A Parallel Group (2-arm), Randomised, Double-blind, 12-week Trial to Explore the Efficacy and Safety of MC2-25 Cream and MC2-25 Vehicle in Women Diagnosed With Vulvar Lichen Sclerosus (VLS)
Phase: PHASE2
Conditions: Vulvar Lichen Sclerosus
Sponsor: MC2 Therapeutics

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 1 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Clinical Trial Protocol  
 
Trial title:  
 
 
 
A parallel group (2-arm), randomised, double-blind, 12-week trial to 
explore the efficacy and safety of MC2-25 cream and MC2-25 
vehicle in women diagnosed with vulvar lichen sclerosus (VLS)  
 
Trial short name 
 
Orchid 1  
Trial short title 
Efficacy and safety of MC2-25 cream & vehicle in women with 
vulvar lichen sclerosus (VLS) 
 
Indication: 
 
Vulvar lichen sclerosus (VLS) 
Trial design: 
 
Parallel group (2-arm), randomised,  
double-blind 
 
 
Trial no.: 
MC2-25-C3  
 
 
 
Investigational medicinal 
product: 
MC2-25 cream  
MC2-25 vehicle 
 
 
 
 
 
Development phase: 
 
 
Phase 2 
 
Trial registry numbers:  
 
EU-CT number: 2023-503516-32-00 
Document Status, Version, 
and Date: 
Final, v4.0, 31-Jul-
2024 
 
 
 
 
 
 
 
Name of the sponsor: 
 
 
 
MC2 Therapeutics Ltd 
1A Guilford Business Park 
Guilford GU2 8XG 
United Kingdom 
EU representative: 
MC2 Therapeutics A/S 
Agern Allé 24-26 
2970 Hørshom  
Denmark 
 
This trial will be conducted in compliance with the protocol, with regulation (EU) No 536/2014, 
and with the principles of Good Clinical Practice (GCP).  
Property of MC2 Therapeutics: The content of this document is confidential. Unauthorised use, 
disclosure, or reproduction without prior written permission from MC2 Therapeutics is prohibited. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 2 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Clinical trial protocol approval 
Investigational Medicinal Product: MC2-25 cream 
Protocol number: MC2-25-C3 
Protocol title: A parallel group (2-arm), randomised, double-blind, 12-week trial to explore the 
efficacy and safety of MC2-25 cream and MC2-25 vehicle in women diagnosed with vulvar lichen 
sclerosus (VLS). 
 
The following persons have approved this clinical trial protocol:  
 
Maj Dinesen, Head of Clinical Development, MC2 Therapeutics  
Gudula Kirtschig, International Coordinating Investigator, Consultant Dermatologist with expertise 
in lichen sclerosus 
 
