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Clinical Trial Results:
“Ensayo clínico, ciego y de grupos paralelos para analizar diferencias en la seguridad de roflumilast administrado una vez al día en días alternos durante dos semanas respecto a la pauta habitual una vez al día”

Summary
EudraCT number	2011-006321-20
Trial protocol	ES
Global end of trial date	20 Apr 2016

Results information
Results version number	v1(current)
This version publication date	07 Apr 2021
First version publication date	07 Apr 2021
Other versions
Summary report(s)	Final report of results

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

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Trial information

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Sponsor protocol code

RO-FLU-2011

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Fundación Pública Andaluza Progreso y Salud

Sponsor organisation address

Parque Científico y Tecnológico Cartuja, Avda. Américo Vespucio, 15. Edificio S-2. 41092 Sevilla, Seville, Spain, 41092

Public contact

Marta Reboredo Ares, Fundación Pública Andaluza Progreso y Salud, 0034 955 04 04 50, gestionensayosclinicos.fps@juntadeandalucia.es

Scientific contact

Marta Reboredo Ares, Fundación Pública Andaluza Progreso y Salud, 0034 955 04 04 50, gestionensayosclinicos.fps@juntadeandalucia.es

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

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

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

Analysis stage

Final

Date of interim/final analysis

20 Apr 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 Apr 2016

Global end of trial reached?

Yes

Global end of trial date

20 Apr 2016

Was the trial ended prematurely?

Main objective of the trial

Analizar si la administración de roflumilast en días alternos durante 2 semanas disminuye la incidencia de abandonos por acontecimientos adversos cuando se compara con la posología habitual.

Protection of trial subjects

This clinical trial has been conducted in accordance with the principles set forth in the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments set forth by the World Medical Assemblies and the ICH guidelines for Good Clinical Practice.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 May 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 105

Worldwide total number of subjects

105

EEA total number of subjects

105

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

105

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Diagnosis of severe COPD according to GOLD criteria, assessed by post-bronchodilation spirometry (FEV1 < 50%, FEV1/FVC < 70% of theoretical); Age over 18 years; Previous smoking history > 15-20 packs/year; One exacerbation in the previous year; Clinical stability in the last 30 days; Recurrent cough and expectoration.

Screening details

Period 1 title

Recruitment and follow-up

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Experimental

Arm description

Arm type

Experimental

Investigational medicinal product name

Roflumilast

Investigational medicinal product code

Other name

Pharmaceutical forms

Compressed lozenge

Routes of administration

Oral use

Dosage and administration details

500 mg every 48 hours.

Control

Arm description

Arm type

Active comparator

Investigational medicinal product name

Roflumilast

Investigational medicinal product code

Other name

Pharmaceutical forms

Compressed lozenge

Routes of administration

Oral use

Dosage and administration details

500 mg every 24 hours.

Number of subjects in period 1	Experimental	Control
Started	50	55
Completed	49	53
Not completed	1	2
Consent withdrawn by subject	1	1
Lost to follow-up	-	1

Period 2 title

Data analysis

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Data analyst ^[1]

Are arms mutually exclusive

Yes

Experimental

Arm description

Arm type

Experimental

Investigational medicinal product name

Roflumilast

Investigational medicinal product code

Other name

Pharmaceutical forms

Compressed lozenge

Routes of administration

Oral use

Dosage and administration details

500 mg every 48 hours.

Control

Arm description

Arm type

Active comparator

Investigational medicinal product name

Roflumilast

Investigational medicinal product code

Other name

Pharmaceutical forms

Compressed lozenge

Routes of administration

Oral use

Dosage and administration details

500 mg every 24 hours.

Notes
[1] - The roles blinded appear inconsistent with a simple blinded trial.
Justification: This study is blinded only to the researcher performing the data analysis.

