Clinical Trials Register

Summary
EudraCT Number:	2021-000103-20
Sponsor's Protocol Code Number:	202000638
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-07-15
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2021-000103-20

A.3

Full title of the trial

An explorative randomized, placebo-controlled and double-blind intervention crossover study:
Transvamix (100mg/mL THC / 50mg/mL CBD) to treat chronic pain in Epidermolysis Bullosa

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study on the effect of Transvamix on pain in adults with epidermolysis bullosa.

Een onderzoek naar het Effect van Transvamix op Pijn bij Volwassenen met Epidermolysis Bullosa.

A.4.1

Sponsor's protocol code number

202000638

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Medical Center Groningen
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DEBRA-UK
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Groningen
B.5.2	Functional name of contact point	Principal Investigator
B.5.3	Address:
B.5.3.1	Street Address	Hanzeplein 1
B.5.3.2	Town/ city	Groningen
B.5.3.3	Post code	9713GZ
B.5.3.4	Country	Netherlands
B.5.6	E-mail	a.p.wolff@umcg.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Transvamix (100mg/mL THC, 50mg/mL CBD)
D.3.4	Pharmaceutical form	Concentrate for oromucosal solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Sublingual use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	THC
D.3.9.3	Other descriptive name	DELTA-9-TETRAHYDROCANNABINOL
D.3.9.4	EV Substance Code	SUB27785
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CBD
D.3.9.1	CAS number	13956-29-1
D.3.9.3	Other descriptive name	CANNABIDIOL
D.3.9.4	EV Substance Code	SUB26600
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	Yes
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for oromucosal solution
D.8.4	Route of administration of the placebo	Sublingual use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Genetic Epidermolysis Bullosa

E.1.1.1

Medical condition in easily understood language

Inherited blistering skin condition

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the effect of Transvamix, relative to placebo, on participant reported pain scores of the quality “unpleasantness” in EB patients with chronic pain.

E.2.2

Secondary objectives of the trial

To explore the effect of Transvamix, relative to placebo, on participant reported general pain quality scores, and pain intensity, in EB patients with chronic pain.

To explore the effect of Transvamix, relative to placebo, on pain self-efficacy in EB patients with chronic pain.

To explore the effect of Transvamix, relative to placebo on pruritus intensity in EB patients with chronic pain.

To explore the effect of Transvamix, relative to placebo on brain connectivity in areas corresponding to the affective pain modulation circuit.

To determine the sub-side effect threshold maintenance dose achieved during titration of Transvamix and placebo.

To determine the frequency and participant-reported burden of adverse-events encountered during titration of Transvamix and placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Clinical diagnosis, supplemented by genetic analysis, immunofluorescent diagnostics or electron microscopy of congenital epidermolysis bullosa (EB). Including the subtypes recessive dystrophic EB, dominant dystrophic EB, junctional EB and EB simplex.
- At least 16 years of age from the date of onset of participation.
- Can read and write in the Dutch language.
- Mentally competent and legally able to appreciate informed consent.
- Reporting an average pain or pruritus mean score ≥4 on NRS (0-10) averaged throughout the previous week at one of the following times of day: morning, afternoon or evening.
- COVID-19 testing will be required prior to participation if deemed necessary by governing guidelines.

E.4

Principal exclusion criteria

- Patients enrolled in other clinical trials that do not allow for a deviation in treatment.
- Have experienced myocardial infarction or clinically significant cardiac dysfunction within the last 12 months or have had a cardiac disorder that, in the opinion of the investigator would have put the participant at risk of a clinically significant arrhythmia or myocardial infarction.
- Patients with known psychotic disorder (including the use of antipsychotic medications), or a history of suicidal ideation.
- Female patients of child-bearing potential and male participants whose partner was of child-bearing potential, unless willing to ensure that they or their partner used effective contraception.
- Patients who have had significantly impaired renal or hepatic function in the last 12 months.
- The patient is currently using or has used cannabis or cannabinoid-based medications within 30 days of study entry and was unwilling to abstain for the duration of the study
- Patients unwilling or unable to refrain from driving road vehicles and/or using potentially dangerous machinery where sufficient concentration is necessary.
- Patients unable to stay within the Netherlands for the duration of the study period.
- History of addiction and/or hospital admission due to addiction to recreational or pharmaceutical drugs.
- Patients with contradictions for MRI determined through the MRI safety form

E.5 End points

E.5.1

Primary end point(s)

• A reduction of 30% and 50% of mean pain scores (of the pain quality “unpleasantness”) between Transvamix and placebo group.
Will be measured as the difference in mean scores pre- (baseline) and post- intervention (Transvamix and placebo) for each group using the pain quality item “unpleasantness” from the pain quality assessment scale (PQAS), a 20-item numerical rating scale (NRS 0-10) survey on pain qualities.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline (day -1)
End of first exposure to Transvamix OR placebo (day 14)
End of second exposure to Transvamix OR placebo (day 42)

E.5.2

Secondary end point(s)

• The difference of mean scores of pain qualities between Transvamix and placebo.
Will be measured as the difference of the mean of all PQAS pain quality items (which have received a score >0 on NRS) between Transvamix and Placebo.
• The difference of mean scores of pain intensity between Transvamix and placebo.
Will be measured as daily changes in pain intensity (1-14 days placebo, 1-14 days Transvamix) using the VAS-Pain ([no pain] 0-100 [worst pain imaginable] unit scale) for pain intensity. The change score (delta) from baseline to Transvamix (day 14) and Placebo (day 14) will be calculated.
• To determine the effect of Transvamix on pain self-efficacy
Will be measured using the PSEQ survey pre-intervention (1x baseline) and during intervention (1x Transvamix, 1x placebo), a 10-item survey on the ability to continue normal life given ongoing pain.
• The difference of mean scores of pruritus intensity between Transvamix and placebo.
Will be measured as daily changes in pruritus intensity (1-14 days placebo, 1-14 days Transvamix) using the VAS-Pruritus ([no pruritus] 0-100 [worst pruritus imaginable] unit scale) for pruritus intensity. The change score (delta) from baseline to Transvamix (day 14) and Placebo (day 14) will be calculated.
• The difference in brain connectivity of the seed regions (anterior cingulate cortex and amygdala) to the brain cortex between Transvamix and placebo.
Will be measured using voxel-based analysis of blood oxygen-level dependent functional magnetic resonance imaging (fMRI-BOLD).
• *To determine sub-side effect threshold maintenance dose achieved of Transvamix during titration and the respective interindividual variability (CV%).
Will be measured as the dose administered on day 14 of placebo and Transvamix interventions. CV% is measured as inter-participant variance of dose achieved on day 14 of placebo and Transvamix interventions.
• ^To inventorize how many and which participant-experienced adverse-events during titration and maintenance of Transvamix and the patient reported burden for each adverse event on numeric rating scale (NRS [not burdensome at all] 0-10 [extremely burdensome]).

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline (day -1)
End of first exposure to Transvamix OR placebo (day 14)
End of second exposure to Transvamix OR placebo (day 42)

*End of first exposure to Transvamix OR placebo (day 14)
*End of second exposure to Transvamix OR placebo (day 42)

^ Continuous (Day 1 to 42)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception