0.164 [p=0.400]). Diseases of digestive system or indirectly related to digestion (chronic gastritis, dental caries, umbilical hernia, diverticulum of the intestine, etc.) were registered in 23.2% [22.9 %] cases in Kolofort group and in 25.3% [25.4%] cases in Placebo group. Respiratory system disorders (asthma, chronic bronchitis, vasomotor rhinitis, etc.) were noted in 2.6% [2.9%] and 3.8% [3.5%] cases, and previous surgery (appendectomy, cesarean section, cauterization of the cervix, rhinoplasty, phlebectomy, etc.) – in 3.3% [3.6%] and 4.4% [4.2%] cases, respectively. Other diseases were registered in a small percentage of patients in both groups.
The most common concomitant pathology was H. pylori-negative chronic gastritis which was detected in 21.2% [20.7%] of patients in Kolofort group and in 23.4% [23.2%] of patients in Placebo group.
Concomitant therapy was registered in 9.9% [9.3%] of cases in Kolofort group and 13.3% [10.6%] of cases in Placebo group (p=0.665 [р=0.949]) and included sex hormones and their modulators, mainly contraceptives (3.3% [3.6%] and 3.8% [3.5%] in both groups, respectively, р=1.00 [р=1.00]). Other concomitant medications were rare. Fisher’s exact test showed no significant difference in co-morbidities and concomitant therapy in both ITT and РР analyses.
Three patients (1.98% [2.1%]) in Kolofort group and 8 patients (5.06% [4.4%]) in Placebo group received medication for functional gastrointestinal disorders: drotaverine in allowed doses in 10 cases and mebeverine considered as a prohibited drug in 1 case (this patient was withdrawn from the study). Z-test showed no significant difference between groups in ITT analysis (р=0.05).
The patients’ compliance was close to 100% and did not have significant difference between groups on Visit 3, Visit 4 and Visit 5 (p=0.9130 [p=0.7537]; р=0.4282 [p=0.6852]; р=0.3944 [p=0.2412]).
Efficacy assessment
By the end of week 8 a reduced severity of FD symptoms was observed according to the GIS score in both groups (by 7.2±3.3 [7.2±3.4] in Kolofort group and by 6.3±4.6 [6.2±4.5] in Placebo group, respectively, p=0.041 [0.039]) (Table 1).
Table 1
Change in the severity of FD symptoms according to the GIS sum score after 8 weeks of treatment
Index
|
ITT analysis
|
PP analysis
|
Kolofort group N=151
|
Placebo group N=158
|
Kolofort group N=140
|
Placebo group N=142
|
Mean±SD
|
7.2±3.3
|
6.3±4.6
|
7.2±3.4
|
6.2±4.5
|
Median
|
7
|
6
|
7
|
6
|
Min and Max
|
1-18
|
-12-33
|
1-18
|
-12–33
|
Lowest and highest quartile (Q1-Q3)
|
5-9
|
4-8
|
5-9
|
4–8
|
95% CI
|
[6.4, 8.0]
|
[5.5, 7.1]
|
[6.4, 8.0]
|
[5.5, 7.1]
|
"Kolofort - Placebo" difference in means 95% CI
|
0.94 [0.04-1.85]
|
0.98 [0.05-1.92]
|
P-value
|
"Group" factor P=0.041
|
"Group" factor P=0.039
|
Notes. Comparison of the average GIS scores was carried out using analysis of variance with fixed “Group” factor. Yeo-Johnson (λ = 0) data transformation was used for the two-factor (“Group” and “Visit” factors) analysis of variance, leading to normalization of distribution of residuals. 95% CI – 95% confidence interval.
The regression of FD symptoms according to the GIS scale at week 8 was analyzed by its degree («category», with decrease by 1, 2, 3, 4 or more points). In Kolofort group the proportion of patients with reduced severity of FD symptoms by ≥1 points was 99.3% [100.0%] at week 8, in Placebo group – 95.6% (p=0.067 [p=0.122]).
In the ITT sample the median GIS sum score decreased by 2 points in 96% of patients in Kolofort group and 89.2% of patients in Placebo group (p=0.029); by ≥3 points in 91.4% of patients in Kolofort group and 84.8% of patients in Placebo group (p=0.082); by ≥4 points in 88.1% of patients in Kolofort group and 79.1% of patients in Placebo group (p=0.046).
The initial score of the average NDI index value was 23.5±7.0 [23.6±7.0] in Kolofort group and 23.5±6.9 [23.4±7.1] points in Placebo group. At week 8 a tendency to reduction in the FD symptom influence on daily activity was seen in the Kolofort group: at weeks 4 and 8 NDI score corresponded to 17.1±5.6 [17.1±5.8] and 14.4 ±5.1 [14.5 ±5.2] in Kolofort group versus 17.0±6.0 [17.1±6.4] and 14.9±6.0 [15.0±6.2] in Placebo group, respectively. Thus, the total change in NDI score in the course of treatment was 9.1±7.1 [9.1±7.2] in Kolofort group and 8.5±6.6 [8.5±6.7] in Placebo group, p=0.435 [p=0.450 ] for the "Group" factor.