Signature pages are separate documents adjoined to this document. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 3 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Table of contents 
Clinical trial protocol approval ......................................................................................................... 2 
Table of contents ................................................................................................................................. 3 
List of tables ........................................................................................................................................ 6 
List of figures ...................................................................................................................................... 7 
List of abbreviations and definitions ................................................................................................ 8 
1 
Protocol summary ..................................................................................................................... 10 
1.1 
Synopsis ........................................................................................................................... 10 
1.2 
Schematic of trial design ................................................................................................. 13 
1.3 
Schedule of assessments (SoA) ....................................................................................... 14 
2 
Introduction............................................................................................................................... 18 
2.1 
Purpose of trial ................................................................................................................ 18 
2.2 
Background ..................................................................................................................... 18 
2.2.1 
Vulvar Lichen Sclerosus (VLS) ........................................................................ 18 
2.2.2 
MC2-25 cream .................................................................................................. 20 
2.3 
Risk/benefit assessment ................................................................................................... 21 
2.3.1 
Known potential risks ....................................................................................... 21 
2.3.2 
Known potential benefits .................................................................................. 22 
2.3.3 
Assessment of potential risks and benefits ........................................................ 22 
3 
Objectives and endpoints ......................................................................................................... 24 
4 
Trial design ................................................................................................................................ 27 
4.1 
Description of trial design ............................................................................................... 27 
4.2 
Rationale for trial design ................................................................................................. 27 
4.2.1 
Design ............................................................................................................... 27 
4.2.2 
Comparator ........................................................................................................ 27 
4.2.3 
Duration of trial ................................................................................................. 27 
4.2.4 
Trial population ................................................................................................. 28 
4.2.5 
Dose strength ..................................................................................................... 28 
4.2.6 
Dosing-regimen ................................................................................................. 29 
4.2.7 
Endpoints ........................................................................................................... 31 
4.3 
Start of trial and end of trial definition ............................................................................ 31 
5 
Trial population ........................................................................................................................ 32 
5.1 
Inclusion criteria .............................................................................................................. 32 
5.2 
Exclusion criteria ............................................................................................................. 33 
5.3 
Inclusion of vulnerable populations ................................................................................ 34 
5.4 
Lifestyle considerations ................................................................................................... 34 
5.5 
Screen failures and re-screening ...................................................................................... 35 
5.6 
Strategies for recruitment and retention .......................................................................... 35 
6 
Trial intervention ...................................................................................................................... 36 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 4 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
6.1 
Trial interventions administration ................................................................................... 36 
6.1.1 
Trial intervention description ............................................................................ 36 
6.1.1.1 
Investigational medicinal product (IMP) ......................................... 36 
6.1.2 
Dosing and administration ................................................................................ 36 
6.2 
Preparation/ handling/ storage/ accountability ................................................................ 36 
6.2.1 
Acquisition and accountability .......................................................................... 36 
6.2.2 
Formulation, appearance, packaging, and labelling .......................................... 37 
6.2.3 
Product storage and stability ............................................................................. 37 
6.2.4 
Preparation and destruction ............................................................................... 37 
6.3 
Measures to minimise bias: randomisation and blinding ................................................ 37 
6.4 
Treatment compliance ..................................................................................................... 38 
6.5 
Prohibited therapies ......................................................................................................... 38 
6.5.1 
Prohibited therapies prior to baseline ................................................................ 38 
6.5.2 
Prohibited therapies after Baseline .................................................................... 39 
6.5.3 
Rescue therapies ................................................................................................ 39 
7 
Trial intervention discontinuation and participant discontinuation / withdrawal ............. 40 
7.1 
Participant discontinuation / discontinuation of trial intervention .................................. 40 
7.2 
Lost to follow-up ............................................................................................................. 40 
7.3 
End-of-treatment visit ...................................................................................................... 40 
8 
Trial assessments and procedures ........................................................................................... 42 
8.1 
Visit schedule .................................................................................................................. 42 
8.2 
Screening ......................................................................................................................... 42 
8.3 
Demographics and medical history ................................................................................. 42 
8.4 
Prior and concomitant therapies ...................................................................................... 42 
8.5 
Efficacy assessments ....................................................................................................... 43 
8.5.1 
Clinician reported outcomes (ClinRO) assessments ......................................... 43 
8.5.1.1 
Imaging of VLS................................................................................ 43 
8.5.1.2 
Vulvar lichen sclerosus Area and Sign Severity Index 
(VASSI)............................................................................................ 43 
8.5.1.3 
Clinician’s Global Assessment (CGA) of VLS ............................... 45 
8.5.1.4 
Clinician’s Global Impression of Change (CGIC) of VLS .............. 46 
8.5.2 
Patient reported outcomes (PRO) assessments ................................................. 47 
8.5.2.1 
Worst Itch Numeric Rating Score (WI-NRS) of VLS ..................... 47 
8.5.2.2 
Worst Pain Numeric Rating Score (WP-NRS) of VLS ................... 47 
8.5.2.3 
Worst Penetrative sex related Pain Numeric Rating Score 
(WPP-NRS) of VLS ......................................................................... 47 
8.5.2.4 
Patient’s Global Impression of Change (PGIC) of VLS .................. 48 
8.5.2.5 
Patient’s rating of importance of improvements of VLS ................. 48 
8.5.2.6 
International Consultation on Incontinence Questionnaire 
Urinary Incontinence Short Form (ICIQ-UI-SF) ............................. 49 
8.5.2.7 
Menopausal status and Menstrual cycle status ................................. 49 
8.5.2.8 
Skindex-29 ....................................................................................... 49 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 5 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
8.5.2.9 
VQLI ................................................................................................ 49 
8.5.2.10 VLS patient journey sheet ................................................................ 50 
8.6 
Safety and other assessments .......................................................................................... 50 
8.6.1 
Physical examination ........................................................................................ 50 
8.6.2 
Vital signs .......................................................................................................... 50 
8.6.3 
Urine pregnancy test ......................................................................................... 51 
8.7 
Laboratory assessments ................................................................................................... 51 
8.7.1 
Analysis of laboratory samples ......................................................................... 51 
8.8 
Adverse events and serious adverse events ..................................................................... 51 
8.8.1 
Definition of adverse events (AE) ..................................................................... 51 
8.8.2 
Definition of serious adverse events (SAE) ...................................................... 51 
8.8.3 
Classification of an adverse event ..................................................................... 52 
8.8.3.1 
Severity of adverse events ................................................................ 52 
8.8.3.2 
Relationship of adverse events to trial treatment ............................. 52 
8.8.3.3 
Outcome of adverse events .............................................................. 53 
8.8.4 
Time period and frequency for event assessment and follow-up ...................... 53 
8.8.4.1 
Adverse event reporting ................................................................... 53 
8.8.4.2 
Serious adverse event reporting ....................................................... 54 
8.8.5 
Reporting events to participants ........................................................................ 55 
8.8.6 
Events of special interest ................................................................................... 55 
8.8.7 
Reporting of pregnancy ..................................................................................... 55 
8.8.8 
Trial medication overdose and trial medication errors...................................... 55 
8.8.9 
Reporting of serious adverse events and pregnancies ....................................... 55 
8.8.9.1 
Contact person(s) and number(s) ..................................................... 55 
9 
Statistical considerations .......................................................................................................... 56 
9.1 
Statistical hypotheses ...................................................................................................... 56 
9.2 
Sample size determination ............................................................................................... 56 
9.3 
Populations for analyses .................................................................................................. 56 
9.4 
Statistical analyses ........................................................................................................... 57 
9.4.1 
General approach .............................................................................................. 57 
9.4.2 
Analysis of efficacy ........................................................................................... 57 
9.4.2.1 
Analysis of the primary efficacy endpoint ....................................... 57 
9.4.2.2 
Analysis of the secondary endpoints ................................................ 58 
9.4.3 
Safety analyses .................................................................................................. 58 
9.4.3.1 
Safety analyses – General ................................................................ 58 
9.4.3.2 
Adverse events ................................................................................. 58 
9.4.4 
Baseline descriptive statistics ............................................................................ 58 
9.4.5 
Planned interim analyses ................................................................................... 59 
9.4.6 
Sub-group analyses ........................................................................................... 59 
9.4.7 
Tabulation of individual participant data .......................................................... 59 
9.4.7.1 
Trial medication/exposure ................................................................ 59 
9.4.7.2 
Prior and concomitant therapies ....................................................... 59 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 6 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
9.4.7.3 
Further tabulation of individual participant data .............................. 59 
9.4.8 
Exploratory analyses ......................................................................................... 59 
10 Supporting documentation and operational considerations ................................................. 60 
10.1 
Regulatory, ethical, and trial oversight considerations ................................................... 60 
10.1.1 
Ethical considerations and conduct of the trial ................................................. 60 
10.1.2 
Institutional review board (IRB) or independent ethics committee (IEC) ........ 60 
10.1.3 
Informed consent process .................................................................................. 61 
10.1.4 
Trial completion, discontinuation, and closure ................................................. 61 
10.1.5 
Confidentiality and privacy ............................................................................... 61 
10.1.5.1 Confidentiality of trial documentation ............................................. 61 
10.1.5.2 Privacy of individual health information ......................................... 62 
10.1.5.3 Patient involvement in the design of the clinical trial ...................... 63 
10.1.6 
Future use of stored specimens and data ........................................................... 63 
10.1.7 
Safety oversight ................................................................................................. 63 
10.1.8 
Quality assurance and quality control ............................................................... 63 
10.1.8.1 Direct Access to source documents .................................................. 63 
10.1.8.2 Monitoring procedures ..................................................................... 63 
10.1.8.3 Audit and inspection ........................................................................ 63 
10.1.9 
Data handling and record keeping ..................................................................... 64 
10.1.9.1 Recording of data ............................................................................. 64 
10.1.9.2 Source documents ............................................................................ 64 
10.1.9.3 Case report forms ............................................................................. 64 
10.1.9.4 Retention of documents .................................................................... 65 
10.1.10 Protocol deviations ............................................................................................ 65 
10.1.11 Publication and data sharing policy .................................................................. 65 
10.1.12 Conflict of interest policy .................................................................................. 65 
10.2 
Additional considerations ................................................................................................ 65 
10.2.1 
Emergency unblinding ...................................................................................... 65 
10.3 
Insurance ......................................................................................................................... 66 
10.4 
Protocol amendments ...................................................................................................... 66 
Signature page for principal investigator ...................................................................................... 67 
Appendices ........................................................................................................................................ 68 
Appendix 1 
Overall data flow of the clinical data ................................................................... 68 
11 References .................................................................................................................................. 69 
 
