Effectiveness, safety and tolerability of a complex homeopathic medicinal product in the prevention of recurrent acute upper respiratory tract infections in children: a multicenter, open, comparative, randomized, controlled clinical trial

Trial design

A prospective, multicenter, randomized, open-label, comparative, controlled clinical
trial with two parallel groups was conducted in the RF, in accordance with the legislation
of the RF and its national standards of Good Clinical Practice. The study protocol
was approved by the independent Ethics Committee of the RF (Protocol No. 50, November
11, 2009), the local Ethics Committees of the four participating study centers and
by the regulatory authorities of the Ministry of Health and Social Development of
the RF (Protocol No. 563, December 28, 2009). On December 31, 2010, approval for a
1-year prolongation of the clinical study (Protocol No. 563) was obtained from the
Ministry of Health and Social Development of the RF. The data of the present clinical
trial were first analyzed in RF and submitted to the Ministry of Health and Social
Development of the RF in December 2011. The data presented in this publication are
based on a new analysis from 2014 to 2015, in line with International Conference on
Harmonization (ICH) guidelines.

Participants

Children were allowed to participate in the study if they met the following inclusion
criteria: boy or girl, up to 6 years of age, three or more episodes of acute URTIs
(diagnosis based on World Health Organization (WHO) International statistical Classification
of Diseases and related health problems (ICD)-10 code J06.9 documented in the child’s
medical record) in the last 6 months prior to the study start, and signed informed
consent from parents for participation of their child in the study. Children were
excluded from participation if they had an acute URTI or exacerbation of a chronic
URTI upon starting the study, severe concomitant diseases (renal failure, heart anomalies,
circulatory failure, cardiomyopathy, decompensated kidney and liver, immunosuppressive
conditions, oncological diseases), known or suspected hypersensitivity to any component
of the study medication, or in case of participation in other clinical studies or
use of immune-modulatory medications or being vaccinated against influenza within
the last 6 months before the start of the study. During the study period children
were not allowed to use immune-modulatory medications and prophylactic medications
for URTIs, or being vaccinated. The study took place at four outpatient pediatric
clinics in the RF: the State Educational Institution for Additional Professional Education
(Russian Medical Academy of Postgraduational Education) and the State Educational
Institution for Higher Professional Education (Russian State Medical University) in
Moscow, the State Educational Institution for Higher Professional Education (Smolensk
State Medical Academy) in Smolensk, and the State Educational Institution for Higher
Professional Education (Nizhegorodksaya State Medical Academy) in Nizhniy Novgorod.
Pediatricians of all four participating clinics informed parents of children with
frequent acute URTIs about the study and directed them to the study investigators,
who consequently invited them to take part in the study, until the planned sample
size was reached. The first child was included in the study on February 15, 2010 and
the last child completed the study on September 7, 2011.

Interventions

The intervention group was treated with the investigational product CalSuli-4-02 tablets
for a period of 3 weeks with a dosage regimen of one tablet, three times a day. For
children aged 3 years the CalSuli-4-02 tablet was dissolved in 5 ml (1 teaspoon)
water to facilitate intake. CalSuli-4-02 is a complex homeopathic medicinal product
containing four active ingredients: Calcium carbonicum Hahnemanni D6, Calcium fluoratum
D6, Calcium phosphoricum D6 and Sulfur jodatum D12. The control group was treated
for a period of 3 weeks with a comparator complex homeopathic medicinal product that
consisted of the following five active ingredients: Gentiana D1, Aconitum D6, Bryonia
D6, Ferrum phosphoricum D12, and Acidum sarcolacticum D12. For children aged 1 year,
half of a tablet of the comparator product was dissolved in one teaspoon of water
or breast milk and one drop of that solution was administered two times a day. For
children aged 1–6 years, half a tablet was administered two times a day. In case of
acute URTIs and other ENT diseases during the study period, the children’s symptoms
were treated with antipyretics and/or other symptomatic treatments (e.g. antitussives,
nasal decongestants, ear drops and throat gargle). If indicated, antibiotics were
prescribed. The use of any kind of drug was documented in the child’s medical record,
which was kept by the parents. Concomitant medication was not additionally included
in trial documentation and monitoring.

A total of five study visits were scheduled and 200 children were planned to be randomly
allocated either to the CalSuli-4-02 or control group. After the start of treatment,
four follow-up (FU) Visits took place. The 1
^st
FU Visit was 3-5 days and the 2
^nd
FU Visit 3 weeks (21 days) after the start of study treatment. The 2
^nd
FU Visit was also the end of treatment period and the study medication was returned.
The 3
^rd
FU Visit was 3 months post-treatment and the last Visit (Termination Visit), 6 months
post-treatment. The individual duration for children in the study, therefore, added
up to 201 days, including the 3 weeks (21 days) treatment and 6 months post-treatment
period. Every time during the follow-up period when a child felt sick with acute complaints
in the upper respiratory tract, the child consulted a pediatrician. The pediatrician
assessed the clinical symptoms and the primary diagnosis according to classification
of WHO ICD-10, which was documented in the child’s medical record. In case the clinical
symptoms applied to an acute URTI, the WHO ICD-10 code J06.9 was documented and the
case was counted as acute URTI for study purposes.