By the week 8, the median score of the SF-36, demonstrating the physical health component, increased from 49.9±7.8 [49.7±7.9] to 56.3±6.5 [56.4±6.6] in Kolofort group, and from 49.4±7.7 [49.4±7.9] to 56.2±6.3 [56.2±6.5] in Placebo group. According to analysis of variance with fixed “Group” factor, the median score increased by 6.4±7.5 [6.7±7.6] in Kolofort group and by 6.8±7.0 [6.8±7.1] in Placebo group (p=0.655 [p=0.908]).
The median score of the SF-36, demonstrating the mental health component, increased from 33.6±5.7 [33.5±5.8] to 37.1±4.5 [37.0±4.5] in Kolofort group, and from 34.0±6.1 [33.8±6.1] to 36.9±4.9 [36.9±5.0] in Placebo group. So the change of median score was 3.5±6.3 [3.5±6.3] in Kolofort group and 2.9±6.6 [3.1±6.6] in Placebo group (p=0.375 [p=0.599]).
None of the patients in Kolofort group had experienced stable persistence or progression of FD symptoms or required additional prohibited therapy throughout 8 weeks of treatment. One patient in Placebo group required additional prohibited therapy for progression of FD symptoms and therefore was withdrawn from the study.
The majority of investigators evaluated the therapeutic effect of Kolofort as “pronounced”. The median therapeutic effect score was 2.67±2.96 [2.71±3.01] in Kolofort group and 3.33±3.49 [3.27±3.49] in Placebo group (p=0.139 [p=0.258]).
According to investigators’ opinion, there were no adverse effects in the majority of patients throughout 8 weeks of therapy. According to the CGI-EI scale the median score of adverse effects in Kolofort and Placebo groups were 1.09±0.31 [1.08±0.27] and 1.04±0.19 [1.04± 0.20], respectively (р=0.08 [р=0.201]).
According to investigators’ estimation the final clinical efficacy index was 3.76±2.98 [3.79±3.04] points in Kolofort group and 4.37±3.51 [4.31±3.52] points in Placebo group (p=0.251 [p=0.371]).
The dynamics of FD symptoms in patients with H. pylori-negative chronic gastritis was analyzed separately. Changes in the GIS sum score (the difference between the first and last visits) show the reduction in symptom severity in cases of FD associated with chronic gastritis (Figure 2). The most significant changes were seen for epigastric pain, bloating and early satiety.
Safety assessment
The safety and tolerability of therapy were evaluated in patients who received at least one dose of Kolofort or Placebo (Safety population, n=309). The safety of the drug was assessed in terms of adverse events (AEs), their severity and relation to the study drug, outcomes.
Statistical analysis with the Bonferroni correction method showed no influence of Kolofort and Placebo on systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and respiration rate.
In the study 16 AEs were recorded in 13 (8.6%) patients in Kolofort group and 13 AEs in 12 (7.6%) patients in Placebo group. Fisher’s exact test showed no significant difference in AE rate in both groups (р=0.836). There was no significant difference in the number of patients with AEs with particular MedDRA codes between the two groups.
Most AEs (7 (4.6%) cases in Kolofort group and 4 (2.5%) in Placebo group) were associated with digestive system dysfunction. Gastrointestinal tract hyperkinesia (n=1), diarrhea (n=1), dyspepsia (n=1), constipation (n=1), mouth dryness (n=2), and nausea (n=1) were recorded in Kolofort group; diarrhea (n=1), constipation (n=2), and mouth dryness (n=1) in Placebo group.
In 4 (2.6%) patients in Kolofort group and 3 (1.9%) patients in Placebo group infections and infestations were detected. Other AEs in Kolofort group included nasopharyngitis (n=1), rhinitis (n=1), (n=1), acute respiratory infection (n=2). In Placebo group acute respiratory infection (n=1), nasopharyngitis (n=1), tonsillitis (n=1), and cystitis (n=1) were detected.
According to investigators’ opinion, the cause-effect relationship of AEs with the study drug (Kolofort) was assessed as negative in 10 cases (n=10; 62.5%), possible in 2 cases (n=2; 12.5%) and probable in 4 cases (n=4; 25.0%). No AE with a reliable connection to the study drug was registered. The distribution of AEs according their severity (p=0.632) and a causal relationship with the study drug (p=0.785) did not differ between the groups. No severe AEs were reported throughout the study.