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Clinical Trial Results:
A Phase II, Multicentre, Randomised, Double-Blind, Placebo-Controlled Study Comparing the Efficacy and Safety of Clonidine Lauriad® 50-µg and 100-µg Mucoadhesive Buccal Tablet (MBT) Applied Once Daily to Those of Placebo in the Prevention and Treatment of Chemoradiation Therapy-Induced Oral Mucositis in Patients with Head and Neck Cancer

Summary
EudraCT number	2009-014870-16
Trial protocol	FR ES DE HU
Global end of trial date	25 Nov 2016

Results information
Results version number	v2(current)
This version publication date	04 Feb 2018
First version publication date	29 Jul 2016
Other versions	v1
Version creation reason	New data added to full data set Addition of the 2-year Overall Survival follow-up 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

BA2009-28-01

ISRCTN number

US NCT number

NCT01385748

WHO universal trial number (UTN)

Sponsor organisation name

Onxeo

Sponsor organisation address

49 boulevard du Général Martial Valin, Paris, France, 75015

Public contact

Olivier de Beaumont, MD, Onxeo, 33 145587600,

Scientific contact

Olivier de Beaumont, MD, Onxeo, 33 145587600,

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

09 Oct 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 Aug 2014

Global end of trial reached?

Yes

Global end of trial date

25 Nov 2016

Was the trial ended prematurely?

Main objective of the trial

To demonstrate the efficacy of clonidine Lauriad® 50-μg and 100-μg mucoadhesive buccal tablet versus placebo in the prevention and treatment of chemoradiotherapy induced oral mucositis.

Protection of trial subjects

The following measures were put in place to protect patients: The doses of clonidine Lauriad used in the study (50 µg and 100 µg of clonidine) were lower than those normally taken for anti-hypertensive treatment in order to prevent hypotensive effects, as well as sedation and dry mouth. After the treatment was completed, there was a 4-week follow-up period to assess oral mucositis resolution and to record adverse events (AEs) and serious adverse events (SAEs). There is also a follow-up period until 2 years after the last patient's last visit (until September 2016) to collect data on survival and tumor status in all patients. Patients could have been discontinued from therapy or from the study for any of the following reasons: 1. Withdrawal of patient consent, or loss to follow-up, or inability to remain under medical observation including post-study examination. 2. Non-compliance by the patient or major deviation from the protocol by the investigator and/or the patient. 3. Occurrence of an SAE. 4. Any other situation where, in the opinion of the investigator, continuation of the study would not be in the interest of the patient, or could modify the benefits or the risks for the patients. 5. Discontinuation of the study.

Background therapy

Patients received treatment with the study medication one day to 3 days before the beginning of chemoradiation therapy for head and neck cancer (active phase) for up to 8 weeks, depending on the subject's prescribed radiation plan.

Evidence for comparator

Actual start date of recruitment

20 Apr 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 52

Country: Number of subjects enrolled

France: 88

Country: Number of subjects enrolled

Germany: 31

Country: Number of subjects enrolled

Hungary: 4

Country: Number of subjects enrolled

Switzerland: 2

Country: Number of subjects enrolled

United States: 6

Worldwide total number of subjects

183

EEA total number of subjects

175

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)

151

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 35 study centres, including clinical study sites in the United States, Switzerland, France, Hungary, Germany and Spain, enrolled patients into the study. The worldwide total number of subjects was the number of randomised patients (183). In total 202 patients were screened and 19 failed screening.

Screening details

Selected patients were male or female, aged > 18 years and suffering from a newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, or larynx histologically-confirmed, having undergone resective surgery and eligible for concurrent chemoradiation.

Period 1 title

Treatment period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Blinding implementation details

The blinding status and the break of the randomisation code were ensured according to the sponsor's standard operating procedures (SOPs). Measures taken to ensure that test drug/investigational product and placebo were indistinguishable and evidence that they were indistinguishable were also ensured according to the sponsor's SOPs. Procedures used to carry out blinding were sealed code list/envelopes.

Are arms mutually exclusive

Yes

Clonidine Lauriad 50-µg MBT

Arm description

Arm type

Experimental

Investigational medicinal product name

Clonidine Lauriad

Investigational medicinal product code

Other name

Pharmaceutical forms

Muco-adhesive buccal tablet

Routes of administration

Gingival use

Dosage and administration details

Each patient received 1 mucoadhesive buccal tablet containing 50 µg of clonidine Lauriad by gingival application one day to 3 days before the beginning of the chemoradiation therapy for up to 8 weeks, depending on the subject's prescribed radiation plan.

Clonidine Lauriad 100-µg MBT

Arm description

Arm type

Experimental

Investigational medicinal product name

Clonidine Lauriad

Investigational medicinal product code

Other name

Pharmaceutical forms

Muco-adhesive buccal tablet

Routes of administration

Gingival use

Dosage and administration details

Each patient received 1 mucoadhesive buccal tablet containing 100 µg of clonidine Lauriad by gingival application one day to 3 days before the beginning of the chemoradiation therapy for up to 8 weeks, depending on the subject's prescribed radiation plan.

Placebo MBT

Arm description

Arm type

Placebo

Investigational medicinal product name

Matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Muco-adhesive buccal tablet

Routes of administration

Gingival use

Dosage and administration details

Each patient received 1 placebo mucoadhesive buccal tablet by gingival application one day to 3 days before the beginning of the chemoradiation therapy for up to 8 weeks, depending on the subject's prescribed radiation plan.

Number of subjects in period 1	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT
Started	56	65	62
Completed	41	51	49
Not completed	15	14	13
Adverse event, serious fatal	4	2	1
Consent withdrawn by subject	7	4	5
Non compliance	3	1	6
Other reasons	1	7	1

Period 2 title

2 year follow-up

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

The break of the randomisation code was ensured according to the sponsor’s standard operating procedures (SOPs). No patient was under treatment during Period 2. The code break was carry out on Dec 2014 and the list of patients treatment was send to all investigators. The investigator was free to inform his patients.

Are arms mutually exclusive

Yes

Clonidine Lauriad 50-µg MBT

Arm description

Follow-up period until until 2-years after the date of Last Patient Completed, for patients who signed a specific inform consent form for survival data (OS) Patients were not treated in the follow-up period.

Arm type

Experimental

Investigational medicinal product name

Clonidine Lauriad

Investigational medicinal product code

Other name

Pharmaceutical forms

Muco-adhesive buccal tablet

Routes of administration

Gingival use

Dosage and administration details

No patient was under treatment during Period 2 (follow-up period)

Clonidine Lauriad 100-µg MBT

Arm description

Arm type

Experimental

Investigational medicinal product name

Clonidine Lauriad

Investigational medicinal product code

Other name

Pharmaceutical forms

Muco-adhesive buccal tablet

Routes of administration

Gingival use

Dosage and administration details

No patient was under treatment during Period 2 (follow-up period)

Placebo MBT

Arm description

Arm type

Placebo

Investigational medicinal product name

Matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Muco-adhesive buccal tablet

Routes of administration

Gingival use

Dosage and administration details

No patient was under treatment during Period 2 (follow-up period)

Number of subjects in period 2 ^[1]	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT
Started	35	42	39
Completed	35	42	39

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Follow-up survival period was added in study protocol amendment 9 in 2013. A specific inform consent form for survival data collection was signed by 116 patients alive at time of the amendment. The collection of OS data during the follow-up period was not possible in near 35% of the patients alive due to the lack of the signed specific OS inform consent form. This justifies the difference between the number of patients who completed the treatment period and patients starting the follow up period

Baseline characteristics

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Reporting group title

Clonidine Lauriad 50-µg MBT

Reporting group description

Reporting group title

Clonidine Lauriad 100-µg MBT

Reporting group description

Reporting group title

Placebo MBT

Reporting group description

Reporting group values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Total
Number of subjects	56	65	62	183
Age categorical
All baseline characteristics were analysed in the intention-to-treat (ITT) population.
Units: Subjects
Adults (18-64 years)	43	58	50	151
From 65 to 84 years	13	7	12	32
85 years and over	0	0	0	0
Age continuous
Units: years
median (full range (min-max))	58.8 (30 to 79)	55.7 (22 to 75)	56.6 (33 to 72)	-
Gender categorical
Units: Subjects
Female	16	16	13	45
Male	40	49	49	138
Ethnicity
Units: Subjects
Black	1	0	0	1
Caucasian	53	61	59	173
Other	2	4	3	9
ECOG
All patients showed no signs of oral mucositis at baseline. There was no obvious difference in disease characteristics between treatment groups. The Eastern Cooperative Oncology Group (ECOG) scores of the treatment groups is provided. The majority of patients had an ECOG score of 2.
Units: Subjects
Score 0	42	41	42	125
Score 1	14	22	20	56
Score 2	0	2	0	2
Disease location
The location of the squamous cell carcinoma at baseline is provided.
Units: Subjects
Oral cavity	26	37	30	93
Oropharynx	19	17	21	57
Hypopharynx	4	2	2	8
Larynx	4	6	5	15
Oral cavity/oropharynx	0	1	1	2
Oral cavity/hypopharynx	0	1	1	2
Oral cavity/larynx	1	0	0	1
Oropharynx/hypopharynx	2	1	1	4
Oropharynx/larynx	0	0	1	1
Disease location in oral cavity or oropharynx
The location of the squamous cell carcinoma (in oral cavity or oropharynx) is provided.
Units: Subjects
Yes	48	57	55	160
No	8	8	7	23
Mucosal irritation
The number of patients with mucosal irritation at baseline is provided.
Units: Subjects
Yes	2	2	1	5
No	53	63	61	177
Missing	1	0	0	1
Tooth extraction
Units: Subjects
Yes	30	32	32	94
No	25	32	30	87
Missing	1	1	0	2
Oral infection
The number of patients presenting with oral infection at baseline is provided.
Units: Subjects
Yes	0	1	0	1
No	55	64	62	181
Missing	1	0	0	1
Prior surgery
The number of patients having undergone prior surgery is provided.
Units: Subjects
Yes	55	64	61	180
No	1	1	1	3
Patients previously treated with radiotherapy and/or chemotherapy
The number of patients having been previously treated with radiotherapy and/or chemotherapy is provided.
Units: Subjects
Yes	54	62	61	177
No	2	3	1	6
Height
Units: cm
median (full range (min-max))	171 (153 to 182)	170 (147 to 186)	172 (145 to 190)	-
Weight
Units: kg
median (full range (min-max))	71.3 (44 to 130)	66 (43 to 123)	69 (48 to 115)	-
BMI
Body Mass Index.
Units: kg/m2
median (full range (min-max))	23.7 (16.1 to 44.4)	23.66 (16.8 to 40.3)	23.23 (16.9 to 43.8)	-
Alcohol consumption
Units: g/day
median (full range (min-max))	0 (0 to 45)	0 (0 to 100)	0 (0 to 50)	-
Disease duration
The duration of the squamous cell carcinoma at baseline is provided.
Units: months
median (full range (min-max))	2 (1 to 14)	2 (1 to 99)	2 (0 to 7)	-

Subject analysis set title

Clonidine Lauriad MBT Pooled

Subject analysis set type

Intention-to-treat

Subject analysis set description

Pool of patients who received 50 µg or 100 µg of clonidine Lauriad MBT.

Subject analysis set title

Overall study - Clonidine lauriad 50-µg MBT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Dataset including all patients who received at least 1 dose of investigational drug (ITT) in the Clonidine Lauriad 50 µg MBT arm, over a period of time going from the date of randomisation of the first parient until 2-years after the date of Last Patient Completed (Period 1 + Period 2)

Subject analysis set title

Overall study - Clonidine lauriad 100-µg MBT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Dataset including all patients who received at least 1 dose of investigational drug (ITT) in the Clonidine Lauriad 100 µg MBT arm, over a period of time going from the date of randomisation of the first parient until 2-years after the date of Last Patient Completed (Period 1 + Period 2)

Subject analysis set title

Overall study - Placebo MBT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Dataset including all patients who received at least 1 dose of investigational drug (ITT) in the Placebo MBT arm, over a period of time going from the date of randomisation of the first parient until 2-years after the date of Last Patient Completed (Period 1 + Period 2)

Subject analysis sets values	Clonidine Lauriad MBT Pooled	Overall study - Clonidine lauriad 50-µg MBT	Overall study - Clonidine lauriad 100-µg MBT	Overall study - Placebo MBT
Number of subjects	121	56	65	62
Age categorical
All baseline characteristics were analysed in the intention-to-treat (ITT) population.
Units: Subjects
Adults (18-64 years)	101
From 65 to 84 years	20
85 years and over	0
Age continuous
Units: years
median (full range (min-max))	57.6 (22 to 79)
Gender categorical
Units: Subjects
Female	32
Male	89
Ethnicity
Units: Subjects
Black	1
Caucasian	114
Other	6
ECOG
All patients showed no signs of oral mucositis at baseline. There was no obvious difference in disease characteristics between treatment groups. The Eastern Cooperative Oncology Group (ECOG) scores of the treatment groups is provided. The majority of patients had an ECOG score of 2.
Units: Subjects
Score 0	83
Score 1	36
Score 2	2
Disease location
The location of the squamous cell carcinoma at baseline is provided.
Units: Subjects
Oral cavity	63
Oropharynx	36
Hypopharynx	6
Larynx	10
Oral cavity/oropharynx	1
Oral cavity/hypopharynx	1
Oral cavity/larynx	1
Oropharynx/hypopharynx	3
Oropharynx/larynx	0
Disease location in oral cavity or oropharynx
The location of the squamous cell carcinoma (in oral cavity or oropharynx) is provided.
Units: Subjects
Yes	105
No	16
Mucosal irritation
The number of patients with mucosal irritation at baseline is provided.
Units: Subjects
Yes	4
No	116
Missing	1
Tooth extraction
Units: Subjects
Yes	62
No	57
Missing	2
Oral infection
The number of patients presenting with oral infection at baseline is provided.
Units: Subjects
Yes	1
No	119
Missing	1
Prior surgery
The number of patients having undergone prior surgery is provided.
Units: Subjects
Yes	119
No	2
Patients previously treated with radiotherapy and/or chemotherapy
The number of patients having been previously treated with radiotherapy and/or chemotherapy is provided.
Units: Subjects
Yes	116
No	5
Height
Units: cm
median (full range (min-max))	170 (147 to 186)
Weight
Units: kg
median (full range (min-max))	69 (43 to 130)
BMI
Body Mass Index.
Units: kg/m2
median (full range (min-max))	23.67 (16.1 to 44.4)
Alcohol consumption
Units: g/day
median (full range (min-max))	0 (0 to 100)
Disease duration
The duration of the squamous cell carcinoma at baseline is provided.
Units: months
median (full range (min-max))	2 (1 to 99)

End points

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Reporting group title

Clonidine Lauriad 50-µg MBT

Reporting group description

Reporting group title

Clonidine Lauriad 100-µg MBT

Reporting group description

Reporting group title

Placebo MBT

Reporting group description

Reporting group title

Clonidine Lauriad 50-µg MBT

Reporting group description

Reporting group title

Clonidine Lauriad 100-µg MBT

Reporting group description

Reporting group title

Placebo MBT

Reporting group description

Subject analysis set title

Clonidine Lauriad MBT Pooled

Subject analysis set type

Intention-to-treat

Subject analysis set description

Pool of patients who received 50 µg or 100 µg of clonidine Lauriad MBT.

Subject analysis set title

Overall study - Clonidine lauriad 50-µg MBT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Overall study - Clonidine lauriad 100-µg MBT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Overall study - Placebo MBT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Cumulative radiation dose at which severe oral mucositis (WHO score ≥ 3) was first observed

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End point title

Cumulative radiation dose at which severe oral mucositis (WHO score ≥ 3) was first observed

End point description

WHO score Grade 3 oral mucositis was defined as ulcers, extensive erythema, and the inability of the patient to swallow a solid diet. WHO score Grade 4 oral mucositis was defined as mucositis to the extent that alimentation was not possible. Each assessment of oral mucositis was associated with the actual cumulative dose of radiotherapy. The primary analysis of the primary endpoint was conducted on the ITT population. As EudraCT only allows numerical data entry, the value of 999 indicates "Not Reached" for the upper limit of the confidence intervals.

End point type

Primary

End point timeframe

The presence of Grade 3 or Grade 4 oral mucositis was assessed using the WHO score scale twice a week for up to 8 weeks during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	56	65	62	121
Units: Cumulative radiation dose (Gy)
median (confidence interval 95%)	66 (44 to 999)	56 (44 to 999)	48 (42 to 61.6)	60 (48 to 999)

Treatment effect of clonidine Lauriad 50-µg MBT

Statistical analysis description

For comparison of the three clonidine Lauriad groups, the log-rank test at 5% significance level was used. This was achieved within a model where treatment was coded with three levels (placebo, clonidine Lauriad 50-µg MBT, clonidine Lauriad 100-µg MBT) for the three pairwise comparisons. The treatment effect was estimated by the hazard ratio of the clonidine Lauriad 50-µg MBT to the placebo with its two-sided 95% confidence interval.

Comparison groups

Placebo MBT v Clonidine Lauriad 50-µg MBT

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.165

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.677

Confidence interval

level

95%

sides

2-sided

lower limit

0.387

upper limit

1.186

Treatment effect of clonidine Lauriad 100-µg MBT

Comparison groups

Clonidine Lauriad 100-µg MBT v Placebo MBT

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.421

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.817

Confidence interval

level

95%

sides

2-sided

lower limit

0.495

upper limit

1.35

Treatment effect of clonidine Lauriad MBT pooled

Statistical analysis description

For comparison of the clonidine Lauriad MBT (both doses pooled) versus placebo, the log-rank test at 5% significance level was used. This was achieved within a model where treatment was coded with two levels (placebo, clonidine). The treatment effect was estimated by the hazard ratio of the clonidine Lauriad MBT (both doses pooled) to the placebo with its two-sided 95% confidence interval.

Comparison groups

Placebo MBT v Clonidine Lauriad MBT Pooled

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.211

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.754

Confidence interval

level

95%

sides

2-sided

lower limit

0.484

upper limit

1.175

Secondary: Opioid use: At least one opioid (class 3 analgesic)

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End point title

Opioid use: At least one opioid (class 3 analgesic)

End point description

End point type

Secondary

End point timeframe

Opioid use was recorded twice weekly for up to 8 weeks during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	54	64	62	118
Units: Number of patients
Missing	2	1	0	3
Yes	23	30	30	53
No	31	34	32	65

No statistical analyses for this end point

Secondary: Opioid use: Minimal total cumulative dose administered

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End point title

Opioid use: Minimal total cumulative dose administered

End point description

Sum of non missing total cumulative doses across all class 3 analgesics recorded for the considered patient.

End point type

Secondary

End point timeframe

Opioid use was recorded twice weekly for up to 8 weeks during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	20	24	29	44
Units: morphine dose equivalent
arithmetic mean (standard deviation)	469.31 ± 633.51	415.49 ± 490.55	624.94 ± 958.81	439.95 ± 553.88

No statistical analyses for this end point

Secondary: Opioid use: Minimal total cumulative dose administered

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End point title

Opioid use: Minimal total cumulative dose administered

End point description

Sum of non missing total cumulative doses across all class 3 analgesics recorded for the considered patient.

End point type

Secondary

End point timeframe

Opioid use was recorded twice weekly for up to 8 weeks during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	20	24	29	44
Units: morphine dose equivalent
median (full range (min-max))	183.6 (12 to 2249.1)	174 (15 to 1804)	215 (20 to 3672)	178.65 (12 to 2249.1)

Clonidine Lauriad 50-µg MBT versus placebo

Comparison groups

Placebo MBT v Clonidine Lauriad 50-µg MBT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.807 ^[1]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[1] - Significance threshold = 5%

Clonidine Lauriad 100-µg MBT versus placebo

Comparison groups

Clonidine Lauriad 100-µg MBT v Placebo MBT

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.971 ^[2]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[2] - Significance threshold = 5%

Secondary: Death

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End point title

Death

End point description

Survival (patient alive or deceased) from the date of randomisation to the date of death from any cause. Patients without death at the time of the analysis were censored at the date they were last known to be alive.

End point type

Secondary

End point timeframe

During period 1 at each study visit and in the follow-up period (for patients who consented), around every 6 months for 2 years after last subject completed.

End point values	Overall study - Clonidine lauriad 50-µg MBT	Overall study - Clonidine lauriad 100-µg MBT	Overall study - Placebo MBT
Number of subjects analysed	56	65	62
Units: Number of death	18	13	18

No statistical analyses for this end point

Secondary: Overall survival

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End point title

Overall survival

End point description

OS was defined as the time from the date of randomisation to the date of death from any cause. Patients without death at the time of the analysis were censored at the date they were last known to be alive. As EudraCT only allows numerical data entry, the value of 999 indicates "Not Reached" for the upper limit of the confidence intervals.

End point type

Secondary

End point timeframe

During period 1 at each study visit and in the follow-up period (for patients who consented), around every 6 months for 2 years after last subject completed.

End point values	Overall study - Clonidine lauriad 50-µg MBT	Overall study - Clonidine lauriad 100-µg MBT	Overall study - Placebo MBT
Number of subjects analysed	56	65	62
Units: months
median (confidence interval 95%)	47 (17.3 to 999)	58.8 (35.9 to 999)	41.8 (27.7 to 999)

No statistical analyses for this end point

Secondary: Cause of death

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End point title

Cause of death

End point description

End point type

Secondary

End point timeframe

During period 1 at each study visit and in the follow-up period (for patients who consented), around every 6 months for 2 years after last subject completed.

End point values	Overall study - Clonidine lauriad 50-µg MBT	Overall study - Clonidine lauriad 100-µg MBT	Overall study - Placebo MBT
Number of subjects analysed	18	13	18
Units: Number of patients
Progressive disease	13	9	16
Unknown	2	2	2
Other	3	2	0

No statistical analyses for this end point

Other pre-specified: Time to onset of severe oral mucositis

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End point title

Time to onset of severe oral mucositis

End point description

Time to onset is the duration until first Severe Oral Mucositis. Severe Oral Mucositis was defined as a Grade 3 or Grade 4 WHO score. As EudraCT only allows numerical data entry, the value of 999 indicates "Not Reached" for the upper limit of the confidence intervals.

End point type

Other pre-specified

End point timeframe

The presence of Grade 3 or Grade 4 oral mucositis was assessed using the WHO score scale twice a week for up to 8 weeks during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	56	65	62	121
Units: weeks
median (confidence interval 95%)	6.4 (4.6 to 999)	6 (4.6 to 8)	5.1 (4.4 to 6.9)	6.4 (5.1 to 999)

Treatment effect of clonidine Lauriad 50-µg MBT

Comparison groups

Clonidine Lauriad 50-µg MBT v Placebo MBT

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.199 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.698

Confidence interval

level

95%

sides

2-sided

lower limit

0.398

upper limit

1.223

Notes
[3] - Significance threshold = 5%

Treatment effect of clonidine Lauriad 100-µg MBT

Comparison groups

Clonidine Lauriad 100-µg MBT v Placebo MBT

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.424 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.817

Confidence interval

level

95%

sides

2-sided

lower limit

0.493

upper limit

1.353

Notes
[4] - Significance threshold = 5%

Treatment effect of clonidine Lauriad MBT pooled

Comparison groups

Placebo MBT v Clonidine Lauriad MBT Pooled

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.235 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.764

Confidence interval

level

95%

sides

2-sided

lower limit

0.489

upper limit

1.193

Notes
[5] - Significance threshold = 5%

Other pre-specified: The maximum severity of oral mucositis

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End point title

The maximum severity of oral mucositis

End point description

The maximum severity of oral mucositis was the maximum score observed during the active phase.

End point type

Other pre-specified

End point timeframe

The presence of oral mucositis was assessed twice weekly for up to 8 weeks during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	56	65	62	121
Units: Number of patients
Grade 0	7	6	4	13
Grade 1	9	7	9	16
Grade 2	15	20	11	35
Grade 3	17	20	30	37
Grade 4	6	10	6	16
No value during the concerned period	2	2	2	4

Clonidine Lauriad 50-µg MBT versus placebo

Statistical analysis description

114 subjects were included in this analysis.

Comparison groups

Clonidine Lauriad 50-µg MBT v Placebo MBT

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.176 ^[6]

Method

Kruskal-wallis

Confidence interval

Notes
[6] - Significance threshold = 5%

Clonidine Lauriad 100-µg MBT versus placebo

Statistical analysis description

123 subjects were included in the analysis.

Comparison groups

Clonidine Lauriad 100-µg MBT v Placebo MBT

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.61 ^[7]

Method

Kruskal-wallis

Confidence interval

Notes
[7] - Significance threshold = 5%

Clonidine Lauriad MBT pooled versus placebo

Statistical analysis description

177 subjects were included in the analysis.

Comparison groups

Placebo MBT v Clonidine Lauriad MBT Pooled

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.295 ^[8]

Method

Kruskal-wallis

Confidence interval

Notes
[8] - Significance threshold = 5%

Other pre-specified: The overall incidence of Grade 3/4 mucositis during the active phase

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End point title

The overall incidence of Grade 3/4 mucositis during the active phase

End point description

Number of patients with at least one grade 3/4 mucositis.

End point type

Other pre-specified

End point timeframe

Assessed during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	56	65	62	121
Units: Number of patients
Missing	2	2	2	4
No	31	33	24	64
Yes	23	30	36	53

Clonidine Lauriad 50-µg MBT versus placebo

Comparison groups

Clonidine Lauriad 50-µg MBT v Placebo MBT

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.063 ^[9]

Method

Chi-squared

Confidence interval

Notes
[9] - Significance threshold = 5%

Clonidine Lauriad 100-µg MBT versus placebo

Comparison groups

Clonidine Lauriad 100-µg MBT v Placebo MBT

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.169 ^[10]

Method

Chi-squared

Confidence interval

Notes
[10] - Significance threshold = 5%

Clonidine Lauriad MBT pooled versus placebo

Comparison groups

Placebo MBT v Clonidine Lauriad MBT Pooled

Number of subjects included in analysis

183

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.064 ^[11]

Method

Chi-squared

Confidence interval

Notes
[11] - Significance threshold = 5%

Other pre-specified: Salivary flow assessment using the NCI-CTC scale (Xerostomia): Time to first grade 2 or more

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End point title

Salivary flow assessment using the NCI-CTC scale (Xerostomia): Time to first grade 2 or more

End point description

Apparition of a grade 2 or more on the following 4-point scoring scale: 0 = normal; 1 = symptomatic (dry or thick saliva) without significant dietary alteration (unstimulated saliva low > 0.2 mL/minute); 2 = symptomatic and significant oral intake alterations (e.g. copious water, other lubricants, diet limited to purees and/or soft, moist foods) (unstimluated saliva 0.1 to 0.2 mL/minute); and 3 = symptoms leading to inability to adequately aliment orally, intravenous fluids, tube feedings, or total parenteral nutrition indicated (unstimulated saliva < 0.1 mL/minute). As EudraCT only allows numerical data entry, the value of 999 indicates "Not Reached" for the upper limit of the confidence intervals.

End point type

Other pre-specified

End point timeframe

Assessed and scored by the investigator weekly for up to 8 weeks during the active phase (radiotherapy). This analysis was performed on the safety population.

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	55	64	62	119
Units: weeks
median (confidence interval 95%)	6 (4.9 to 9.4)	7.4 (6 to 999)	5.1 (4.1 to 7.1)	7.1 (5.7 to 9.4)

Treatment effect of clonidine Lauriad 50-µg MBT

Comparison groups

Clonidine Lauriad 50-µg MBT v Placebo MBT

Number of subjects included in analysis

117

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.388 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.824

Confidence interval

level

95%

sides

2-sided

lower limit

0.484

upper limit

1.401

Notes
[12] - Significance threshold = 5%

Treatment effect of clonidine Lauriad 100-µg MBT

Statistical analysis description

126 subjects were included in this analysis.

Comparison groups

Clonidine Lauriad 100-µg MBT v Placebo MBT

Number of subjects included in analysis

126

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.054 ^[13]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.601

Confidence interval

level

95%

sides

2-sided

lower limit

0.357

upper limit

1.012

Notes
[13] - Significance threshold = 5%

Treatment effect of clonidine Lauriad MBT pooled

Comparison groups

Placebo MBT v Clonidine Lauriad MBT Pooled

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.102 ^[14]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.692

Confidence interval

level

95%

sides

2-sided

lower limit

0.444

upper limit

1.078

Notes
[14] - Significance threshold = 5%

Other pre-specified: Overall treatment compliance according to the patient diary

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End point title

Overall treatment compliance according to the patient diary

End point description

Compliance = [ nb tablets / (end date of treatment - start date treatment + 1 ) ] * 100 The "number of tablets" is the number of days with a tablet applied and treatment start and end dates are the first and last dates of the patient diary with a tablet applied.

End point type

Other pre-specified

End point timeframe

All patients completed a daily questionnaire during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	55	64	62	119
Units: percent
arithmetic mean (standard deviation)	94.28 ± 8.23	93.12 ± 11.89	96.12 ± 5.59	93.66 ± 10.34

No statistical analyses for this end point

Other pre-specified: Overall treatment compliance according to the patient diary

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End point title

Overall treatment compliance according to the patient diary

End point description

End point type

Other pre-specified

End point timeframe

All patients completed a daily questionnaire during the active phase (radiotherapy).

End point values	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled
Number of subjects analysed	55	64	62	119
Units: percent
median (full range (min-max))	96.97 (63.2 to 100)	98.02 (42.9 to 100)	98.15 (72 to 100)	97.78 (42.9 to 100)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were recorded during the treatment period, and for 4 weeks after treatment was completed.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Clonidine Lauriad 50-µg MBT

Reporting group description

Reporting group title

Clonidine Lauriad 100-µg MBT

Reporting group description

Reporting group title

Placebo MBT

Reporting group description

Reporting group title

Clonidine Lauriad MBT Pooled

Reporting group description

Reporting group title

All patients

Reporting group description

Serious adverse events	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled	All patients
Total subjects affected by serious adverse events
subjects affected / exposed	16 / 55 (29.09%)	21 / 64 (32.81%)	14 / 62 (22.58%)	37 / 119 (31.09%)	51 / 181 (28.18%)
number of deaths (all causes)	1	0	0	1	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
Vascular disorders
Hypotension
subjects affected / exposed	2 / 55 (3.64%)	0 / 64 (0.00%)	0 / 62 (0.00%)	2 / 119 (1.68%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
General physical health deterioration
subjects affected / exposed	4 / 55 (7.27%)	1 / 64 (1.56%)	0 / 62 (0.00%)	5 / 119 (4.20%)	5 / 181 (2.76%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	1 / 62 (1.61%)	1 / 119 (0.84%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Localised oedema
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	1 / 62 (1.61%)	1 / 119 (0.84%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 55 (1.82%)	1 / 64 (1.56%)	0 / 62 (0.00%)	2 / 119 (1.68%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Testicular oedema
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 55 (1.82%)	1 / 64 (1.56%)	0 / 62 (0.00%)	2 / 119 (1.68%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	1 / 62 (1.61%)	1 / 119 (0.84%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound complication
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	1 / 55 (1.82%)	1 / 64 (1.56%)	0 / 62 (0.00%)	2 / 119 (1.68%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Stomatitis
subjects affected / exposed	2 / 55 (3.64%)	4 / 64 (6.25%)	2 / 62 (3.23%)	6 / 119 (5.04%)	8 / 181 (4.42%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 2	0 / 6	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	2 / 55 (3.64%)	2 / 64 (3.13%)	2 / 62 (3.23%)	4 / 119 (3.36%)	6 / 181 (3.31%)
occurrences causally related to treatment / all	0 / 2	0 / 2	1 / 2	0 / 4	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 55 (1.82%)	3 / 64 (4.69%)	0 / 62 (0.00%)	4 / 119 (3.36%)	4 / 181 (2.21%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 55 (0.00%)	2 / 64 (3.13%)	0 / 62 (0.00%)	2 / 119 (1.68%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral pain
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	1 / 55 (1.82%)	3 / 64 (4.69%)	3 / 62 (4.84%)	4 / 119 (3.36%)	7 / 181 (3.87%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 4	0 / 6	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection
subjects affected / exposed	2 / 55 (3.64%)	1 / 64 (1.56%)	0 / 62 (0.00%)	3 / 119 (2.52%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis viral
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 55 (0.00%)	1 / 64 (1.56%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 55 (1.82%)	2 / 64 (3.13%)	3 / 62 (4.84%)	3 / 119 (2.52%)	6 / 181 (3.31%)
occurrences causally related to treatment / all	0 / 1	0 / 3	1 / 4	0 / 4	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 55 (0.00%)	2 / 64 (3.13%)	1 / 62 (1.61%)	2 / 119 (1.68%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abnormal loss of weight
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cachexia
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 55 (0.00%)	0 / 64 (0.00%)	1 / 62 (1.61%)	0 / 119 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 55 (1.82%)	0 / 64 (0.00%)	0 / 62 (0.00%)	1 / 119 (0.84%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Clonidine Lauriad 50-µg MBT	Clonidine Lauriad 100-µg MBT	Placebo MBT	Clonidine Lauriad MBT Pooled	All patients
Total subjects affected by non serious adverse events
subjects affected / exposed	48 / 55 (87.27%)	60 / 64 (93.75%)	61 / 62 (98.39%)	108 / 119 (90.76%)	169 / 181 (93.37%)
Vascular disorders
Hypotension
subjects affected / exposed	3 / 55 (5.45%)	4 / 64 (6.25%)	1 / 62 (1.61%)	7 / 119 (5.88%)	8 / 181 (4.42%)
occurrences all number	4	4	1	8	9
General disorders and administration site conditions
Asthenia
subjects affected / exposed	9 / 55 (16.36%)	11 / 64 (17.19%)	14 / 62 (22.58%)	20 / 119 (16.81%)	34 / 181 (18.78%)
occurrences all number	12	14	18	26	44
Mucosal inflammation
subjects affected / exposed	8 / 55 (14.55%)	11 / 64 (17.19%)	6 / 62 (9.68%)	19 / 119 (15.97%)	25 / 181 (13.81%)
occurrences all number	21	19	12	40	52
Fatigue
subjects affected / exposed	5 / 55 (9.09%)	5 / 64 (7.81%)	8 / 62 (12.90%)	10 / 119 (8.40%)	18 / 181 (9.94%)
occurrences all number	5	6	10	11	21
Pyrexia
subjects affected / exposed	5 / 55 (9.09%)	10 / 64 (15.63%)	3 / 62 (4.84%)	15 / 119 (12.61%)	18 / 181 (9.94%)
occurrences all number	5	13	3	18	21
Pain
subjects affected / exposed	3 / 55 (5.45%)	2 / 64 (3.13%)	4 / 62 (6.45%)	5 / 119 (4.20%)	9 / 181 (4.97%)
occurrences all number	3	3	4	6	10
General physical health deterioration
subjects affected / exposed	3 / 55 (5.45%)	1 / 64 (1.56%)	2 / 62 (3.23%)	4 / 119 (3.36%)	6 / 181 (3.31%)
occurrences all number	4	2	2	6	8
Oedema
subjects affected / exposed	0 / 55 (0.00%)	4 / 64 (6.25%)	0 / 62 (0.00%)	4 / 119 (3.36%)	4 / 181 (2.21%)
occurrences all number	0	4	0	4	4
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 55 (5.45%)	5 / 64 (7.81%)	8 / 62 (12.90%)	8 / 119 (6.72%)	16 / 181 (8.84%)
occurrences all number	3	6	8	9	17
Oropharyngeal pain
subjects affected / exposed	4 / 55 (7.27%)	3 / 64 (4.69%)	3 / 62 (4.84%)	7 / 119 (5.88%)	10 / 181 (5.52%)
occurrences all number	4	6	4	10	14
Dysphonia
subjects affected / exposed	3 / 55 (5.45%)	3 / 64 (4.69%)	3 / 62 (4.84%)	6 / 119 (5.04%)	9 / 181 (4.97%)
occurrences all number	3	3	3	6	9
Psychiatric disorders
Anxiety
subjects affected / exposed	5 / 55 (9.09%)	1 / 64 (1.56%)	3 / 62 (4.84%)	6 / 119 (5.04%)	9 / 181 (4.97%)
occurrences all number	5	1	4	6	10
Investigations
Blood creatinine increased
subjects affected / exposed	7 / 55 (12.73%)	3 / 64 (4.69%)	7 / 62 (11.29%)	10 / 119 (8.40%)	17 / 181 (9.39%)
occurrences all number	7	3	7	10	17
Injury, poisoning and procedural complications
Radiation skin injury
subjects affected / exposed	14 / 55 (25.45%)	22 / 64 (34.38%)	24 / 62 (38.71%)	36 / 119 (30.25%)	60 / 181 (33.15%)
occurrences all number	24	45	35	69	104
Nervous system disorders
Headache
subjects affected / exposed	5 / 55 (9.09%)	2 / 64 (3.13%)	9 / 62 (14.52%)	7 / 119 (5.88%)	16 / 181 (8.84%)
occurrences all number	6	2	9	8	17
Dizziness
subjects affected / exposed	2 / 55 (3.64%)	6 / 64 (9.38%)	2 / 62 (3.23%)	8 / 119 (6.72%)	10 / 181 (5.52%)
occurrences all number	2	10	3	12	15
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	9 / 55 (16.36%)	12 / 64 (18.75%)	11 / 62 (17.74%)	21 / 119 (17.65%)	32 / 181 (17.68%)
occurrences all number	11	16	12	27	39
Leukopenia
subjects affected / exposed	10 / 55 (18.18%)	12 / 64 (18.75%)	8 / 62 (12.90%)	22 / 119 (18.49%)	30 / 181 (16.57%)
occurrences all number	17	19	11	36	47
Neutropenia
subjects affected / exposed	7 / 55 (12.73%)	12 / 64 (18.75%)	8 / 62 (12.90%)	19 / 119 (15.97%)	27 / 181 (14.92%)
occurrences all number	9	15	9	24	33
Lymphopenia
subjects affected / exposed	7 / 55 (12.73%)	8 / 64 (12.50%)	5 / 62 (8.06%)	15 / 119 (12.61%)	20 / 181 (11.05%)
occurrences all number	10	12	10	22	32
Thrombocytopenia
subjects affected / exposed	6 / 55 (10.91%)	6 / 64 (9.38%)	4 / 62 (6.45%)	12 / 119 (10.08%)	16 / 181 (8.84%)
occurrences all number	13	11	4	24	28
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	2 / 55 (3.64%)	4 / 64 (6.25%)	3 / 62 (4.84%)	6 / 119 (5.04%)	9 / 181 (4.97%)
occurrences all number	2	5	3	7	10
Gastrointestinal disorders
Nausea
subjects affected / exposed	29 / 55 (52.73%)	29 / 64 (45.31%)	44 / 62 (70.97%)	58 / 119 (48.74%)	102 / 181 (56.35%)
occurrences all number	63	41	82	104	186
Dysphagia
subjects affected / exposed	18 / 55 (32.73%)	19 / 64 (29.69%)	29 / 62 (46.77%)	37 / 119 (31.09%)	66 / 181 (36.46%)
occurrences all number	25	23	40	48	88
Dry mouth
subjects affected / exposed	22 / 55 (40.00%)	17 / 64 (26.56%)	17 / 62 (27.42%)	39 / 119 (32.77%)	56 / 181 (30.94%)
occurrences all number	26	21	22	47	69
Vomiting
subjects affected / exposed	14 / 55 (25.45%)	15 / 64 (23.44%)	24 / 62 (38.71%)	29 / 119 (24.37%)	53 / 181 (29.28%)
occurrences all number	26	20	32	46	78
Constipation
subjects affected / exposed	18 / 55 (32.73%)	17 / 64 (26.56%)	16 / 62 (25.81%)	35 / 119 (29.41%)	51 / 181 (28.18%)
occurrences all number	20	19	16	39	55
Oral pain
subjects affected / exposed	16 / 55 (29.09%)	19 / 64 (29.69%)	16 / 62 (25.81%)	35 / 119 (29.41%)	51 / 181 (28.18%)
occurrences all number	40	70	40	110	150
Dysgeusia
subjects affected / exposed	14 / 55 (25.45%)	11 / 64 (17.19%)	12 / 62 (19.35%)	25 / 119 (21.01%)	37 / 181 (20.44%)
occurrences all number	15	13	12	28	40
Diarrhoea
subjects affected / exposed	7 / 55 (12.73%)	14 / 64 (21.88%)	13 / 62 (20.97%)	21 / 119 (17.65%)	34 / 181 (18.78%)
occurrences all number	15	22	22	37	59
Odynophagia
subjects affected / exposed	7 / 55 (12.73%)	14 / 64 (21.88%)	8 / 62 (12.90%)	21 / 119 (17.65%)	29 / 181 (16.02%)
occurrences all number	11	21	22	32	54
Stomatitis
subjects affected / exposed	6 / 55 (10.91%)	8 / 64 (12.50%)	8 / 62 (12.90%)	14 / 119 (11.76%)	22 / 181 (12.15%)
occurrences all number	15	18	17	33	50
Dyspepsia
subjects affected / exposed	1 / 55 (1.82%)	6 / 64 (9.38%)	6 / 62 (9.68%)	7 / 119 (5.88%)	13 / 181 (7.18%)
occurrences all number	1	6	6	7	13
Abdominal pain upper
subjects affected / exposed	2 / 55 (3.64%)	2 / 64 (3.13%)	5 / 62 (8.06%)	4 / 119 (3.36%)	9 / 181 (4.97%)
occurrences all number	2	3	5	5	10
Aptyalism
subjects affected / exposed	1 / 55 (1.82%)	4 / 64 (6.25%)	3 / 62 (4.84%)	5 / 119 (4.20%)	8 / 181 (4.42%)
occurrences all number	1	5	4	6	10
Salivary hypersecretion
subjects affected / exposed	3 / 55 (5.45%)	0 / 64 (0.00%)	2 / 62 (3.23%)	3 / 119 (2.52%)	5 / 181 (2.76%)
occurrences all number	3	0	2	3	5
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	11 / 55 (20.00%)	9 / 64 (14.06%)	8 / 62 (12.90%)	20 / 119 (16.81%)	28 / 181 (15.47%)
occurrences all number	27	17	17	44	61
Erythema
subjects affected / exposed	4 / 55 (7.27%)	4 / 64 (6.25%)	3 / 62 (4.84%)	8 / 119 (6.72%)	11 / 181 (6.08%)
occurrences all number	5	4	3	9	12
Renal and urinary disorders
Renal failure
subjects affected / exposed	3 / 55 (5.45%)	2 / 64 (3.13%)	1 / 62 (1.61%)	5 / 119 (4.20%)	6 / 181 (3.31%)
occurrences all number	3	2	1	5	6
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
subjects affected / exposed	3 / 55 (5.45%)	1 / 64 (1.56%)	2 / 62 (3.23%)	4 / 119 (3.36%)	6 / 181 (3.31%)
occurrences all number	3	1	3	4	7
Infections and infestations
Oral candidiasis
subjects affected / exposed	3 / 55 (5.45%)	10 / 64 (15.63%)	9 / 62 (14.52%)	13 / 119 (10.92%)	22 / 181 (12.15%)
occurrences all number	4	11	13	15	28
Fungal infection
subjects affected / exposed	2 / 55 (3.64%)	2 / 64 (3.13%)	7 / 62 (11.29%)	4 / 119 (3.36%)	11 / 181 (6.08%)
occurrences all number	2	2	7	4	11
Candida infection
subjects affected / exposed	2 / 55 (3.64%)	2 / 64 (3.13%)	4 / 62 (6.45%)	4 / 119 (3.36%)	8 / 181 (4.42%)
occurrences all number	2	2	4	4	8
Metabolism and nutrition disorders
Abnormal loss of weight
subjects affected / exposed	4 / 55 (7.27%)	11 / 64 (17.19%)	17 / 62 (27.42%)	15 / 119 (12.61%)	32 / 181 (17.68%)
occurrences all number	4	13	19	17	36
Decreased appetite
subjects affected / exposed	6 / 55 (10.91%)	8 / 64 (12.50%)	5 / 62 (8.06%)	14 / 119 (11.76%)	19 / 181 (10.50%)
occurrences all number	8	11	6	19	25

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Were there any global substantial amendments to the protocol? Yes

26 Nov 2009

Added 2 exclusion criteria: hypotension and orthostatic hypotension; added dosage of cytokine levels in serum and saliva to evaluate mechanism of action of clonidine and added forbidden concomitant treatments aiming to prevent or treat oral mucositis (e.g. GM-CSF, IL-11, Pilocarpine).

26 Feb 2010

Added sedation assessment at each visit; clarified that SAE reporting is not requested in case of planned hospitalisation; deleted the cytokines dosage because not feasible.

14 Jan 2011

Deleted 1 exclusion criterion excluding patients with unknown primary cancer.

07 Apr 2011

Only applicable to Germany: added that in case of a positive HIV test at screening, notification had to be done to Robert-Koch-Institute anonymously.

09 Sep 2011

Updated the total number of centres and prolonged the study duration extension; deleted the sedation assessment because not feasible.

03 Jul 2012

Added 1 inclusion criterion authorising previous neoadjuvant chemotherapy; modified 1 inclusion criterion authorising other chemotherapy in combination with cisplatin or carboplatin instead of cisplatin (or carboplatin) alone; prolonged study duration.

12 Oct 2012

Added administrative information following the submission in the United States; clarified that oral mucositis WHO score ≥ 3 was to be done by treatment.

15 Mar 2013

Harmonised NCI-CTC-AE classification between Europe and the United States.

09 Oct 2013

Added a follow-up period of 2 years to collect information on overall survival and progression; modified the primary endpoint to clarify and propose that in the situation where some patients would not reach the cumulative dose of 50 Gy, the cumulative dose at onset of an oral mucositis WHO score ≥ 3 was to be analysed using the Kaplan-Meier method; added that a severe oral mucositis should be considered as an event based on one evaluation instead of two successive evaluations showing a severe oral mucositis; revised the timelines of the study including the follow-up period.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cumulative radiation dose at which severe oral mucositis (WHO score ≥ 3) was first observed

Primary: Cumulative radiation dose at which severe oral mucositis (WHO score ≥ 3) was first observed

Secondary: Opioid use: At least one opioid (class 3 analgesic)

Secondary: Opioid use: At least one opioid (class 3 analgesic)

Secondary: Opioid use: Minimal total cumulative dose administered

Secondary: Opioid use: Minimal total cumulative dose administered

Secondary: Opioid use: Minimal total cumulative dose administered

Secondary: Opioid use: Minimal total cumulative dose administered

Secondary: Death

Secondary: Death

Secondary: Overall survival

Secondary: Overall survival

Secondary: Cause of death

Secondary: Cause of death

Other pre-specified: Time to onset of severe oral mucositis

Other pre-specified: Time to onset of severe oral mucositis

Other pre-specified: The maximum severity of oral mucositis

Other pre-specified: The maximum severity of oral mucositis

Other pre-specified: The overall incidence of Grade 3/4 mucositis during the active phase

Other pre-specified: The overall incidence of Grade 3/4 mucositis during the active phase

Other pre-specified: Salivary flow assessment using the NCI-CTC scale (Xerostomia): Time to first grade 2 or more

Other pre-specified: Salivary flow assessment using the NCI-CTC scale (Xerostomia): Time to first grade 2 or more

Other pre-specified: Overall treatment compliance according to the patient diary

Other pre-specified: Overall treatment compliance according to the patient diary

Other pre-specified: Overall treatment compliance according to the patient diary

Other pre-specified: Overall treatment compliance according to the patient diary

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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