Number of subjects in period 2	Experimental	Control
Started	49	53
Completed	49	53

Baseline characteristics

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Reporting group title

Experimental

Reporting group description

Reporting group title

Control

Reporting group description

Reporting group values	Experimental	Control	Total
Number of subjects	50	55	105
Age categorical
Units: Subjects
>18 years	50	55	105
Age continuous
Units: years
arithmetic mean (standard deviation)	69.20 ( 8.69 )	66.89 ( 8.04 )	-
Gender categorical
No data are available on the gender of the participants. As this is a mandatory field that must be filled in, each group has been completed with 50% men and 50% women.
Units: Subjects
Female	25	28	53
Male	25	27	52
Cigarette packets/year
Units: cigarette packets/year
arithmetic mean (standard deviation)	57.93 ( 28.61 )	60.22 ( 30.73 )	-
Weight
Units: Kg
arithmetic mean (standard deviation)	84.29 ( 17.52 )	82.57 ( 18.81 )	-
Height
Units: Metres
arithmetic mean (standard deviation)	1.66 ( 0.07 )	4.67 ( 0.08 )	-
IMC
Units: Kg/m2
arithmetic mean (standard deviation)	30.29 ( 5.95 )	29.38 ( 6.11 )	-
Number of exacerbations in the previous year
Units: Number of exacerbations in the previous
arithmetic mean (standard deviation)	2.72 ( 1.64 )	2.83 ( 1.9 )	-
FVCcc
Units: FVCcc
arithmetic mean (standard deviation)	2297.02 ( 619.08 )	2357.22 ( 675.38 )	-
FVC %
Units: FVC %
arithmetic mean (standard deviation)	64.86 ( 13.55 )	61.95 ( 13.79 )	-
FEV 1 cc
Units: FEV 1 cc
arithmetic mean (standard deviation)	1126.66 ( 310.04 )	1130.37 ( 401.65 )	-
FEV 1 %
Units: FEV 1 %
arithmetic mean (standard deviation)	40.79 ( 7.03 )	37.57 ( 8.95 )	-
6' metres test
Units: 6' metres test
arithmetic mean (standard deviation)	374.45 ( 135.43 )	386.77 ( 121.82 )	-
CAT
Units: CAT
arithmetic mean (standard deviation)	17.68 ( 7.78 )	17.56 ( 7.44 )	-
Anxiety test
Units: Anxiety test
arithmetic mean (standard deviation)	5.4 ( 3.82 )	6.5 ( 4.11 )	-
Depression test
Units: Depression test
arithmetic mean (standard deviation)	4.26 ( 3.04 )	5.2 ( 4.24 )	-
BODE
Units: BODE
arithmetic mean (standard deviation)	4 ( 1.85 )	3.91 ( 1.59 )	-

End points

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Reporting group title

Experimental

Reporting group description

Reporting group title

Control

Reporting group description

Reporting group title

Experimental

Reporting group description

Reporting group title

Control

Reporting group description

Primary: Study dropout rate due to adverse events

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End point title

Study dropout rate due to adverse events ^[1]

End point description

The different adverse events that have been measured are: diarrhoea, nausea, weight loss, vomiting, anxiety, depression, nasopharyngitis, upper respiratory tract infection, lumbago, headache, bronchitis, insomnia, flu, vertigo, decreased appetite, pneumonia, hypersensitivity, gynaecomastia, tremor, dizziness, reflux, gastritis, dyspepsia, constipation, myalgia, malaise, fatigue and asthenia.

End point type

Primary

End point timeframe

During the study

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Not all the data required are available. However, the final analysis of the results is attached, in which all the information relating to the statistical analysis carried out appears.

End point values	Experimental	Control
Number of subjects analysed	49	53
Units: Participants
Drop-outs due to adverse events after the 2º visit	9	11
no drop-outs	40	42

No statistical analyses for this end point

Primary: Study dropout rate due to adverse events

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End point title

Study dropout rate due to adverse events ^[2]

End point description

End point type

Primary

End point timeframe

During the study

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Not all the data required are available. However, the final analysis of the results is attached, in which all the information relating to the statistical analysis carried out appears.

End point values	Experimental	Control
Number of subjects analysed	49	53
Units: Participants
drop-outs due to adverse events up to the 3º visit	15	12
no drop-outs	34	41

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

During the study

Assessment type

Systematic

Dictionary name

Not Known

Dictionary version

Reporting group title

Both groups

Reporting group description

Serious adverse events	Both groups
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 102 (0.00%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0

