Clinical Trials Register

Summary
EudraCT Number:	2022-000245-33
Sponsor's Protocol Code Number:	VN21
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-05-11
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2022-000245-33

A.3

Full title of the trial

To evaluate the effect of low-dose naltrexone (LDN) on pain perception and quality of life in women

Ocena wpływu niskich dawek Naltreksonu (LDN) na odczuwanie bólu i jakość życia kobiet z wulwodynią

A.3.1

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

To evaluate the effect of low-dose naltrexone (LDN) on pain perception and quality of life in women

Ocena wpływu niskich dawek Naltreksonu (LDN) na odczuwanie bólu i jakość życia kobiet z wulwodynią

A.3.2

Name or abbreviated title of the trial where available

To evaluate the effect of low-dose naltrexone (LDN) on pain perception and quality of life in women

Ocena wpływu niskich dawek Naltreksonu (LDN) na odczuwanie bólu i jakość życia kobiet z wulwodynią

A.4.1

Sponsor's protocol code number

VN21

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	Medical University of Lublin
B.1.3.4	Country	Poland
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	Medical Research Agency
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Terpa Limited Liability Company Limited partnership
B.5.2	Functional name of contact point	Principal Investigator
B.5.3	Address:
B.5.3.1	Street Address	Pogodna 34
B.5.3.2	Town/ city	Lublin
B.5.3.3	Post code	20-333
B.5.3.4	Country	Poland
B.5.4	Telephone number	0048501 018 138
B.5.6	E-mail	ebarad@gmail.com

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	naltrexone
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NALTREXONE HYDROCHLORIDE
D.3.9.3	Other descriptive name	NALTREXONE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB14629MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	Coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Vulvodynia

E.1.1.1

Medical condition in easily understood language

Chronic pain in the vulva, the area on the outside of a woman's genitals.

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10047781
E.1.2	Term	Vulvodynia
E.1.2	System Organ Class	100000004872

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluation of the effectiveness of LDL in reducing chronic pain and improvement of quality of life in women with provoked, spontaneous and mixed vulvodynia assessed on the basis of the test results recommended according to IMMPACT, compared to the placebo arm

E.2.2

Secondary objectives of the trial

Assessment of the tolerability of LDN therapy based on the assessment of side effects compared to the placebo arm

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Women from the age of 18 to the menopause or to the age of 50 (on the day of inclusion
for testing).
2. Patients who are not pregnant and do not plan to become pregnant in the next 9 months from the inclusion in the study
3. Signing the patient's informed and voluntary consent to participate in the study.
4. General health of the patient (WHO = 0-2).
5. Diagnosis of vulvodynia.
6. Negative drug test found at the visit randomization.
7. Documented correct cytology result from 3 years ago (before the visit screening).
8. Stable dose of drugs acting on the central nervous system used min. 1 month before the screening visit and during the entire patient's participation in the study.
9. Acceptance or readiness to use a highly effective method of contraception from the screening visit throughout the study. Sexual abstinence is not accepted.
10. The ability to understand the principles of testing and operating electronic devices.

DETAILED CRITERIA (ASSIGNMENT TO A SUB-GROUP):
1. Fulfillment of one of the following criteria characteristic for individual groups:
i. Provoked vulvodynia: complaints only due to penetration. On the Marinoff scale ≥ 1 point, on the scale (0-3) mostly penetration or no intercourse due to pain.
ii. Mixed vulvodynia: complaints that occur spontaneously and during penetration
iii. Spontaneous vulvodynia: complaints not related to an external factor (it can be cyclical, e.g. related to the menstrual cycle). Monthly pain intensity with daily follow-up NRS ≥ 3, at least 10 days / 28 days.

E.4

Principal exclusion criteria

MAIN EXCLUSION CRITERIA
1. Severe, hepatic and renal dysfunction defined as:
i. An ASPT or ALT result 5 times the upper limit;
ii. The level of bilirubin 3 times above the upper limit of normal - excluding patients with Gilbert's syndrome;
iii. EGFR result below 30 ml / min / m2,
on the basis of historical studies not older than 3 years before the screening visit or from the tests performed during the screening visit according with point 12 of the Protocol, version 1.0 of March 28, 2022.
2. Abuse of alcohol (more than 14 units per week) and other stimulants.
3. Taking psychoactive substances, including drugs, except for SSRI, SNRI, SARI (Trazodone), and anticonvulsants (Gabapentin, Pregabalin, Lamotrigine) in fixed doses from the screening visit.
4. Taking opioid drugs in the last 2 months before the screening visit (also in OTC preparations, eg Loperamide).
5. Taking naltrexone hydrochloride and Mysimba for weight loss at any time in your life.
6. BTA injection in the vulva in the last 4 months before the screening visit.
7. Endovascular procedures in the area of the small pelvis in the last 6 months before the screening visit.
8. Previous surgical procedures requiring general anesthesia (with general anesthesia) in the last 2 months before the screening visit.
9. Completed multidisciplinary therapeutic program in the treatment of vulvodynia in the last 4 months before the screening visit.
10. Diseases of the vulva: lichen, current contact vulvovaginitis, bacterial and / or yeast infections, other dermatological diseases, recurrent genital herpes (HSV; min 4 times / year).
11. Diagnosis of current or past serious mental disorders according to the criteria of ICD-10 and DSM-5, including psychotic and organic disorders (except depression and anxiety disorders).
12. Gynecological abnormalities requiring medical treatment: current HSIL, CIN II / III, pelvic inflammation, mixed or solid ovarian tumors, simple ovarian cysts greater than 5 cm, abnormal vaginal inter-cycle bleeding.
13. Pelvic venous diseases (PeVD), 4 criteria met on USG.
14. Pregnancy and lactation.
15. Spastic diseases: multiple sclerosis (MS), connective tissue diseases (Marfan syndrome and marfan-like syndromes), reactive arthritis (RA).
16. Vaginismus, Lamont scale 3-5 (gynecological examination impossible due to anxiety).
17. Significant and / or uncorrected disability in the field of sight or hearing, making it difficult to perform psychological tests.