 
List of tables 
Table 1: 
Schedule of assessments ............................................................................................. 14 
Table 2: 
Summary of risks and mitigation strategies ............................................................... 21 
Table 3: 
Prohibited therapies prior to baseline ......................................................................... 38 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 7 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Table 4: 
Vulvar lichen sclerosus Area and Sign Severity Index (VASSI) ............................... 44 
Table 5: 
Clinician’s Global Assessment (CGA) of VLS .......................................................... 45 
 
List of figures 
Figure 1: 
The reaction of isocyanic acid with protein amino groups (Jaisson et al., 2018) ....... 20 
Figure 2: 
Vulvar areas ................................................................................................................ 44 
 
 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 8 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
List of abbreviations and definitions 
Abbreviation 
Definition 
AE 
Adverse Event 
Ala-Gln 
Alanyl-Glutamine 
CFR 
Code of Federal Regulation  
CGA 
Clinician’s Global Assessment 
CGIC 
Clinician’s Global Impression of Change 
CKD 
Chronic Kidney Disease 
CKD-aP 
Chronic Kidney Disease-associated Pruritus 
ClinRO 
Clinician-Reported Outcome 
COA 
Clinical Outcome Assessment 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EoT 
End of Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FTU 
Fingertip Unit 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
hCG 
Human Chorionic Gonadotropin 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ICIQ-UI-SF 
International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
LS 
Lichen Sclerosus 
MedDRA 
Medical Dictionary for Regulatory Activities  
MFAS 
Modified Full Analysis Set 
MMRM 
Mixed Model of Repeated Measures 
PGIC 
Patient’s Global Impression of Change 
PPS 
Per Protocol Set 
PRO 
Patient Reported Outcome 
RSI 
Reference Safety Information 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SoA 
Schedule of Assessments 
SmPC 
Summary of Product Characteristics 
SS 
Screened Set 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 9 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Abbreviation 
Definition 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TOMS 
Technical Operational Measures 
UV-A 
Ultraviolet A 
UV-B 
Ultraviolet B 
UTI 
Urinary Tract Infection 
VAS 
Visual Analogue Scale 
VASSI 
Vulvar lichen sclerosus Area and Sign Severity Index 
VLS 
Vulvar Lichen Sclerosus (Note: in the context of this trial ‘Vulvar’ region includes the clitoris 
and periclitoral skin, interlabial sulci, labia minora, posterior fourchette and perineum, anal and 
perianal skin) 
VQLI 
Vulvar disease Quality of Life Index 
w/w 
Weight by weight 
WI 
Worst Itch 
WI-NRS 
Worst Itch – Numeric Rating Score 
WPP 
Worst Penetrative sex related Pain 
WPP-NRS 
Worst Penetrative sex related Pain – Numeric Rating Score 
WP 
Worst Pain 
WP-NRS 
Worst Pain – Numeric Rating Score 
 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 10 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
1 
Protocol summary 
1.1 
Synopsis 
Title 
A parallel group (2-arm), randomised, double-blind, 12-week trial to explore 
the efficacy and safety of MC2-25 cream and MC2-25 vehicle in women 
diagnosed with vulvar lichen sclerosus (VLS). 
Protocol Number (EU 
trial number) 
MC2-25-C3 (EU-CT 2023-503516-32-00) 
Rationale 
VLS is a serious condition with major impact on the quality of life of affected 
women. There is evidence that urea-derived isocyanate could be an important 
triggering factor in the development of signs and symptoms in patients with 
VLS. There is a high unmet need for an authorised, efficient, and safe 
treatment of VLS. Topically applied cream with Ala-Gln as an effective 
isocyanate scavenger in form of MC2-25 cream may prove to be an effective 
and safe treatment of VLS.  
Phase 
Phase 2 
Objectives 
Primary objective:  
To explore the efficacy of MC2-25 cream compared to MC2-25 vehicle in 
vulvar lichen sclerosus (VLS). 
Secondary objectives: 
• To explore the safety of MC2-25 cream compared to MC2-25 vehicle in 
VLS. 
• To explore the burden of VLS on women’s lives. 
Design 
Multicentre, phase 2, randomised, double-blind, 2-arm, parallel-group, vehicle-
controlled trial in VLS.  
The trial consists of 3 consecutive periods adding up to a maximum trial 
duration for each patient of 18 weeks: Screening (up to 4 weeks), Treatment 
(12 weeks) and Follow-Up (2 weeks). 
Planned Sample Size: 
33 patients will be randomised in a 1:1 ratio to MC2-25 cream or MC2-25 
vehicle. 
Trial population 
Main inclusion criteria:  
• Women, of any race or ethnicity, who are ≥18 years of age at the time of 
screening. 
• Clinical diagnosis of VLS (i.e., biopsy for histological confirmation not 
required except if needed to rule out malignancy or differential diagnosis of 
e.g., vulvar lichen planus) made by either a dermatologist or a gynaecologist 
familiar with VLS. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 11 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
• Presence of at least one of the following signs of VLS: a. Hyperkeratosis 
(i.e., patches/plaques of bright white skin with a ‘powdery’ texture) and/or b. 
Sclerosis (i.e., areas of yellowish/ivory white skin with a smooth/waxy/firm 
texture. Sclerosis is often seen at the tips of the labia minora, or on 
periclitoral or perineal skin) in at least one of the following vulvar areas: 
Clitoris and/or periclitoral skin (C); Right interlabial sulcus and labium 
minus (R); Left interlabial sulcus and labium minus (L); Posterior Fourchette 
and/or perineum (P) (see protocol section 8.5.1.2). 
• First symptoms of VLS (e.g., itching and/or pain) noticed by the patient at 
least 6 months before baseline. 
• At least moderate itch defined as average WI-NRS ≥4 at the Baseline visit 
(average WI-NRS is calculated as the average of all available and at least 
four WI-NRS scores which are to be reported once daily by the patient in the 
diary for 7 days prior to the Baseline visit (7 days in total)). 
 
