Clinical Trial Results:
A Comparative, Open-Label, Randomized, Parallel Group Study to determine Intraperitoneal fluids, tissue, and serum concentrations of VML-0501 following five days of daily vaginal applications of single dose of VML-0501 (100 mg Danazol), in comparison to five days of Danazol treatment administered as an oral capsules (Danatrol) at a daily dose of 600 mg, in two groups of twelve each consisting of women with suspected or confirmed endometriosis and scheduled for laparoscopy.

Trial information Top of page
Trial identification
Sponsor protocol code	VML-0501-001
Additional study identifiers
ISRCTN number	-
US NCT number	NCT03352076
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Viramal Ltd
Sponsor organisation address	106 New Bond Street, 3rd floor, London, United Kingdom, W1S 1DN
Public contact	Chief Medical Officer, Viramal Ltd 106 New Bond Street London United Kingdom W1S 1DN, 020 74953052, info@viramal.com
Scientific contact	Chief Medical Officer, Viramal Ltd 106 New Bond Street London United Kingdom W1S 1DN, 020 74953052, info@viramal.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	28 Apr 2020
Is this the analysis of the primary completion data?	Yes
Primary completion date	28 Apr 2020
Global end of trial reached?	Yes
Global end of trial date	28 Apr 2020
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To assess the bioavailability of VML-0501 in comparison to oral Danazol in terms of: - Concentrations in serum - Concentrations in peritoneal fluid.
Protection of trial subjects	The Study was covered with a clinical study insurance and a liability insurance, and received relevant Ethics approval. Safety assessments included analysis of adverse events, physical examinations, vital signs, blood and urine tests to investigate the effects of the study drug on the clinical tolerability. All the clinical activities were carried out under a controlled environment under the supervision of qualified medical staff.
Background therapy	No background therapy was included
Evidence for comparator	Danatrol capsule, therapeutic indication is symptomatic treatment of Endometriosis.
Actual start date of recruitment	30 Oct 2017
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Italy: 30
Worldwide total number of subjects	30
EEA total number of subjects	30
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	30
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Subject who fulfilled the inclusion and exclusion criteria were recruited in the study. Women aged 18 to 42 years, with suspected or confirmed endometriosis and scheduled for laparoscopy were screened and invited to participate in the study. Of 30 subjects enrolled 29 were randomized (16 to the VML-0501 group and 13 to the Danatrol group).
Pre-assignment
Screening details	All subjects were screened for suspected or clinically diagnosed endometriosis. A number of assessments were performed during the Screening period to determine patient eligibility, e.g.physical examination, height and weight, blood pressure and heart rate, pregnancy test, routine blood and urine test.
Period 1
Period 1 title	Overall trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Not blinded
Arms
Are arms mutually exclusive	Yes
Arm title	VML-0501
Arm description	Subjects in the VML-0501 group were administered vaginally with 1.5 g of VML-0501 cream (containing 100 mg of Danazol)
Arm type	Experimental
Investigational medicinal product name	VML-0501
Investigational medicinal product code	VML-0501
Other name	Danazol Vaginal Cream
Pharmaceutical forms	Cream
Routes of administration	Vaginal use
Dosage and administration details	Subjects in the VML-0501 group were administered with 1.5 g of VML-0501 cream (containing 100 mg of Danazol) deeply within the vagina using an internal applicator, followed by 30 minutes of lying on their back in a supine position. Subjects were dosed once daily every morning for 5 – 7 consecutive days until the date of their laparoscopy.
Arm title	Comparator
Arm description	The Danatrol comparator was obtained from a local pharmacy and was not modified in any way. Danatrol was given in a dose of 200 mg three times daily for 5-7 consecutive days.
Arm type	Active comparator
Investigational medicinal product name	Danatrol
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Oral use
Dosage and administration details	200 mg three times daily for 5-7 days, to be taken orally with a glass of water.
Number of subjects in period 1 [1] VML-0501 Comparator Started 16 13 Completed 15 11 Not completed 1 2      Consent withdrawn by subject 1 1      drop-out - 1
Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: on the VML-0501 arm one subject drop-out on the the Comparator arm one subject drop-out and one subject withdrew consent.

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Overall trial
Reporting group description	Women with suspected or confirmed Endometriosis scheduled for laparoscopy.
Reporting group values Overall trial Total Number of subjects 29 29 Age categorical females 18-42 years of age Units: Subjects     In utero 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0     Newborns (0-27 days) 0 0     Infants and toddlers (28 days-23 months) 0 0     Children (2-11 years) 0 0     Adolescents (12-17 years) 0 0     Adults (18-64 years) 29 29     From 65-84 years 0 0     85 years and over 0 0 Gender categorical Women with suspected or confirmed Endometriosis scheduled for laparoscopy. Units: Subjects     Female 29 29     Male 0 0 Endometriosis Women with suspected or confirmed Endometriosis scheduled for laparoscopy. Units: Subjects     suspected endometriosis 29 29 Laparoscopy Women with suspected or confirmed Endometriosis scheduled for laparoscopy. Units: Subjects     scheduled for laparoscopy 29 29
Subject analysis sets
Subject analysis set title	Safety set
Subject analysis set type	Full analysis
Subject analysis set description	This included all the subjects that enrolled in the study and received at least one dose of the investigational drug.
Subject analysis set title	Primary Population
Subject analysis set type	Intention-to-treat
Subject analysis set description	These are subjects who have been selected, randomized and took at least one dose of the study medication.
Subject analysis set title	Secondary Population
Subject analysis set type	Per protocol
Subject analysis set description	These are subjects who have completed the study and took at least 80% of the study medication.
Subject analysis sets values Safety set Primary Population Secondary Population Number of subjects 30 29 26 Age categorical females 18-42 years of age Units: Subjects     In utero 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0     Newborns (0-27 days) 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 0 0 0     Adolescents (12-17 years) 0 0 0     Adults (18-64 years) 29 29 26     From 65-84 years 0 0 0     85 years and over 0 0 0 Age continuous Units:      ± ± ± Gender categorical Women with suspected or confirmed Endometriosis scheduled for laparoscopy. Units: Subjects     Female 29 29 26     Male 0 0 0 Endometriosis Women with suspected or confirmed Endometriosis scheduled for laparoscopy. Units: Subjects     suspected endometriosis 29 29 26 Laparoscopy Women with suspected or confirmed Endometriosis scheduled for laparoscopy. Units: Subjects     scheduled for laparoscopy 29 29 26

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	VML-0501
Reporting group description	Subjects in the VML-0501 group were administered vaginally with 1.5 g of VML-0501 cream (containing 100 mg of Danazol)
Reporting group title	Comparator
Reporting group description	The Danatrol comparator was obtained from a local pharmacy and was not modified in any way. Danatrol was given in a dose of 200 mg three times daily for 5-7 consecutive days.
Subject analysis set title	Safety set
Subject analysis set type	Full analysis
Subject analysis set description	This included all the subjects that enrolled in the study and received at least one dose of the investigational drug.
Subject analysis set title	Primary Population
Subject analysis set type	Intention-to-treat
Subject analysis set description	These are subjects who have been selected, randomized and took at least one dose of the study medication.
Subject analysis set title	Secondary Population
Subject analysis set type	Per protocol
Subject analysis set description	These are subjects who have completed the study and took at least 80% of the study medication.

