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Clinical Trial Results:
Randomized placebo controlled trial assessing the efficacy and safety of BP1.4979 in smoking cessation

Summary
EudraCT number	2012-002731-28
Trial protocol	CZ PL
Global end of trial date	09 Oct 2014

Results information
Results version number	v1(current)
This version publication date	26 Jun 2022
First version publication date	26 Jun 2022
Other versions

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

P12-01/BP1.4979

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bioprojet

Sponsor organisation address

9 Rue Rameau, Paris, France, 75002

Public contact

Clinical Development Director, Bioprojet Pharma, +33 1 47 03 66 33, contact@bioprojet.com

Scientific contact

Clinical Development Director, Bioprojet Pharma, +33 1 47 03 66 33, contact@bioprojet.com

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

18 Apr 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Jul 2014

Global end of trial reached?

Yes

Global end of trial date

09 Oct 2014

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to assess efficacy on smoking abstinence of BP1.4979 administered at 3, 10, 15 mg o.d. vs placebo during 12 weeks in healthy male or female heavy smokers.

Protection of trial subjects

The study was conducted according to ICH and GCP guidelines related to subject's welfare. A Data Safety Monitoring Board (DSMB) was implemented and served to monitor the study progress and safety data. The SDMC reviewed blinded study information during the conduct of the study and provided the sponsor with recommendations regarding study modification, continuation or termination. Monitoring visits to the study centers were conducted periodically during the study, in order to ensure that the clinical investigators continued to meet their contractual, clinical and regulatory obligations with regard to protocol compliance, adherence to regulatory and ethical requirements and the protection of the patients’ rights and safety.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Feb 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 81

Country: Number of subjects enrolled

Czechia: 41

Country: Number of subjects enrolled

France: 96

Worldwide total number of subjects

218

EEA total number of subjects

218

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)

217

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

During the screening visit, the investigator checked the inclusion and exclusion criteria and performed all required screening assessments. 290 patients were screened for inclusion. Of those, 219 patients were randomized and 218 were enrolled and started study treatment.

Period 1 title

Double-Blind (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

Prior to the start of the study, a copy of the master randomization code was supplied in sealed envelopes to the Investigator and pharmacist, and the bioanalytical centre. These copies were stored in confidential manner up to the unblinding after database lock. The study blind was to be only broken after database lock except in the case of emergency to protect patients.

Are arms mutually exclusive

Yes

BP1.4979 3mg treatment arm (Double-blind period)

Arm description

Patients receiving one tablet of BP1.4979 3 mg orally daily.

Arm type

Experimental

Investigational medicinal product name

BP1.4979

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients were to take one tablet of 3mg per day in the morning during breakfast with a glass of water for 12 weeks.

BP1.4979 10 mg treatment arm (Double-blind period)

Arm description

Patients receiving one tablet of BP1.4979 10 mg orally daily.

Arm type

Experimental

Investigational medicinal product name

BP1.4979

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients were to take one tablet of 10mg per day in the morning during breakfast with a glass of water for 12 weeks.

BP1.4979 15 mg treatment arm (Double-blind period)

Arm description

Patients receiving one tablet of BP1.4979 15 mg orally daily.

Arm type

Experimental

Investigational medicinal product name

BP1.4979

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients were to take one tablet of 15 mg per day in the morning during breakfast with a glass of water for 12 weeks.

Placebo treatment arm (Double-blind period)

Arm description

Patients taking one placebo tablet orally daily

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients were to take one tablet of placebo per day in the morning during breakfast with a glass of water for 12 weeks.

Number of subjects in period 1	BP1.4979 3mg treatment arm (Double-blind period)	BP1.4979 10 mg treatment arm (Double-blind period)	BP1.4979 15 mg treatment arm (Double-blind period)	Placebo treatment arm (Double-blind period)
Started	52	53	58	55
Completed	37	35	30	33
Not completed	15	18	28	22
Other	15	18	28	22

Baseline characteristics

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Reporting group title

BP1.4979 3mg treatment arm (Double-blind period)

Reporting group description

Patients receiving one tablet of BP1.4979 3 mg orally daily.

Reporting group title

BP1.4979 10 mg treatment arm (Double-blind period)

Reporting group description

Patients receiving one tablet of BP1.4979 10 mg orally daily.

Reporting group title

BP1.4979 15 mg treatment arm (Double-blind period)

Reporting group description

Patients receiving one tablet of BP1.4979 15 mg orally daily.