E.5 End points

E.5.1

Primary end point(s)

The efficacy of LDN in reducing chronic pain as assessed by the test results recommended in the IMMPACT agreement:
1. Pain Assessment:
a) Change in pain intensity on an 11-point NRS scale based on spontaneous sensation of vulvovaginal pain and during vaginal penetration during sexual intercourse from baseline (VISIT 1) to final visit (VISIT 4) in the eDiaries in daily follow-up (from VISIT 1 to VISITS 4) and after the completion of treatment at VISIT 5, by telephone. The change in the quality and intensity of pain will also be assessed according to the McGill Questionnaire (SF-MPQ) and the CSI from pre-treatment values (VISIT 2) to end-of-treatment visit (VISIT 4).
2. Assessment of physical functioning on the basis of psychological tests performed during VISIT 2 and VISIT 4:
a) Change in general functioning on the basis of the SF-36 quality of life questionnaire.
b) Change in sexual functioning, satisfaction, suffering in connection with intercourse according to female sexual function index FSFI - Female sexual function index and pl-FSDS - Female sexual distress scale.
c) Change in sexual satisfaction based on the Sexual Satisfaction Scale (Davies 2006).
3. Assessment of emotional functioning from the initial value (VISIT 2) to the final visit (VISIT 4):
a) Changing the severity of depression using the Beck Depression Inventory - Second Edition; BDI-II.
b) Change in anxiety severity using the state anxiety inventory and trait anxiety (STAI).
4. Patient's assessment of improvement in health and satisfaction with treatment: using an 11-point scale (0 = completely dissatisfied to 10 = completely satisfied), diary assessment using The 5-level EQ-5D version (EQ-5D-5L ) from the initial value (VISIT 2) to the final visit (VISIT 4) and during the summary visit by phone (VISIT 5).
5. Symptoms and adverse events monitored throughout the treatment period (from VISIT 2 to VISIT 4 and at the summary visit, VISIT 5 by phone (on a scale of 0 complete no symptoms and adverse events -10 most severe symptoms), evaluation in the eDiaries (side effects of the drug (22 possible): after 3 days of treatment; after 10 days, then at the end of each 4th week of treatment (4, 8, 12 weeks from the start of treatment) and the last question one week before the end of treatment (6 times in total).
6. Instruction of the participants:
• the number of patients who did not choose to participate in the study and why.
• Number of subjects excluded from the study after screening or randomization, and reasons for exclusion.
• The number of subjects who withdrew from the study or dropped out of contact and why subjects did not complete the study.
Interpersonal functioning as an additional criterion in a clinical trial according to IMMPACT will be assessed using the RAS-PL 7 questionnaire (The Relationship Assessment Scale) and the quality of life questionnaire in relation to sex - female © (Polish version of the SQOL-F).

E.5.1.1

Timepoint(s) of evaluation of this end point

1. V1-V5
2. V2 and V4
3. V2 and V4
4. V2 to V4
5. V2-V5
6. throughout the study

E.5.2

Secondary end point(s)

1.Tolerance of LDN therapy (assessment of side effects and vital signs)
2.Validation of the physical examination of the pelvis (VAMP protocol) in women with vulvodynia (assessed during W 1,2,4)
3. Assessment of psychological characteristics, physiotherapeutic diagnosis and LDN treatment outcomes, from baseline (W 2) to final visit (W 4) in vulvodynia subgroups (provoked, spontaneous and mixed)
4. Assessment of the improvement in the quality of life with the use of LDN in women with many types of chronic pain (based on the Central Sensitization Questionnaire) and in the field of coexisting diseases with vulvodynia (irritable bowel syndrome, fibromyalgia) and urinary incontinence using: IBS Symptoms Scale (IBS Symptoms) Severity Score - IBS-SSS), Irritable Bowel Syndrome IBS-QoL, King's Questionnaire: The KHQ and Fibromyalgia Questionnaire acc. ACR 2010, (from W1 to W 4 and during the summary visit by telephone W 5).
5. Developing the principles of diagnosing women with vulvodynia (interview, gynecological examination and physiotherapeutic evaluation) - throughout the entire examination.
6.Identification of patients' psychological characteristics that affect the effectiveness of LDN treatment, based on: evaluation of depression using the Beck Depression Inventory - Second Edition (BDI-II), evaluation of anxiety using the state and trait anxiety inventory (STAI) (W 2, 4) and the T.E.C trauma questionnaire (W2).
7. Examination of patients with vulvodynia according to the principles of Fascia Manipulation (CFMS) L. Stecco and the Beighton scale as well as the assessment of the influence of LDN on myofascial markers in patients with vulvodynia (W2, 4).
Number of patients with adverse events (AEs) and serious adverse events (SAEs).

E.5.2.1

Timepoint(s) of evaluation of this end point

1. V2-V5
2. V1, V2, V4
3. V2 to V4
4. V2 to V5
5. throughout the study
6. V2 and V4
7. V2 and V4

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

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

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

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

300

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

300

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

none

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-05-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-04-28

P. End of Trial
P.	End of Trial Status	Ongoing

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