End points Top of page

Primary: Concentration of Danazol in Serum Top of page
End point title	Concentration of Danazol in Serum
End point description	The primary efficacy endpoint analysis was pre-defined to be based on the comparison of the concentrations of danazol in the afore mentioned parameters within and between patients in both arms of the study (VML-0501 vs. Danatrol).
End point type	Primary
End point timeframe	day 5 to day 14 of the treatment
End point values VML-0501 Comparator Safety set Primary Population Secondary Population Number of subjects analysed 16 13 29 29 29 Units: ng/ml     number (not applicable) 16 13 29 29 26
Statistical analysis title	SAS® System version 9.4
Comparison groups	Safety set v Primary Population v Secondary Population
Number of subjects included in analysis	87
Analysis specification	Pre-specified
Analysis type	other [1]
P-value	< 0.001 [2]
Method	Wilcoxon (Mann-Whitney)
Parameter type	Median difference (final values)
Confidence interval
level	95%
Variability estimate	Standard deviation
Notes [1] - proof of concept [2] - the concentration of Danazol in the serum

Primary: Concentration of Danazol in Serum Top of page

Primary: Concentration of Danazol in peritoneal fluid Top of page
End point title	Concentration of Danazol in peritoneal fluid
End point description
End point type	Primary
End point timeframe	day 5 to day 14
End point values VML-0501 Comparator Number of subjects analysed 16 13 Units: ng/ml     number (not applicable) 16 13
Statistical analysis title	SAS® System version 9.4
Statistical analysis description	concentration of Danazol in Peritoneal fluid
Comparison groups	VML-0501 v Comparator
Number of subjects included in analysis	29
Analysis specification	Pre-specified
Analysis type	other [3]
P-value	< 0.5
Method	Wilcoxon (Mann-Whitney)
Parameter type	Median difference (final values)
Confidence interval
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [3] - Proof of Concept

Primary: Concentration of Danazol in peritoneal fluid Top of page

Secondary: Concentration of Danazol measured in tissue Top of page
End point title	Concentration of Danazol measured in tissue
End point description	Tissue samples (selected pelvic and peritoneal samples) were collected from subjects in both arms.
End point type	Secondary
End point timeframe	At the time of the laparoscopy.
End point values VML-0501 Comparator Number of subjects analysed 16 13 Units: ng/g number (not applicable)     secondary endpopint 6 11
Statistical analysis title	SAS® System version 9.4
Statistical analysis description	Concentration of Danazol in Tissue
Comparison groups	VML-0501 v Comparator
Number of subjects included in analysis	29
Analysis specification	Pre-specified
Analysis type	other [4]
P-value	= 0.0031
Method	Wilcoxon (Mann-Whitney)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [4] - Proof of Concept

Secondary: Concentration of Danazol measured in tissue Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Adverse events were collected for all patients from the time of the first dose to the day of final follow-up.
Adverse event reporting additional description	Adverse events were collected regardless of causality.
Assessment type	Non-systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	22
Reporting groups
Reporting group title	VML-0501
Reporting group description	This group received the Investigational Medicinal Product (IMP) VML-0501.
Reporting group title	Comparator
Reporting group description	This group of subjects was randomized to receive the comparator drug-Danatrol.
Serious adverse events VML-0501 Comparator Total subjects affected by serious adverse events      subjects affected / exposed 0 / 16 (0.00%) 0 / 13 (0.00%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events VML-0501 Comparator Total subjects affected by non serious adverse events      subjects affected / exposed 2 / 16 (12.50%) 1 / 13 (7.69%) Surgical and medical procedures Phlebitis Additional description: Phlebitis in the upper right limb, resolved and not related alternative assessment type: Systematic      subjects affected / exposed 1 / 16 (6.25%) 0 / 13 (0.00%)      occurrences all number 1 0 Social circumstances Road traffic accident Additional description: not related and resolved      subjects affected / exposed 0 / 16 (0.00%) 1 / 13 (7.69%)      occurrences all number 0 1 Respiratory, thoracic and mediastinal disorders Bronchitis Additional description: Subject presented with Bronchitis and Fever.Resolved and Not related. alternative assessment type: Systematic      subjects affected / exposed 1 / 16 (6.25%) 0 / 13 (0.00%)      occurrences all number 1 0

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
01 Jul 2018	(1) Change of PI (2) Planned number of patients increased from 24 to 34 (3) Addition of new exploratory endpoints to investigate the concentration of danazol in endometrium and myometrium tissue (if applicable)
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None

More information Top of page