Outcome

The objective of the study was to assess the effectiveness, safety and tolerability
of CalSuli-4-02 compared to another complex homeopathic medicinal product in the prevention
of acute URTIs in children. The primary outcome parameter was the frequency of acute
URTIs assessed at the 3
^rd
FU Visit (1–3 months post-treatment) and at Termination Visit (4–6 months and full
6 months post-treatment) by means of documented URTIs (WHO ICD-10 code J06.9) in the
child’s medical record within the respective time period. Secondary outcome parameters
were changes in total scores and severity of individual complaints (fatigability,
cough, nasal discharge (blocked/runny nose), appetite disorder, irritability – each
of the above with a maximum of two points, and a maximum total score of ten points)
and objective or symptoms examined by the investigator (fever, nasal discharge (rhinorrhea/mucopurulent),
skin pallor, rales in lungs, restlessness for unknown reason, atopic dermatitis manifestations,
child’s activities impairment – each of the above with a maximum score of two points,
except atopic dermatitis: maximum four points and skin pallor: maximum one point,
and a maximum total score of 15 points). Complaints and objectives were evaluated
and scored at each visit by the investigator either according to children’s/parents’
self-report or according to the child’s examination results. The total scores were
calculated by the investigator based on the single answers. Other secondary outcome
was treatment satisfaction assessment by children/parents using the 5-point verbal
rating Integrative Medicine Patient Satisfaction Scale (IMPSS, very satisfied, satisfied,
neutral, dissatisfied, very dissatisfied 19]) at the 2
^nd
, 3
^rd
FU and Termination Visit. Furthermore, the use of antibiotics with respect to treatment
of URTIs and other ENT diseases such as sinusitis, otitis media and bronchitis was
assessed as always (used in all occasions that there was an URTI/ENT), sometimes (estimated
by the physician), seldom (estimated by the physician) or never (in none of the occasions
antibiotics were used), based on the documentation in the child’s medical record at
baseline, 3
^rd
FU and Termination Visit. Secondary outcome regarding safety of study treatment was
assessed by systematic review of the incidence of adverse events (AEs) and adverse
drug reactions (ADRs). Tolerability of treatment was evaluated by investigator’s and
children’s/parents’ assessment using a 4-point verbal rating scale (excellent, good,
satisfactory, poor) at the 1
^st
, 2
^nd
FU and Termination Visit.

Sample size

The study has an explorative character and, therefore, a formal sample size calculation
was not necessarily required. However, the planned number of children had been justified
as follows: a treatment related difference in acute URTI occurrence of one event was
assumed as clinical meaningful difference and simulations (Poisson regression modelling)
with the sample size of 100 children in each treatment group were performed to obtain
the power of the study. It was calculated that if the mean number of acute URTIs 1
year prior to study start, is four or less, and a difference of one event is taken
into account, the study would have more than 82.8 % power to detect the effect (0.05
% alpha level).

Randomization

The randomization list was generated by the Laboratory of Biostatistics State Research
Center for Preventative Medicine (Moscow, RF) and the random block size was four.
At each center, children were assigned a study number in ascending order based on
entry in the study. For each study number, the investigator received a sealed envelope
containing the name of the investigational product to be given to the child according
to the randomization list. The envelope was opened after the children’s parents had
provided signed informed consent.

Statistical methods

All effectiveness analyses were based on the intention-to-treat (ITT) analysis principle.
The ITT population included those children who were randomized, had received at least
one dose of study medication and had at least one post-baseline response measurement.
Safety analysis included all randomized children, who received at least one dose of
study medication. The homogeneity of the two treatment groups was assessed by regarding
possible clinical relevance of group specific differences of (demographic) data at
baseline. Primary outcome data were presented by descriptive statistics. As primary
analysis method, post-treatment frequencies of acute URTIs were investigated by Poisson
regression modelling. Treatment related difference in response was reported as relative
risk (RR) presented with their 95 %-confidence interval (CI) and related p-values. Secondary variables were presented by descriptive statistics. To test for
treatment related differences ordinal logistic regression using the proportional odds
model (POM) and repeated measures of covariance analysis (ANCOVA) were applied for
change of complaints and symptoms severity total score. For the other secondary variables
chi-square (?²
)-tests were performed to test for treatment related differences. A rejection-criterion
of 0.05 was set for all statistical tests. If tests allowed, the statistics were two-tailed.