Frequency threshold for reporting non-serious adverse events: 4%

Non-serious adverse events	Both groups
Total subjects affected by non serious adverse events
subjects affected / exposed	102 / 102 (100.00%)
Nervous system disorders
nervousness
subjects affected / exposed	61 / 102 (59.80%)
occurrences all number	61
headache
subjects affected / exposed	51 / 102 (50.00%)
occurrences all number	51
insomnia
subjects affected / exposed	51 / 102 (50.00%)
occurrences all number	51
vertigo
subjects affected / exposed	11 / 102 (10.78%)
occurrences all number	11
General disorders and administration site conditions
MEG
subjects affected / exposed	20 / 102 (19.61%)
occurrences all number	20
asthenia
subjects affected / exposed	32 / 102 (31.37%)
occurrences all number	32
Immune system disorders
hypersensitivity
subjects affected / exposed	4 / 102 (3.92%)
occurrences all number	4
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	72 / 102 (70.59%)
occurrences all number	72
Nausea
subjects affected / exposed	35 / 102 (34.31%)
occurrences all number	35
weight loss
subjects affected / exposed	102 / 102 (100.00%)
occurrences all number	145
no weight gain
subjects affected / exposed	102 / 102 (100.00%)
occurrences all number	212
decreased appetite
subjects affected / exposed	44 / 102 (43.14%)
occurrences all number	44
dysgeusia
subjects affected / exposed	9 / 102 (8.82%)
occurrences all number	9
gastro-oesophageal reflux
subjects affected / exposed	21 / 102 (20.59%)
occurrences all number	21
gastritis
subjects affected / exposed	9 / 102 (8.82%)
occurrences all number	9
dyspepsia
subjects affected / exposed	12 / 102 (11.76%)
occurrences all number	12
constipation
subjects affected / exposed	10 / 102 (9.80%)
occurrences all number	10
fatigue
subjects affected / exposed	11 / 102 (10.78%)
occurrences all number	11
Reproductive system and breast disorders
gynaecomastia
subjects affected / exposed	1 / 102 (0.98%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
nasopharyngitis
subjects affected / exposed	6 / 102 (5.88%)
occurrences all number	6
Bronchitis
subjects affected / exposed	25 / 102 (24.51%)
occurrences all number	25
pneumonia
subjects affected / exposed	2 / 102 (1.96%)
occurrences all number	2
Psychiatric disorders
suicidal thoughts
subjects affected / exposed	1 / 102 (0.98%)
occurrences all number	1
dizziness
subjects affected / exposed	24 / 102 (23.53%)
occurrences all number	24
Musculoskeletal and connective tissue disorders
lumbar pain
subjects affected / exposed	27 / 102 (26.47%)
occurrences all number	27
tremor
subjects affected / exposed	52 / 102 (50.98%)
occurrences all number	52
myalgia
subjects affected / exposed	24 / 102 (23.53%)
occurrences all number	24
Infections and infestations
TRS Infection
subjects affected / exposed	11 / 102 (10.78%)
occurrences all number	11
flu symptoms
subjects affected / exposed	3 / 102 (2.94%)
occurrences all number	3

More information

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Were there any global substantial amendments to the protocol? Yes

02 Dec 2014

Inclusion of new centres and further specification of exclusion criteria that could lead to errors in the inclusion of participants in the study.

Were there any global interruptions to the trial? No

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

The major limitation of the study has been the recruitment of patients, the "n" foreseen in the development of the protocol was not reached, which has been a crucial point in the failure to demonstrate the initial hypothesis.

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Clinical trials

Clinical Trial Results:
“Ensayo clínico, ciego y de grupos paralelos para analizar diferencias en la seguridad de roflumilast administrado una vez al día en días alternos durante dos semanas respecto a la pauta habitual una vez al día”

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Study dropout rate due to adverse events

Primary: Study dropout rate due to adverse events

Primary: Study dropout rate due to adverse events

Primary: Study dropout rate due to adverse events

Adverse events

Adverse events

More information

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Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: “Ensayo clínico, ciego y de grupos paralelos para analizar diferencias en la seguridad de roflumilast administrado una vez al día en días alternos durante dos semanas respecto a la pauta habitual una vez al día”

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Study dropout rate due to adverse events

Primary: Study dropout rate due to adverse events

Primary: Study dropout rate due to adverse events

Primary: Study dropout rate due to adverse events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
“Ensayo clínico, ciego y de grupos paralelos para analizar diferencias en la seguridad de roflumilast administrado una vez al día en días alternos durante dos semanas respecto a la pauta habitual una vez al día”