Main exclusion criteria: 
• Any (other than VLS) ongoing localised or systemic disease involving the 
vulvar region – e.g., lichen planus, psoriasis, eczema, ulcerative colitis or 
known active infection (bacterial, viral or fungal). 
• Ongoing or prior diagnosis of any genitoanal malignancy or pre-malignancy 
(e.g., differentiated intraepithelial neoplasia or squamous cell carcinoma). 
• Any kind of ongoing cancer (or anti-cancer treatment within 3 months or 5 
half-lives (whichever is longest) prior to the Baseline visit). Note: non-
metastasising basal cell carcinoma which does not involve the genitoanal 
area is acceptable. 
• Use of emollients (including but not limited to creams, ointments, oils, or 
soaps with emollient properties) on the vulvar region within 3 days prior to 
the Baseline visit. Note: Only water and, if necessary, a soap bar without 
emollient properties, may be used to wash the vulvar region (intimate 
hygiene) when bathing or showering from within 3 days prior to the Baseline 
visit. 
• Use of any topical treatment on the vulvar region, including but not limited 
to calcineurin inhibitors, corticosteroids or anti-infectives within 14 days 
prior to the Baseline visit. 
• Use of any light therapy on the vulvar region, including but not limited to 
UV-B, UV-A, and laser, within 28 days prior to the Baseline visit. 
Main endpoints 
Primary endpoint: 
 
Mean change in weekly mean Worst Itch Numeric Rating Score (WI-NRS) 
recorded in the patient’s diary from Baseline to Week 12 for MC2-25 cream 
compared to MC2-25 vehicle. (Weekly mean WI-NRS is calculated as the 
average of WI-NRS values recorded in the patient’s diary for 7 days prior to 
the in-clinic visits). 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 12 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Secondary endpoints: 
 
• Mean change in weekly mean Worst Pain Numeric Rating Score (WP-NRS) 
recorded in the patient’s diary from Baseline to Week 12 for MC2-25 cream 
compared to MC2-25 vehicle. (Weekly mean WP-NRS is calculated as the 
average of WP-NRS values recorded in the patient’s diary for 7 days prior to 
the in-clinic visits.) 
• Percentage of patients obtaining a ≥4-point improvement in weekly mean 
WI-NRS recorded in the patient’s diary from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle.  
• Percentage of patients obtaining a ≥4-point improvement in weekly mean 
WP-NRS recorded in the patient’s diary from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle.  
• Percentage of patients obtaining a ≥3-point improvement in weekly mean 
WI-NRS recorded in the patient’s diary from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle.  
• Percentage of patients obtaining a ≥3-point improvement in weekly mean 
WP-NRS recorded in the patient’s diary from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle.  
• Change in Skindex-29 domains from baseline to week 12 for MC2-25 cream 
compared to MC2-25 vehicle. 
Other endpoints: 
 
• Frequencies of treatment emergent adverse events (AEs), SAEs, adverse drug 
reactions, AEs leading to treatment discontinuation or trial withdrawal, Other 
important AEs and deaths during the trial for MC2-25 cream compared to 
MC2-25 vehicle. 
• Mean changes in Vital signs from Baseline to week 12 for MC2-25 cream 
compared to MC2-25 vehicle.  
Trial sites 
6 sites will be opened in Denmark. 
Investigational 
Medicinal Product 
 
Trial participants will be randomized (1:1) to receive either: 
• 
MC2-25 cream (with active product ingredient) or 
• 
MC2-25 vehicle (without active product ingredient) 
The IMP must be applied after each toilet visit during the 12-week treatment 
period. 
Participant duration 
(including follow-up) 
For each participant, there will be three consecutive trial periods, adding up to 
a maximum trial duration of 18 weeks:  
• Screening (up to 4 weeks) 
• Treatment (12 weeks) and  
• Follow-up (2 weeks). 
Statistical Methods 
The primary endpoint, mean change in weekly mean Worst Itch – Numeric 
Rating Score (WI-NRS) from baseline to Week 12 for MC2-25 cream 
compared to MC2-25 vehicle, will be analysed by a mixed model of repeated 
measures (MMRM) adjusting for visit, menopausal status at baseline, urinary 
incontinence status (ICIQ-UI-SF score) at baseline and weekly mean WI-NRS 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 13 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
at baseline. At Week 12, the estimated treatment difference will be reported 
together with the associated standard error, 95% confidence intervals and p-
values based on F-statistics. 
Benefit-risk 
There are only few known potential risks associated with the 
investigational medicinal product or the trial, i.e., application site 
reaction, use during pregnancy or lack of effect due to use of MC2-25 
vehicle. Use of a vehicle control is considered justified as there are no 
approved treatments for VLS in Europe, off label systemic treatments 
for VLS may be continued during the trial and the IMP is an emollient 
and emollients are normally recommended for VLS.  In view of the 
major impact of VLS on patient’s quality of life, the potential benefits of 
MC2-25 cream on VLS, and the benign safety profile of MC2-25 cream, 
the benefit-risk ratio for the current trial is considered positive.  
 
1.2 
Schematic of trial design 
 
*   Site to call patient on day (-11 to) -8 to remind about daily WI-NRS and WP-NRS assessment in diary (day-7 to day -1),  

Clinical Trial Protocol
Clinical Trial No.: MC2-25-C3
 
 
 
 
Confidential 
  
Page 14 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
 
1.3 
Schedule of assessments (SoA) 
Table 1: 
Schedule of assessments 
Trial Period 
Screening  
Treatment  
FU 
Visit Number1 
(Visit name) 
1 
(Screening1) 
2 
(Screening 2) 
3  
(Baseline) 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
(EoT2)  
11 
(FU3) 
Trial Week 
 
 
0 
1 
3 
4 
7 
8 
11 
12 
14 
Days from Baseline  
Visit Window 
-28 to -8 
NA 
(-11 to) -8 
 
0 
NA 
7 
±1 
18 
±2 
28 
±4 
46 
±2 
56 
±4 
74 
±2 
84 
±4 
98 
±4 
Visit type4 
In-Clinic 
Phone 
In-Clinic 
In-Clinic 
Phone 
In-Clinic 
Phone 
In-Clinic 
Phone 
In-Clinic 
In-Clinic/ 
Phone 
Informed Consent5 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment X 
 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Menopausal status and 
Menstrual cycle status  
 
X 
 
 
 
 
 
 
X 
 
Prior & concomitant 
therapies6 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VLS History 
X 
 
 
 
