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Clinical Trial Results:
A one-year placebo-controlled phase III trial evaluating the efficacy and safety of the house dust mite (HDM) SLIT-tablet in children (5-11 years of age) with HDM allergic rhinitis/rhinoconjunctivitis with or without asthma

Summary
EudraCT number	2019-000560-22
Trial protocol	FR SK DE PL ES BG LT
Global end of trial date	21 Apr 2023

Results information
Results version number	v1(current)
This version publication date	04 Nov 2023
First version publication date	04 Nov 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Sponsor protocol code

MT-12

ISRCTN number

-

US NCT number

NCT04145219

WHO universal trial number (UTN)

-

Sponsor organisation name

ALK-Abelló A/S

Sponsor organisation address

Bøge Allé 6-8, Hørsholm, Denmark, 2970

Public contact

Global pharmacovigilance and Clinical Development, ALK-Abelló A/S, 45 45747576, clinicaltrials@alk.net

Scientific contact

Global pharmacovigilance and Clinical Development, ALK-Abelló A/S, 45 45747576, clinicaltrials@alk.net

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001258-PIP01-11

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

25 Sep 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Mar 2023

Global end of trial reached?

Yes

Global end of trial date

21 Apr 2023

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective was to demonstrate the efficacy of the HDM sublingual immunotherapy (SLIT)-tablet compared to placebo in the treatment of HDM allergic rhinitis (AR) in children (5-11 years of age) based on total combined rhinitis symptoms and medication use (TCRS) during the primary efficacy assessment period.

Protection of trial subjects

Safety surveillance. Access to rescue/reliever medication.

Background therapy

Rescue medication: Subjects were provided with medication to treat rhinitis/rhinoconjunctivitis symptoms (antihistamine/intranasal corticosteroid) and asthma symptoms (short-acting β2-agonist, SABA), and, in countries where required, adrenaline auto-injector to treat severe allergic reactions. Asthma controller and reliever medication: Subjects with a diagnosis of asthma and using low or medium daily dose inhaled corticosteroids (ICS) (with or without long-acting β2-agonists, [LABA]) for asthma control, were allowed to continue with the same medication during the trial. In addition, the use of leukotriene receptor antagonists was permitted as concomitant medication for continued use on same dose only.

Evidence for comparator

-

Actual start date of recruitment

12 Oct 2019

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 353

Country: Number of subjects enrolled

Slovakia: 66

Country: Number of subjects enrolled

Spain: 7

Country: Number of subjects enrolled

Bulgaria: 181

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Lithuania: 94

Country: Number of subjects enrolled

Canada: 38

Country: Number of subjects enrolled

Russian Federation: 329

Country: Number of subjects enrolled

Ukraine: 330

Country: Number of subjects enrolled

United States: 40

Worldwide total number of subjects

1458

EEA total number of subjects

721

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

1458

Adolescents (12-17 years)

0

Adults (18-64 years)

0

From 65 to 84 years

0

85 years and over

0

Subject disposition

Recruitment details

Subjects were recruited from 95 trial sites in 11 countries (Bulgaria, Canada, France, Germany, Lithuania, Poland, Russia, Slovakia, Spain, Ukraine and United States). First subject first visit: 12-Oct-2019 Last subject last visit/contact: 21-Apr-2023

Screening details

Main criteria: - 5-11 years of age - Clinical history of HDM allergic rhinitis/conjunctivitis (AR/C) (+/- asthma) and with AR symptoms despite having received symptom-relieving medication during 1 year prior to screening - Positive SPT and IgE against D. pteronysimus and/or D. farinae - FEV1 percent predicted ≥ 70%

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo

Arm type

Placebo

Investigational medicinal product name

Placebo SLIT-tablet

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral lyophilisate

Routes of administration

Sublingual use

Dosage and administration details

The subject was instructed to preferably take the tablet in the morning, placed under the tongue, and swallowing should be avoided for approximately 1 minute. Food and beverages should not be taken for 5 minutes after intake of IMP. When the first dose was administered, the subject was under medical supervision for a minimum of 30 minutes after the tablet intake.

12 SQ-HDM

Arm description

HDM SLIT-tablet (12 SQ-HDM)

Arm type

Experimental

Investigational medicinal product name

HDM SLIT-tablet

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral lyophilisate

Routes of administration

Sublingual use

Dosage and administration details

The subject was instructed to preferably take the tablet in the morning, placed under the tongue, and swallowing should be avoided for approximately 1 minute. Food and beverages should not be taken for 5 minutes after intake of IMP. When the first dose was administered, the subject was under medical supervision for a minimum of 30 minutes after the tablet intake.

Number of subjects in period 1	Placebo	12 SQ-HDM
Started	731	727
Completed	707	691
Not completed	24	36
Consent withdrawn by subject	8	12
Reason stated as "other" in CRF	7	7
Adverse event, non-fatal	6	14
Severe or persistent symptoms of oesophagitis	-	1
Lost to follow-up	3	2

Baseline characteristics

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

12 SQ-HDM

Reporting group description

HDM SLIT-tablet (12 SQ-HDM)

Reporting group values	Placebo	12 SQ-HDM	Total
Number of subjects	731	727	1458
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	731	727	1458
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Gender categorical
Units: Subjects
Female	254	241	495
Male	477	486	963

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

Full analysis set, defined as all randomised subjects who received at least 1 dose of IMP. Subjects were analysed as randomised, i.e., according to their randomised assignment of treatment.

Subject analysis set title

Safety analysis set

Subject analysis set type

Safety analysis

Subject analysis set description

Safety analysis set, defined as all randomised subjects who received at least 1 dose of IMP. Subjects were analysed as treated, i.e., according to the treatment they actually received.

Subject analysis sets values	Full analysis set	Safety analysis set
Number of subjects	1458	1458
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	1458	1458
Adolescents (12-17 years)	0	0
Adults (18-64 years)	0	0
From 65-84 years	0	0
85 years and over	0	0
Age continuous
Units:
	±	±
Gender categorical
Units: Subjects
Female	495	495
Male	963	963

End points

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

12 SQ-HDM

Reporting group description

HDM SLIT-tablet (12 SQ-HDM)

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

Full analysis set, defined as all randomised subjects who received at least 1 dose of IMP. Subjects were analysed as randomised, i.e., according to their randomised assignment of treatment.

Subject analysis set title

Safety analysis set

Subject analysis set type

Safety analysis

Subject analysis set description

Safety analysis set, defined as all randomised subjects who received at least 1 dose of IMP. Subjects were analysed as treated, i.e., according to the treatment they actually received.

Primary: Average daily total combined rhinitis symptoms and medication use (TCRS) during the primary efficacy assessment period

End point title

Average daily total combined rhinitis symptoms and medication use (TCRS) during the primary efficacy assessment period

End point description

The primary endpoint of the trial was the average daily total combined rhinitis symptoms and medication use (TCRS) during the primary efficacy assessment period. The average daily TCRS evaluates the treatment effect based on the reduction in daily rhinitis symptoms and medication use (on a scale of 0-24). Higher scores indicate more severe symptoms and/or more medication use.

End point type

Primary

End point timeframe

8 weeks (primary efficacy assessment period), which started 44-49 weeks after initiation of IMP

End point values	Placebo	12 SQ-HDM
Number of subjects analysed	706 ^[1]	693 ^[2]
Units: Adjusted mean
least squares mean (standard error)	4.4 ± 0.3	3.4 ± 0.3

Notes
[1] - Subjects from the full analysis set with observations in the primary efficacy assessment period
[2] - Subjects from the full analysis set with observations in the primary efficacy assessment period

Primary analysis

Statistical analysis description

The average daily TCRS was analysed using a linear mixed effect (LME) model with square root transformation. The model includes the square root of the endpoint as response variable, treatment and cohort as fixed factors, the square root of the baseline value as a covariate, country/region within cohort as a random effect, and with different residual errors specified for each treatment. No missing data approach was applied.

Comparison groups

Placebo v 12 SQ-HDM

Number of subjects included in analysis

1399

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Linear mixed effect (LME)

Parameter type

Mean difference (final values)

Point estimate

1

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

1.4

Secondary: Average rhinitis daily symptom score (DSS) during the primary efficacy assessment period

End point title

Average rhinitis daily symptom score (DSS) during the primary efficacy assessment period

End point description

Average rhinitis daily symptom score (DSS) evaluates the treatment effect based on the reduction in daily rhinitis symptoms (on a scale of 0-12). Higher scores indicate more severe symptoms.

End point type

Secondary

End point timeframe

8 weeks (primary efficacy assessment period), which started 44-49 weeks after initiation of IMP

End point values	Placebo	12 SQ-HDM
Number of subjects analysed	706 ^[3]	693 ^[4]
Units: Adjusted mean
least squares mean (standard error)	1.9 ± 0.1	1.5 ± 0.1

Notes
[3] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
[4] - Subjects from the full analysis set with observations in the primary efficacy assessment period.

Analysis of key secondary endpoint

Statistical analysis description

The average rhinitis DSS was analysed using a linear mixed effect (LME) model with square root transformation. The model includes the square root of the endpoint as response variable, treatment and cohort as fixed factors, the square root of the baseline value as a covariate, country/region within cohort as a random effect, and with different residual errors specified for each treatment. No missing data approach was applied.

Comparison groups

Placebo v 12 SQ-HDM

Number of subjects included in analysis

1399

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Linear mixed effect (LME)

Parameter type

Mean difference (final values)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

0.6

Secondary: Average rhinitis daily medication score (DMS) during the primary efficacy assessment period

End point title

Average rhinitis daily medication score (DMS) during the primary efficacy assessment period

End point description

Average rhinitis daily medication score (DMS) evaluates the treatment effect based on the reduction in daily rhinitis medication use (on a scale of 0-12). Higher scores indicate more medication use.

End point type

Secondary

End point timeframe

8 weeks (primary efficacy assessment period), which started 44-49 weeks after initiation of IMP

End point values	Placebo	12 SQ-HDM
Number of subjects analysed	706 ^[5]	693 ^[6]
Units: Adjusted mean
least squares mean (standard error)	1.9 ± 0.2	1.4 ± 0.2

Notes
[5] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
[6] - Subjects from the full analysis set with observations in the primary efficacy assessment period.

Analysis of key secondary endpoint

Statistical analysis description

The average rhinitis DMS was analysed using a linear mixed effect (LME) model with square root transformation. The model includes the square root of the endpoint as response variable, treatment and cohort as fixed factors, the square root of the baseline value as a covariate, country/region within cohort as a random effect, and with different residual errors specified for each treatment. No missing data approach was applied.

Comparison groups

Placebo v 12 SQ-HDM

Number of subjects included in analysis

1399

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016

Method

Linear mixed effect (LME)

Parameter type

Mean difference (final values)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

0.8

Secondary: Average daily total combined score (TCS) during the primary efficacy assessment period

End point title

Average daily total combined score (TCS) during the primary efficacy assessment period

End point description

Average rhinoconjunctivitis total combined score (TCS) evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis symptoms and medication use (on a scale of 0-38). Higher scores indicate more severe symptoms and/or more medication use.

End point type

Secondary

End point timeframe

8 weeks (primary efficacy assessment period), which started 44-49 weeks after initiation of IMP

End point values	Placebo	12 SQ-HDM
Number of subjects analysed	706 ^[7]	693 ^[8]
Units: Adjusted mean
least squares mean (standard error)	5.2 ± 0.4	4.0 ± 0.4

Notes
[7] - Subjects from the full analysis set with observations in the primary efficacy assessment period.
[8] - Subjects from the full analysis set with observations in the primary efficacy assessment period.

Analysis of key secondary endpoint

Statistical analysis description

The average rhinitis TCS was analysed using a linear mixed effect (LME) model with square root transformation. The model includes the square root of the endpoint as response variable, treatment and cohort as fixed factors, the square root of the baseline value as a covariate, country/region within cohort as a random effect, and with different residual errors specified for each treatment. No missing data approach was applied.

Comparison groups

Placebo v 12 SQ-HDM

Number of subjects included in analysis

1399

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Linear mixed effect (LME)

Parameter type

Mean difference (final values)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

1.7

Adverse events

Timeframe for reporting adverse events

AEs were collected from consent to last follow-up phone contact. Only treatment-emergent AEs are presented (AEs with start time on or after the time of first IMP administration and no later than 7 days after the last day of IMP administration).

Adverse event reporting additional description

For the first 28 days of treatment, subjects used an eDiary daily to capture presence/absence of 15 pre-specified signs/symptoms, identified as local side effects of sublingual immunotherapy. These were assessed and reported as AEs in the eCRF at the discretion of the investigator and are included in TEAEs presented.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

23

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

12 SQ-HDM

Reporting group description

HDM SLIT-tablet (12 SQ-HDM)

Serious adverse events	Placebo	12 SQ-HDM
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 731 (0.82%)	16 / 727 (2.20%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Carbon monoxide poisoning
subjects affected / exposed	1 / 731 (0.14%)	0 / 727 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Immune system disorder
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Testicular torsion
subjects affected / exposed	1 / 731 (0.14%)	0 / 727 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Attention deficit hyperactivity disorder
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hallucinations, mixed
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Gastroenteritis norovirus
subjects affected / exposed	0 / 731 (0.00%)	2 / 727 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 731 (0.27%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonas bronchitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 731 (0.00%)	1 / 727 (0.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 731 (0.14%)	0 / 727 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 731 (0.14%)	0 / 727 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	12 SQ-HDM
Total subjects affected by non serious adverse events
subjects affected / exposed	534 / 731 (73.05%)	608 / 727 (83.63%)
Nervous system disorders
Taste disorder
subjects affected / exposed	116 / 731 (15.87%)	123 / 727 (16.92%)
occurrences all number	218	213
Ear and labyrinth disorders
Ear pruritus
subjects affected / exposed	135 / 731 (18.47%)	242 / 727 (33.29%)
occurrences all number	299	547
Gastrointestinal disorders
Oral pruritus
subjects affected / exposed	185 / 731 (25.31%)	419 / 727 (57.63%)
occurrences all number	425	1149
Abdominal pain upper
subjects affected / exposed	164 / 731 (22.44%)	243 / 727 (33.43%)
occurrences all number	320	512
Lip swelling
subjects affected / exposed	38 / 731 (5.20%)	151 / 727 (20.77%)
occurrences all number	63	282
Glossodynia
subjects affected / exposed	41 / 731 (5.61%)	142 / 727 (19.53%)
occurrences all number	54	313
Nausea
subjects affected / exposed	81 / 731 (11.08%)	135 / 727 (18.57%)
occurrences all number	125	260
Mouth swelling
subjects affected / exposed	27 / 731 (3.69%)	99 / 727 (13.62%)
occurrences all number	41	210
Swollen tongue
subjects affected / exposed	20 / 731 (2.74%)	99 / 727 (13.62%)
occurrences all number	29	203
Diarrhoea
subjects affected / exposed	74 / 731 (10.12%)	95 / 727 (13.07%)
occurrences all number	107	151
Mouth ulceration
subjects affected / exposed	53 / 731 (7.25%)	93 / 727 (12.79%)
occurrences all number	80	162
Tongue ulceration
subjects affected / exposed	27 / 731 (3.69%)	50 / 727 (6.88%)
occurrences all number	34	82
Vomiting
subjects affected / exposed	33 / 731 (4.51%)	48 / 727 (6.60%)
occurrences all number	38	76
Tooth loss
subjects affected / exposed	35 / 731 (4.79%)	40 / 727 (5.50%)
occurrences all number	61	66
Respiratory, thoracic and mediastinal disorders
Throat irritation
subjects affected / exposed	236 / 731 (32.28%)	401 / 727 (55.16%)
occurrences all number	504	1072
Pharyngeal irritation
subjects affected / exposed	22 / 731 (3.01%)	68 / 727 (9.35%)
occurrences all number	33	134
Asthma
subjects affected / exposed	38 / 731 (5.20%)	14 / 727 (1.93%)
occurrences all number	49	16
Infections and infestations
Nasopharyngitis
subjects affected / exposed	164 / 731 (22.44%)	185 / 727 (25.45%)
occurrences all number	206	250
COVID-19
subjects affected / exposed	38 / 731 (5.20%)	38 / 727 (5.23%)
occurrences all number	38	38
Pharyngitis
subjects affected / exposed	37 / 731 (5.06%)	38 / 727 (5.23%)
occurrences all number	49	44
Bronchitis
subjects affected / exposed	45 / 731 (6.16%)	36 / 727 (4.95%)
occurrences all number	52	42
Upper respiratory tract infection
subjects affected / exposed	37 / 731 (5.06%)	22 / 727 (3.03%)
occurrences all number	53	29

More information

Were there any global substantial amendments to the protocol? Yes

13 Dec 2019

The amendment was prepared to update selected inclusion criteria and the main changes were: - For subjects for whom medical records of HDM AR/C diagnosis were not available, verbal history from subject/parent/caregiver could be used - Subjects that were 7 years old or younger and did not have asthma were not required to meet the inclusion criterion of FEV1 ≥ 70%, if despite coaching they were not able to perform a reproducible FEV1 manoeuvre

19 Mar 2021

The trial started before the COVID-19 pandemic and ended during the pandemic. At the outbreak of the COVID-19 pandemic, measures to protect the safety and integrity of trial subjects were implemented in March and April 2020 (see also Section on Trial Interruptions). An amendment was later prepared, in which the main changes included updates to trial procedures to mitigate the risks associated with the COVID-19 pandemic.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
20 Mar 2020	Due to the COVID-19 pandemic, screening and randomisation of cohort 1 was stopped on 20-Mar-2020 prior to the planned deadline of 01-Apr-2020. Subjects screened in Cohort 1 (but not randomised) were screen failed and offered a re-screening in Cohort 2. Screening of subjects for Cohort 2 was initiated as planned on 07-July-2020. A cohort 3 was subsequently added to recruit a sufficient number of subjects. Generally, the following mitigations were implemented due to COVID-19: - Option to convert on-site visits to remote visits via telephone or video was introduced - Introduction of direct-to-patient shipment of IMP and rescue medication, if on-site pick-up was not possible - Option to perform remote monitoring visits over telephone was introduced	07 Jul 2020

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None.

3

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