In vivo efficacy of Salbutamol Sandoz versus salbutamol Ventolin GSK in children with asthma

Since 2016, pediatricians have regularly seen children with an asthma
exacerbation, in which case salbutamol Sandoz was used as
rescue medication in case of dyspnoea. The subjective impression is often that
these children responded less well to this
preparation in comparison to before or to the reference product, Ventolin.
After switching from the reference product (Ventolin,
Salbutamol Reference, SalbR) to generic Salbutamol Sandoz (Salbutamol Generic,
SalbG), parents also regularly spontaneously
reported that they had the impression of reduced efficacy of SalbG.

Lareb received a striking number of reports in 2016 (63 of which 40 were
reports concerning children) regarding an alleged reduced
effect of SalbG compared to previous (reference) products containing
salbutamol, such as Ventolin and Airomir. These reports
mainly came after SalbG became the preferred drug of the Dutch health insurers.
In 2015, the concentration of SalbG in the aerosol
dose doubled, whilst the release in micrograms would have remained the same,
and oleic acid was added (as is also present in
other dose aerosols).

Reports received by Lareb came from both healthcare providers and (parents of)
patients and did not clearly decrease in the course
of 2016. An inventory via social media by the "LongFonds" clearly displayed the
perception of lower efficacy amongst children as
well as adults. This also led to a column in the broadcast of EenVandaag.

The CBG has studied and investigated the reports and signals, but has concluded
that the quality control as carried out by the EMA
was not a reason to remove Salbutamol Sandoz from the market. Various insurers
have since accepted other generic products
containing salbutamol in dose aerosol as an alternative instead of SalbG.

According to our information, there is currently no other party that will
initiate a further in vivo efficacy study of SalbG. Pediatricians
suspect Salbutamol Sandoz is less effective than the reference product, thus
creating uncertainty and insufficiënt confidence
regarding the quality of the product. However, this is essential as patients,
parents and healthcare providers must be able to rely on
the effectiveness of the "rescue medication".

We consider it conceivable that a different composition of a dose aerosol can
lead to a larger particle size (MMAD) and reduced
lung deposition. Due to the lower suction power of children, this difference
could especially occur with the first 100 microgram
inhalation. In other words, the shape of the flow-volume curve differs between
children. However, children may also react differently
to the full 400 microgram dose. We also consider it conceivable that the
registration requirements set by the EMA for the properties
of a generic dose aerosol are not strict enough when it comes to administration
to children, especially because the product has not
been studied in the target group: children with acute asthma. For European
registration of generic dose aerosols, it is sufficient if the
MMAD particle size is within a range comparable to that of the reference
product, and when the biological equivalence (plasma
levels) is within a range equal to that of the reference product. The latter is
often tested in a small group of healthy adult subjects.
According to the EMA, the registration of a generic inhalation medication for
children does not require that the efficacy in vivo (lung
function, airway patency) or the bioavailability in children with (acute)
asthma be investigated.

SalbG is the most commonly prescribed rescue drug in the Netherlands, so it is
likely that many patients experiencing an asthma
exacerbation use SalbG. It is therefore unclear whether SalbG is less effective
than SalbR, or whether there must be another
explanation for the reports.

We consider it necessary for responsible care that rescue medication in
children should be proven to be effective in the rescue
setting. To gain clarity regarding the effectiveness of SalbG compared to
SalbR, an in vivo study should be conducted in the target
group, children with reduced asthma control.

The hypothesis of this study is that the reference product SalbR is more
effective than SalbG in improving lung function in children
with asthma, and that this difference is greater the more severe the airway
resistance is. (Null hypothesis: there is no difference).
This could be explained by different properties and deposition of the aerosol.

In this study, we hypothesize that the reference product (SalbR/Ventolin) is
more effective than SalbG (Salbutamol Sandoz) at
improving the lungfunction in children with asthma, and that this difference
increases alongside the severity of the airway resistance.
(Null hypothesis: There is no difference). This could be explained by different
properties and deposition of the aerosol.

Purpose of this research:
Rejecting the null hypothesis. This is based on the answers to the questions
below.

Research questions:
1. Is there a difference between the increase in FEV1 (and FVC) after 100 µg
SalbG versus FEV1 after 100 µg SalbR in children
aged 4-14 years with insufficient asthma control? (primary question)
2. Is there a difference in the subjective feeling of the children after
inhalation with 100 µg SalbR and after 100 µg SalbG, measured
with a VAS score?
3. Is the increase in FEV1 (and FVC) in children with asthma between 4-14 years
of age with insufficient asthma control after
inhalation of 400 µg SalbR different than after inhalation of 400 µg SalbG?
4. Is there a difference in the subjective feeling of the children after
inhalation with 400 µg SalbR and after 400 µg SalbG, measured
with a VAS score?

It is generally thought that bronchodilation with 400 µg substantially results
in maximal bronchodilation.

I - Research design
A prospective, randomized, double-blind, comparative study with 2 registered
drugs. Only children with a diagnosis of asthma
between 4-14 years who undergo a lung function test as part of regular care are
eligible for participation.
After determining whether the patient meets the inclusion criteria and informed
consent has has been retrieved, the participants will
be randomized into 4 study arms with different combinations of Salbutamol: They
will receive 100+300 µg Salbutamol in the following 4 combinations:

1. SalbG - SalbG
2. SalbR - SalbR
3. SalbG -SalbR
4. SalbR - SalbG.

In each group, 20 children will be enrolled after randomization in blocks
(random block size of 4 or 8 children), stratified for the
severity of the airway obstruction measured by the first lung function test
(FEV1% predicted for medication). In accordance with
regular care, children will perform a lung function before and after the
administration of salbutamol in one of the above
combinations. The total dose of salbutamol administered is 400 µg, the usual
dose in regular lung function tests. A low dose of 100
µg is initially administered as this increases the chance of detecting a
possible difference in effect on lung function (on the advice of
a delegation of the CBG that was consulted for this). The lung function test
usually takes place with video animations so that
children experience it as an attractive game (knocking down cones, blow out
candles). The difference with regular care is that the
children undergo an extra lung function test once. This, together with filling
in a short questionnaire 3 times, is the extra burden on
the child in the context of this study

II - Setting
The effectiveness is relevant in a critical care situation, meaning that the
study should simulate the situation when asthma control is
inadequate (and lung deposition may be reduced). Patients for whom a lung
function is performed as part of regular care will be
included. The research will be conducted at the pediatric outpatient clinic of
Canisius Wilhelmina Hospital in Nijmegen.

III - Procedure
1. Approach parents/carers and/or the patient who must have a lung function
performed as part of regular care by means of an
invitation letter.
2. Send a general letter of invitation via an online asthma platform to
approach (parents/caregivers of) the patient, who may be able
to participate in the study.
3. If there is interest, a medical examiner will assess whether the patient has
'doctor's diagnosed asthma'
4. The parents/patient will be contacted by phone to discuss the study and
participation. The PIF is also sent to the parents/patient.
Informed consent is discussed and parents/patients are requested to bring the
completed PIF with them to the next outpatient visit.
5. If there is no 'doctor's diagnosed asthma', an email will be sent stating
that the patient does not meet the criteria to participate in
the study.
6. The (c)-ACT is entered digitally before the outpatient visit by
parents/carers and/or patient, if this has not taken place, this is done
on paper during the outpatient visit.
7. Determining whether the patient meets the criteria for participation in the
study based on inclusion criteria.
8. Register: (c)-ACT and when SABA or LABA was most recently used (regular care)
9. T=0 measurement = 1st VAS score (entered by parent(s)/patient) and lung
function (performed by pediatric pulmonary nurse) in
the context of regular patient care, in which parent/caregiver/patient,
pediatric (pulmonologist) physician and pediatric pulmonary
nurse are blinded for the administration of the type of salbutamol.
10. Stratification according to the table based on the baseline
FEV1(%predicted) and randomization in blocks of 4, by a doctor's
assistant whom is not involved in the lung function measurement: this
randomization results in one of the 4 codes and determines
which combination of medication the patient will receive.
11. The 1st medication (100 µg salbutamol via VZK Cannister A or B) is to be
administered by a doctor's assistant. The doctor's
assistant is not blinded to the cannisters. The parent/caregiver/patient,
pediatric (pulmonologist) doctor and pediatric pulmonary
nurse who will perform further lung function measurements are blinded for the
given medication. The cannister is not visible to the
patient because it is shielded by a cardboard casing that is positioned around
the cannister. The spacer is visible to the patient but
will be wrapped so that the aerosol properties are not visible. The doctor's
assistant will give the medication as prescribed
(https://inhalatorspreis.nl/contents/uploads/iseringsbedrijven/76_1.aerochamber-
mondstuk_werkingsmanufactured-20.pdf). The time
of administration is noted down in hours and minutes.
12. 2nd VAS score (completed by parent(s)/young person); lung function after
T15 = 15 min: MEFV curve exactly 15 min after
administration of 100 µg Salbutamol performed by pediatric pulmonary nurse who
was not involved in the administration, and is
blinded to canisters and randomisation of the patients.
13. Medication administration immediately (< 2 minutes) after measurement: T15,
(300 µg salbutamol) administered by a doctor's
assistant as before. Time is noted in hours and minutes.
14. 3rd VAS score (completed by parent(s)/young person); T= 30: MEFV curve 15
min after 2nd medication by pediatric pulmonary
nurse who was not involved in the administration, blinded to canisters and
randomisation of the patients.
15. Afterwards a short questionnaire follows (by a pediatric pulmonary nurse):
1) Does the first puff taste different from the second puff?
2) Does one feel different from the other? If so how?
3) Do you feel that one or the other works better?
4) Does any of the puffs taste like the ones you have at home?
The patient is not shown the lung function data until the entire study
protocol, including the questionnaires, has been completed.
This is in order to prevent the data from being influenced.

There are no risks associated with participation.

The estimated burden on the patient is considered to be negligible.

The lung function test is performed as a part of regular care. The patient or
parents will not have to undergo additional hospital
visits. The burden for the child consists of performing one extra lung function
test, and answering three short questionnaires about
their perceived shortness of breath at the given point in time. The
questionnaires will be filled in at 20 minute intervals. There is no
difference in the amount of salbutamol used in comparison to a regular visit
involving a lung function test, the lung function
measurement is the same as in regular care.

Children with asthma generally like the lung function tests, as it is linked to
an animation ("computer game", throwing pins, blowing
out candles on the screen), and they are familiar with it. The two forms of
salbutamol used in this study are registered and are
commonly used in the daily practice, both for the treatment of asthma symptoms
at home by the patient and parents, as well as in
the hospital