In Vivo Efficacy of Salbutamol (Sandoz) Versus Salbutamol Ventolin (GSK) in Children With Asthma (Salsa)

In this study, the investigators hypothesize that the reference product (SalbR/Ventolin) is more effective than SalbG (Salbutamol Sandoz) at improving the lung function 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?

Study Overview

• Status: Recruiting
• Conditions: Asthma in Children; Agents, Anti Asthmatic
• Intervention / Treatment: Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Sandoz"; Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Ventolin GSK"; Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Sandoz"; Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Ventolin GSK"

Detailed Description

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".

The investigators 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.

The investigators 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.

The investigators 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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ellen Croonen, dr; Phone Number: 0243658708; Email: e.croonen@cwz.nl
• Study Contact Backup: Name: Lotte van Nimwegen, drs; Phone Number: 0243658708; Email: l.vannimwegen@cwz.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6532 SZ
      • Recruiting
      • Canisius Wilhelmina Hospital
      • Contact: Ellen Croonen, dr; Phone Number: 0243648708; Email: e.croonen@cwz.nl
      • Contact: Lotte van Nimwegen, drs; Phone Number: 0243648708; Email: l.vannimwegen@cwz.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Informed consent both parents in case of children aged < 12 years, informed consent both parents and patient of children aged 12-14 years
• Patients classified as doctor's diagnosed asthma, preferably with confirmed bronchial hyperreactivity or reversibility (FEV1 > 9% predicted) in earlier lung function assessment and/or known efficacy of salbutamol as rescue medication (either subjective or clinically)
• Indication for lung function assessment as part of regular medical care
• A score of < 20 on the C-ACT (children astma control questionnaire, 4-11 years) or ACT (12-16 years) and/or FEV1 <10% when compared to personal's best and/or FEV1 < 80% predicted and/or actual subjective impression of dyspnea in such severity that patient or caretaker would normally have used their bronchusdilatator

Exclusion Criteria:

• Status asthmaticus with a need for (continuous) nebulisation of salbutamol
• Inability of performing a technically adequate and reliable lung function assessment
• Inability of adequate instruction of patient and/or caretakers due to difficulty in communication and/or language barrier
• Clinically relevant comorbidities with impact on the lung function assessment (eg (cardio)pulmonary disease, muscle disease etc)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FEV1 >90%; Children with lung function FEV1 > 90%	Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference)
Active Comparator: FEV1 80-90%; Children with lung function FEV1 80-90%	Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference)
Active Comparator: FEV1 70-80%; Children with lung function FEV1 70-80%	Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference)
Active Comparator: FEV1 60-70%; Children with lung function FEV1 60-70%	Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference)
Active Comparator: FEV1 < 60%; Children with lung function FEV1 < 60%	Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Sandoz" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Sandoz"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference); Drug: "100 mcg Salbutamol Ventolin GSK" and "300 mcg Salbutamol Ventolin GSK"; Efficacy of Salbutamol Sandoz will be compared to Salbutamol Ventolin GSK (reference)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FEV1 (%) 100ug salbutamol	FEV1 (%) after inhalation of 100 microgram salbutamol	baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VAS 100ug salbutamol	VAS score after inhalation of 100 microgram salbutamol	baseline
FEV1 (%) 400ug salbutamol	FEV1 (%) after inhalation of 400 microgram salbutamol	baseline
VAS 400ug salbutamol	VAS score after inhalation of 400 microgram salbutamol	baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age	Age (years)	baseline
Length	Length (cms)	baseline
Weight	Weight (kgs)	baseline
Gender	Gender (F/M)	baseline
Allergies	Any known allergies	baseline
Inhalation corticosteroids (ICs)	Use of inhalation corticosteroids (Yes/No)	baseline

Collaborators and Investigators

• Sponsor: Canisius-Wilhelmina Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2023
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: March 30, 2023
• First Submitted That Met QC Criteria: May 22, 2023
• First Posted (Actual): June 1, 2023

Study Record Updates

• Last Update Posted (Actual): June 1, 2023
• Last Update Submitted That Met QC Criteria: May 22, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: albuterol; salbutamol; ventolin; sandoz
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: NL67238.091.19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes