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Clinical Trial Results:
Randomised, double-blind, vehicle controlled trial comparing Amphotericin B 100.000 I.E./g oral gel vs. Ampho-Moronal® suspension vs. modified vehicle to suspension in adult patients with oropharyngeal candidiasis

Summary
EudraCT number	2013-000371-32
Trial protocol	DE
Global end of trial date	11 Apr 2019

Results information
Results version number	v1(current)
This version publication date	14 May 2020
First version publication date	14 May 2020
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

13-02/AM-MG

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Dermapharm AG

Sponsor organisation address

Lil-Dagover Ring 7, Gruenwald, Germany, 82031

Public contact

Clinical Research Department, Dermapharm AG, Clinicaltrials.Dermapharm@dermapharm.com

Scientific contact

Clinical Research Department, Dermapharm AG, Clinicaltrials.Dermapharm@dermapharm.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

08 Apr 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Apr 2019

Global end of trial reached?

Yes

Global end of trial date

11 Apr 2019

Was the trial ended prematurely?

Main objective of the trial

Evaluation of the safety and efficacy of a new dosage form containing Amphotericin B on an oral gel base in comparison to the approved Ampho-Moronal® suspension. The study aimed to show therapeutic non-inferiority of the test preparation compared to the reference preparation and superiority of both active medications over the vehicle.

Protection of trial subjects

The study was conducted in accordance with the principles of ICH GCP, the declaration of Helsinki, as well as all other applicable ethical and legal requirements. The reference product Ampho Moronal suspension is already registered for the application in the study indication and commercially available for years in Germany. For the purpose of approval the efficacy and safety of this medicinal product has already been shown in clinical trials. Any patient with lack of efficacy and/or deterioration of symptoms could stop treatment at any moment based on the clinical judgment of the investigator or on his/ her own request and without giving reasons. The planned procedures within the trial represented no special risks to the patients as, apart from usual medicinal practice procedures, no additional invasive procedures were planned.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Oct 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 391

Worldwide total number of subjects

391

EEA total number of subjects

391

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)

214

From 65 to 84 years

172

85 years and over

Subject disposition

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Recruitment details

Multi-centric study in Germany; first volunteer enrolled: 11-Nov-2014; date of last completion: 11-Apr-2019

Screening details

Diagnosis and main criteria for inclusion: Men and women aged ≥ 18 years; clinical signs and symptoms of oropharyngeal candidiasis (OPC) with a sum score of ≥ 4 of the parameters erythematous areas, removable white patches, soreness/burning and extent of oral lesions (single scores between 0 and 3); existence of predisposing risk factors for OPC

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

Blinding implementation details

The preparations were filled in brown glass bottles and labelled indistinguishably. All study preparations were coloured and contained flavouring substances. So the investigator and patients could not draw any conclusion from colour and flavour about the preparation with which they were treated.

Are arms mutually exclusive

Yes

Test product

Arm description

Arm type

Experimental

Investigational medicinal product name

Amphotericin B oral gel

Investigational medicinal product code

A07AA07

Other name

Pharmaceutical forms

Oromucosal gel

Routes of administration

Buccal use

Dosage and administration details

1 g four times a day into the oral cavity

Reference product

Arm description

Arm type

Active comparator

Investigational medicinal product name

Ampho-Moronal Suspension

Investigational medicinal product code

A07AA07

Other name

Pharmaceutical forms

Oromucosal suspension

Routes of administration

Buccal use

Dosage and administration details

1 ml four times a day into the oral cavity

Vehicle

Arm description

Arm type

Placebo

Investigational medicinal product name

Modified vehicle to reference product

Investigational medicinal product code

Other name

Pharmaceutical forms

Oromucosal suspension

Routes of administration

Buccal use

Dosage and administration details

1 g four times a day into the oral cavity

Number of subjects in period 1	Test product	Reference product	Vehicle
Started	126	133	132
Completed	113	118	114
Not completed	13	15	18
Physician decision	1	4	1
Consent withdrawn by subject	3	5	4
Adverse event, non-fatal	6	5	6
Lost to follow-up	1	-	4
Healing	1	-	1
Lack of efficacy	1	1	2

Period 2 title

Follow up

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject, Data analyst

Are arms mutually exclusive

Yes

Test - Follow up

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Reference Follow up

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Vehicle Follow up

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Test - Follow up	Reference Follow up	Vehicle Follow up
Started	113	118	114
Completed	110	111	110
Not completed	3	7	4
Consent withdrawn by subject	3	7	4

Baseline characteristics

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End points

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Reporting group title

Test product

Reporting group description

Reporting group title

Reference product

Reporting group description

Reporting group title

Vehicle

Reporting group description

Reporting group title

Test - Follow up

Reporting group description

Reporting group title

Reference Follow up

Reporting group description

Reporting group title

Vehicle Follow up

Reporting group description

Primary: Primary endpoint

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End point title

Primary endpoint

End point description

The primary endpoint of the study was the clinical success rate at the end of treatment (Day 14). The success rate was defined as clinical and mycological cure. Clinical cure is gained when the total score of the 4 clinical parameters is ≤ 1 on Day 14 and no further treatment is necessary. Mycological cure is specified as a fungal culture score of ≤ 1 (only single forms of Candida albicans).

End point type

Primary

End point timeframe

Initial examination to main examination (EOT, day 14)

End point values	Test product	Reference product	Vehicle
Number of subjects analysed	105	114	106
Units: percentage	26	49	28

Non-Inferiority

Statistical analysis description

The primary objective of this study was to show non-inferiority of the test product in comparison to the reference product. Non-inferiority was statistically proven if the lower limit of the two-sided 95% confidence interval (CI) was > -D, where Δ = 0.20 was the non-inferiority limit.

Comparison groups

Test product v Reference product

Number of subjects included in analysis

219

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Parameter type

Median difference (final values)

Point estimate

-18.22

Confidence interval

level

95%

sides

2-sided

lower limit

-31.41

upper limit

-5.03

Superiority of test product to vehicle

Statistical analysis description

The analysis was intended to provide supportive evidence with regard to assay sensitivity.

Comparison groups

Test product v Vehicle

Number of subjects included in analysis

211

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 1

Method

Fisher exact

Confidence interval

Notes
[1] - Difference between success rates

Superiority of reference product to vehicle

Statistical analysis description

This analysis was intended to provide supportive evidence with regard to assay sensitivity.

Comparison groups

Reference product v Vehicle

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.05

Method

Fisher exact

Confidence interval

Notes
[2] - Difference between success rates

Adverse events

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Timeframe for reporting adverse events

From baseline to the end of follow-up.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Test product

Reporting group description

Reporting group title

Reference product

Reporting group description

Reporting group title

Vehicle

Reporting group description

Serious adverse events	Test product	Reference product	Vehicle
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	2 / 127 (1.57%)
number of deaths (all causes)	0	0	1
number of deaths resulting from adverse events	0	0	1
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Urosepsis
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0.05%

Non-serious adverse events	Test product	Reference product	Vehicle
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 125 (14.40%)	26 / 130 (20.00%)	25 / 127 (19.69%)
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	0 / 125 (0.00%)	2 / 130 (1.54%)	4 / 127 (3.15%)
occurrences all number	0	2	4
Pyrexia
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Respiratory, thoracic and mediastinal disorders
Dysphonia
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Dyspnoea
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Oropharyngeal discomfort
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Throat tightness
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Investigations
Blood lactic acid increased
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Body temperature increased
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Injury, poisoning and procedural complications
Ligament rupture
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Ligament sprain
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Thermal burn
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Headache
subjects affected / exposed	2 / 125 (1.60%)	3 / 130 (2.31%)	1 / 127 (0.79%)
occurrences all number	2	3	1
Migraine
subjects affected / exposed	1 / 125 (0.80%)	2 / 130 (1.54%)	0 / 127 (0.00%)
occurrences all number	1	2	0
Sciatica
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Abdominal pain
subjects affected / exposed	1 / 125 (0.80%)	2 / 130 (1.54%)	1 / 127 (0.79%)
occurrences all number	1	2	1
Abdominal pain upper
subjects affected / exposed	1 / 125 (0.80%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	1	1	0
Aphthous ulcer
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	1 / 127 (0.79%)
occurrences all number	0	1	1
Constipation
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Diarrhoea
subjects affected / exposed	1 / 125 (0.80%)	2 / 130 (1.54%)	0 / 127 (0.00%)
occurrences all number	1	2	0
Dry mouth
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Dyspepsia
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Faeces hard
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Flatulence
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Gingival bleeding
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Glossodynia
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Nausea
subjects affected / exposed	3 / 125 (2.40%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	3	1	0
Oesophageal pain
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Oral discomfort
subjects affected / exposed	2 / 125 (1.60%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	2	0	0
Paraesthesia oral
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Stomatitis
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Swollen tongue
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Vomiting
subjects affected / exposed	2 / 125 (1.60%)	2 / 130 (1.54%)	0 / 127 (0.00%)
occurrences all number	2	2	0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Dermatitis allergic
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Dermatitis contact
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Eczema
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Lichen sclerosus
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
rash
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	1	0	1
Rosacea
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Stasis dermatitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Renal and urinary disorders
Urinary hesitation
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	1 / 127 (0.79%)
occurrences all number	0	1	1
Rheumatoid arthritis
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	1	0	1
Conjunctivitis
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Gastrointestinal candidiasis
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Gastrointestinal infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Gonococcal infection
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Laryngitis
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0
Paronychia
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Rhinitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Sinusitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Tonsillitis
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 125 (0.00%)	0 / 130 (0.00%)	1 / 127 (0.79%)
occurrences all number	0	0	1
Urethritis
subjects affected / exposed	0 / 125 (0.00%)	1 / 130 (0.77%)	0 / 127 (0.00%)
occurrences all number	0	1	0
Viral infection
subjects affected / exposed	1 / 125 (0.80%)	0 / 130 (0.00%)	0 / 127 (0.00%)
occurrences all number	1	0	0

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Were there any global substantial amendments to the protocol? No

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

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Clinical trials

Clinical Trial Results:
Randomised, double-blind, vehicle controlled trial comparing Amphotericin B 100.000 I.E./g oral gel vs. Ampho-Moronal® suspension vs. modified vehicle to suspension in adult patients with oropharyngeal candidiasis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary endpoint

Primary: Primary endpoint

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: Randomised, double-blind, vehicle controlled trial comparing Amphotericin B 100.000 I.E./g oral gel vs. Ampho-Moronal® suspension vs. modified vehicle to suspension in adult patients with oropharyngeal candidiasis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary endpoint

Primary: Primary endpoint

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Randomised, double-blind, vehicle controlled trial comparing Amphotericin B 100.000 I.E./g oral gel vs. Ampho-Moronal® suspension vs. modified vehicle to suspension in adult patients with oropharyngeal candidiasis