Reporting group title

Placebo treatment arm (Double-blind period)

Reporting group description

Patients taking one placebo tablet orally daily

Reporting group values	BP1.4979 3mg treatment arm (Double-blind period)	BP1.4979 10 mg treatment arm (Double-blind period)	BP1.4979 15 mg treatment arm (Double-blind period)	Placebo treatment arm (Double-blind period)	Total
Number of subjects	52	53	58	55	218
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	52	53	57	55	217
From 65-84 years	0	0	1	0	1
85 years and over	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	45.9 ( 10.8 )	48.4 ( 10.4 )	46.2 ( 9.1 )	43.4 ( 8.7 )	-
Gender categorical
Units: Subjects
Female	28	20	26	32	106
Male	24	33	32	23	112

End points

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Reporting group title

BP1.4979 3mg treatment arm (Double-blind period)

Reporting group description

Patients receiving one tablet of BP1.4979 3 mg orally daily.

Reporting group title

BP1.4979 10 mg treatment arm (Double-blind period)

Reporting group description

Patients receiving one tablet of BP1.4979 10 mg orally daily.

Reporting group title

BP1.4979 15 mg treatment arm (Double-blind period)

Reporting group description

Patients receiving one tablet of BP1.4979 15 mg orally daily.

Reporting group title

Placebo treatment arm (Double-blind period)

Reporting group description

Patients taking one placebo tablet orally daily

Primary: Continuous Abstinence Proportion (CAP)

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End point title

Continuous Abstinence Proportion (CAP)

End point description

The primary efficacy criterion was the CAP defined as the ratio of abstinence period over the treatment period (Double-blind). The continuous abstinence was measured from the patient’s diary and was to be confirmed by exhaled CO (≤10 ppm).

End point type

Primary

End point timeframe

From beginning of treatment to end of double-blind treatment period

End point values	BP1.4979 3mg treatment arm (Double-blind period)	BP1.4979 10 mg treatment arm (Double-blind period)	BP1.4979 15 mg treatment arm (Double-blind period)	Placebo treatment arm (Double-blind period)
Number of subjects analysed	10 ^[1]	9 ^[2]	8 ^[3]	14 ^[4]
Units: CAP
arithmetic mean (standard deviation)	57.0 ( 36.1 )	45.9 ( 27.0 )	59.1 ( 28.1 )	53.3 ( 24.8 )

Notes
[1] - The CAP was calculated in patients who were abstinent during the study.
[2] - The CAP was calculated in patients who were abstinent during the study.
[3] - The CAP was calculated in patients who were abstinent during the study.
[4] - The CAP was calculated in patients who were abstinent during the study.

Linear mixed model adjusted

Statistical analysis description

No statistically significant difference between treatment groups was shown using the linear mixed model adjusted for the baseline FTND (Fagerström Test of Nicotine Dependence).

Comparison groups

BP1.4979 10 mg treatment arm (Double-blind period) v BP1.4979 3mg treatment arm (Double-blind period) v BP1.4979 15 mg treatment arm (Double-blind period) v Placebo treatment arm (Double-blind period)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Mixed models analysis

Confidence interval

Secondary: Daily cigarettes consumption

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End point title

Daily cigarettes consumption

End point description

Mean change in the daily cigarette consumption from baseline to V4.

End point type

Secondary

End point timeframe

From beginning of treatment to end of double-blind treatment period.

End point values	BP1.4979 3mg treatment arm (Double-blind period)	BP1.4979 10 mg treatment arm (Double-blind period)	BP1.4979 15 mg treatment arm (Double-blind period)	Placebo treatment arm (Double-blind period)
Number of subjects analysed	41	35	35	33
Units: Number of cigarettes per day
arithmetic mean (standard deviation)	-9.3 ( 7.0 )	-10.6 ( 8.9 )	-11.7 ( 7.2 )	-11.6 ( 7.4 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From beginning of treatment to 1 week after end of treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

6.1

Reporting group title

BP1.4979 3mg treatment arm

Reporting group description

Patients who received BP1.4979 3mg during Double-blind period.

Reporting group title

BP1.4979 10 mg treatment arm

Reporting group description

Patients who received BP1.4979 10 mg during Double-blind period.

Reporting group title

P1.4979 15 mg treatment arm

Reporting group description

Patients who received BP1.4979 15 mg during Double-blind period.

Reporting group title

Placebo arm

Reporting group description

Patients taking placebo during Double-blind period.