 
 
 
 
 
 
 
VLS Patient Journey7 
X 
 
 
 
 
 
 
 
 
 
 
ICIQ-UI-SF 
 
 
X 
 
 
 
 
 
 
X 
 
WI-NRS and WP-
NRS – in-clinic 
assessment7,8 
X 
 
X 
X 
 
X 
 
X 
 
X 
 

Clinical Trial Protocol
Clinical Trial No.: MC2-25-C3
 
 
 
 
Confidential 
  
Page 15 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Trial Period 
Screening  
Treatment  
FU 
Visit Number1 
(Visit name) 
1 
(Screening1) 
2 
(Screening 2) 
3  
(Baseline) 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
(EoT2)  
11 
(FU3) 
Trial Week 
 
 
0 
1 
3 
4 
7 
8 
11 
12 
14 
Days from Baseline  
Visit Window 
-28 to -8 
NA 
(-11 to) -8 
 
0 
NA 
7 
±1 
18 
±2 
28 
±4 
46 
±2 
56 
±4 
74 
±2 
84 
±4 
98 
±4 
Visit type4 
In-Clinic 
Phone 
In-Clinic 
In-Clinic 
Phone 
In-Clinic 
Phone 
In-Clinic 
Phone 
In-Clinic 
In-Clinic/ 
Phone 
WI-NRS and WP-
NRS Diary 
(Handout)9 
X 
 
X 
X 
 
X 
 
X 
 
 
 
WI-NRS and WP-
NRS diary completion 
reminder4 
  
X 
X 
 
X 
 
X 
 
X 
 
 
WI-NRS and WP-
NRS Diary (return & 
review) 10  
 
 
X 
X 
 
X 
 
X 
 
X 
 
WPP-NRS – in-clinic 
assessment8 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Patient’s Global 
Impression of Change 
(PGIC)7 
 
 
 
 
 
X 
 
X 
 
X 
 
Patient’s rating of 
importance of 
improvement7 
 
 
 
 
 
X 
 
X 
 
X 
 
VQLI7 
 
 
X 
 
 
X 
 
X 
 
X 
 
Skindex-297 
 
 
X 
 
 
X 
 
X 
 
X 
 
Imaging of VLS11 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
VASSI 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
CGA 
X 
 
X 
X 
 
X 
 
X 
 
X 
 

Clinical Trial Protocol
Clinical Trial No.: MC2-25-C3
 
 
 
 
Confidential 
  
Page 16 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Trial Period 
Screening  
Treatment  
FU 
Visit Number1 
(Visit name) 
1 
(Screening1) 
2 
(Screening 2) 
3  
(Baseline) 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
(EoT2)  
11 
(FU3) 
Trial Week 
 
 
0 
1 
3 
4 
7 
8 
11 
12 
14 
Days from Baseline  
Visit Window 
-28 to -8 
NA 
(-11 to) -8 
 
0 
NA 
7 
±1 
18 
±2 
28 
±4 
46 
±2 
56 
±4 
74 
±2 
84 
±4 
98 
±4 
Visit type4 
In-Clinic 
Phone 
In-Clinic 
In-Clinic 
Phone 
In-Clinic 
Phone 
In-Clinic 
Phone 
In-Clinic 
In-Clinic/ 
Phone 
CGIC 
 
 
 
X 
 
X 
 
X 
 
X 
 
Physical 
examination12  
X 
 
X 
 
 
 
 
 
 
X 
(X) 
Vital signs13  
 
 
X 
 
 
 
 
 
 
X 
(X) 
Urine pregnancy test14 X 
 
X 
X 
 
X 
 
X 
 
X 
(X) 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
Application Diary 
(Handout) 
 
 
X 
X 
 
X 
 
X 
 
 
 
Application Diary 
(Return and review)10 
 
 
 
X 
 
X 
 
X 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP dispensation 
 
 
X 
 
 
X 
 
X 
 
 
 
IMP return, 
compliance and 
accountability 
 
 
 
 
 
X 
 
X 
 
X 
 
IMP application15 
 
 
X 
 
1. An unscheduled visit can be conducted to perform any of the post-baseline assessments or procedures included in the schedule of assessments (SoA) if deemed necessary by 
the Investigator. 
2. In the case of trial withdrawal or treatment discontinuation, all assessments of the Week 12 (End of Treatment [EoT]) visit must be performed to the extent possible. The end 
of treatment (EoT) form must be completed when treatment is permanently discontinued, and the end of trial form must be completed at end of the trial or in case of trial 
withdrawal.  