Serious adverse events	BP1.4979 3mg treatment arm	BP1.4979 10 mg treatment arm	P1.4979 15 mg treatment arm	Placebo arm
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 52 (0.00%)	1 / 53 (1.89%)	1 / 58 (1.72%)	2 / 55 (3.64%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0
Investigations
Investigation
Additional description: The patient was hospitalized to perform a Ventilatory Polygraphy for Obstructive Sleep Apnea syndrome (OSA) suspicion with a complaint of blockpnea.
subjects affected / exposed	0 / 52 (0.00%)	0 / 53 (0.00%)	0 / 58 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Surgery
Additional description: Surgery for inguinal hernia (10mg treatment arm) Surgery for discal hernia (placebo arm)
subjects affected / exposed	0 / 52 (0.00%)	1 / 53 (1.89%)	0 / 58 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 52 (0.00%)	0 / 53 (0.00%)	1 / 58 (1.72%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	BP1.4979 3mg treatment arm	BP1.4979 10 mg treatment arm	P1.4979 15 mg treatment arm	Placebo arm
Total subjects affected by non serious adverse events
subjects affected / exposed	26 / 52 (50.00%)	37 / 53 (69.81%)	42 / 58 (72.41%)	34 / 55 (61.82%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 52 (0.00%)	1 / 53 (1.89%)	1 / 58 (1.72%)	2 / 55 (3.64%)
occurrences all number	0	1	1	3
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 52 (0.00%)	1 / 53 (1.89%)	1 / 58 (1.72%)	3 / 55 (5.45%)
occurrences all number	0	1	1	3
Influenza like illness
subjects affected / exposed	1 / 52 (1.92%)	1 / 53 (1.89%)	3 / 58 (5.17%)	0 / 55 (0.00%)
occurrences all number	1	1	3	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	2 / 52 (3.85%)	0 / 53 (0.00%)	0 / 58 (0.00%)	0 / 55 (0.00%)
occurrences all number	2	0	0	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	0 / 52 (0.00%)	3 / 53 (5.66%)	2 / 58 (3.45%)	0 / 55 (0.00%)
occurrences all number	0	3	2	0
Cough
subjects affected / exposed	0 / 52 (0.00%)	0 / 53 (0.00%)	2 / 58 (3.45%)	0 / 55 (0.00%)
occurrences all number	0	0	2	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 52 (0.00%)	4 / 53 (7.55%)	3 / 58 (5.17%)	2 / 55 (3.64%)
occurrences all number	0	4	4	2
Anxiety
subjects affected / exposed	1 / 52 (1.92%)	1 / 53 (1.89%)	2 / 58 (3.45%)	0 / 55 (0.00%)
occurrences all number	1	1	2	0
Depression
subjects affected / exposed	0 / 52 (0.00%)	0 / 53 (0.00%)	0 / 58 (0.00%)	3 / 55 (5.45%)
occurrences all number	0	0	0	3
Sleep disorder
subjects affected / exposed	1 / 52 (1.92%)	2 / 53 (3.77%)	0 / 58 (0.00%)	0 / 55 (0.00%)
occurrences all number	1	2	0	0
Investigations
Laboratory test abnormal
subjects affected / exposed	0 / 52 (0.00%)	2 / 53 (3.77%)	2 / 58 (3.45%)	1 / 55 (1.82%)
occurrences all number	0	2	2	1
Weight increased
subjects affected / exposed	1 / 52 (1.92%)	2 / 53 (3.77%)	0 / 58 (0.00%)	1 / 55 (1.82%)
occurrences all number	1	2	0	1
Injury, poisoning and procedural complications
Ligament sprain
subjects affected / exposed	0 / 52 (0.00%)	2 / 53 (3.77%)	0 / 58 (0.00%)	0 / 55 (0.00%)
occurrences all number	0	2	0	0
Nervous system disorders
Headache
subjects affected / exposed	5 / 52 (9.62%)	5 / 53 (9.43%)	7 / 58 (12.07%)	5 / 55 (9.09%)
occurrences all number	6	8	8	11
Migraine
subjects affected / exposed	2 / 52 (3.85%)	1 / 53 (1.89%)	2 / 58 (3.45%)	0 / 55 (0.00%)
occurrences all number	3	1	3	0
Dizziness
subjects affected / exposed	0 / 52 (0.00%)	2 / 53 (3.77%)	0 / 58 (0.00%)	0 / 55 (0.00%)
occurrences all number	0	2	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 52 (0.00%)	0 / 53 (0.00%)	2 / 58 (3.45%)	2 / 55 (3.64%)
occurrences all number	0	0	2	2
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 52 (1.92%)	1 / 53 (1.89%)	4 / 58 (6.90%)	1 / 55 (1.82%)
occurrences all number	1	1	4	1
Diarrhoea
subjects affected / exposed	1 / 52 (1.92%)	1 / 53 (1.89%)	3 / 58 (5.17%)	0 / 55 (0.00%)
occurrences all number	1	1	3	0
Toothache
subjects affected / exposed	0 / 52 (0.00%)	2 / 53 (3.77%)	1 / 58 (1.72%)	1 / 55 (1.82%)
occurrences all number	0	2	1	1
Abdominal discomfort
subjects affected / exposed	1 / 52 (1.92%)	0 / 53 (0.00%)	0 / 58 (0.00%)	2 / 55 (3.64%)
occurrences all number	1	0	0	2
Dry mouth
subjects affected / exposed	0 / 52 (0.00%)	0 / 53 (0.00%)	0 / 58 (0.00%)	3 / 55 (5.45%)
occurrences all number	0	0	0	3
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 52 (0.00%)	1 / 53 (1.89%)	2 / 58 (3.45%)	1 / 55 (1.82%)
occurrences all number	0	1	2	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	6 / 52 (11.54%)	7 / 53 (13.21%)	8 / 58 (13.79%)	4 / 55 (7.27%)
occurrences all number	7	8	10	4
Bronchitis
subjects affected / exposed	3 / 52 (5.77%)	1 / 53 (1.89%)	2 / 58 (3.45%)	1 / 55 (1.82%)
occurrences all number	3	1	2	1
Urinary tract infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 53 (0.00%)	1 / 58 (1.72%)	2 / 55 (3.64%)
occurrences all number	0	0	1	2
Tooth abscess
subjects affected / exposed	0 / 52 (0.00%)	0 / 53 (0.00%)	2 / 58 (3.45%)	0 / 55 (0.00%)
occurrences all number	0	0	2	0
Metabolism and nutrition disorders
Increased appetite
subjects affected / exposed	1 / 52 (1.92%)	1 / 53 (1.89%)	2 / 58 (3.45%)	1 / 55 (1.82%)
occurrences all number	1	1	2	1

More information

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Were there any global substantial amendments to the protocol? Yes

27 Jul 2012

The name of visit 2 (V2) was changed to V-TQD (Tobacco Quit Date visit) leading to the change in the name of subsequent visits. A phone contact was decided 15 days before the follow-up visits V6, V7, and V8. If the patient was abstinent, the visit was maintained and in case of smoking resumption, the patient was withdrawn from the study. Modification of inclusion criteria No. 4 and No. 6, and non-inclusion criteria No. 4, No. 11, and No. 16. Update of the center/investigator list.

22 Oct 2012

Addition of questionnaires to assess sexual (PATHOS) and gambling addictions (BBGS) and extrapyramidal symptoms (SAS). Modification of inclusion criterion No. 10 to allow the inclusion of patients treated with fluoxetine and paroxetine. Update of the center/investigator list.

07 Nov 2012

Reduction of the follow-up period from 9 months to 3 months (Consequently, the telephone call approved in Amendment No1 was cancelled). Follow-up of all patients whether or not they had stop smoking. For Poland only: modification of inclusion criterion No. 11: “females of child-bearing potential must use a medically accepted highly effective method of birth control (e.g. combined contraceptive pills, progestogen-only pill (POP), intrauterine device (IUD), contraceptive implant (inserted for less than 3 years) and contraceptive patch (oestrogen and progestogen)).

18 Dec 2013

Modification of the exclusion criterion No. 11 in order to select patients without bias of smoking cigars or pipes and No. 16 in order to select patients without Nicotine treatment. In addition, based on the safety and efficacy analysis of the 46 patients who completed the 12-weeks double-blind period (at V4 as planned in the protocol) and on pharmacokinetic considerations, the possibility was accepted to increase the number of randomized patients from 250 to 350 in order to assess the effect of an additional arm of patients treated with 15 mg BP1.4979 b.i.d. for 12 weeks. The enrolment of new randomized patients had to lead to 5 balanced groups of 60 patients.

23 May 2014

Based on the futility analysis planned in the protocol and detailed in the Futility Analysis Plan (See Appendix 16.3.1) dated on 17 January 2014, the inclusion of randomized patients to assess the effect of an additional arm consisting in 15 mg BP1.4979 b.i.d. was not implemented. Addition of an interim analysis on both efficacy and safety results before the study completion, but after the completion of the treatment period. This required intermediate database lock on 01 April 2015.

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.

None reported

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Clinical trials

Clinical Trial Results:
Randomized placebo controlled trial assessing the efficacy and safety of BP1.4979 in smoking cessation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Continuous Abstinence Proportion (CAP)

Primary: Continuous Abstinence Proportion (CAP)

Secondary: Daily cigarettes consumption

Secondary: Daily cigarettes consumption

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: Randomized placebo controlled trial assessing the efficacy and safety of BP1.4979 in smoking cessation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Continuous Abstinence Proportion (CAP)

Primary: Continuous Abstinence Proportion (CAP)

Secondary: Daily cigarettes consumption

Secondary: Daily cigarettes consumption

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Randomized placebo controlled trial assessing the efficacy and safety of BP1.4979 in smoking cessation