Clinical Trial Protocol
Clinical Trial No.: MC2-25-C3
 
 
 
 
Confidential 
  
Page 17 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
3.  (X) indicates assessments to be performed if judged necessary by the investigator. This visit could be an in-clinic visit or a phone visit depending on the follow up 
assessments considered needed by the investigator. 
4. The patients should be reminded about when to fill in the WI-NRS and WP-NRS diary. In case of phone visits, the phone call should be made as close as possible to the first 
WI-NRS and WP-NRS diary completion day. Note: if Screening 1 visit is performed on day -8, then Screening 2 visit will be omitted.  
5.   Informed consent must be signed by both patient and investigator before any trial-related procedures are performed. 
6.  “Therapies” encompassing medications and non-pharmacological treatments.  
7.   At all in-clinic visits, all patient-reported outcome (PRO) assessments should be completed before all other clinical assessments or procedures. 
8. The WI-NRS and WP-NRS must also be reported by the patient at in-clinic visits.  
9. WI-NRS and WP-NRS diary assessments must be performed at home once daily (i.e., every day around the same timepoint, e.g., morning, afternoon, or evening) for a total 
of 7 days before each in-clinic visit (i.e., from day -7 to day -1 before the next in-clinic visit). 
10. When returned the Diaries should be checked for completeness and any irregularities while the patient is still in the clinic. 
11.  Imaging is mandatory, and must be done at Screening 1, Baseline, Week 1, Week 4, Week 8 and Week 12 (or early termination).  
12.  Physical exam: A complete physical examination is required at Screening 1 and Week 12 (EoT or Early Termination) visits. An abbreviated physical examination is 
required at the Baseline visit and at the FU visit (if physical examination is judged necessary by the investigator).  
13.  Vital signs include blood pressure, heart rate, and body temperature measurement. Blood pressure and pulse rate must be taken with the patient in the sitting position with 
approximately 5 minutes rest prior to measurement.  
14. Highly sensitive urine pregnancy tests are conducted for women of childbearing potential.  
15. Before the first IMP application, the site staff shall provide thorough instruction to the patient regarding the area to apply the cream to, the amount of cream to be applied 
and the required frequency of application.   
 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 18 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
2 
Introduction 
2.1 
Purpose of trial 
As explained in the following sections, VLS is a serious condition with major impact on the quality 
of life of affected women. There is a high unmet need for an authorised, efficient, and safe 
treatment of VLS. The aetiology of VLS is largely unknown, but one hypothesis is that exposure to 
isocyanate (a degradation product from urea in the urine) may be a triggering factor via a process 
known as carbamylation. Based on currently available in-vitro data the active drug substance 
(Alanyl-Glutamine) in MC2-25 cream appears to be an efficient isocyanate scavenger and MC2-25 
cream may thereby counteract the effects of carbamylation and potentially alleviate VLS. The 
purpose of this trial is to explore the efficacy and safety of MC2-25 cream in women diagnosed 
with vulvar lichen sclerosus (VLS). 
2.2 
Background 
2.2.1 
Vulvar Lichen Sclerosus (VLS) 
The true prevalence of VLS is unknown, and probably underestimated as it is often either 
asymptomatic or under-recognised (Goldstein et al., 2005; Walkden et al., 1997). Prevalences found 
in a few very small studies in highly selected patient groups are frequently cited and range from 3% 
in nursing home residents to 1.7% in gynaecology practice and down to 0.1% in dermatology 
departments (Goldstein et al., 2005; Leibovitz et al., 2000; Wallace, 1971). There are only a few 
studies investigating the incidence or prevalence of VLS in larger and broader populations, but they 
all conclude that the incidence and or prevalence increase with age (Bleeker et al., 2016; Halonen et 
al., 2020; Melnick et al., 2020). 
VLS is an inflammatory, potentially scarring dermatosis, that has a predilection for the genital skin 
(Smith & Haefner, 2004). The characteristic sites involved are the interlabial sulci, labia minora, 
clitoral hood, clitoris with possible extension to the perineal body and perianal area giving rise to 
the characteristic ‘figure of eight’ shape. In adult women with VLS, itch is the main symptom, but 
pain may be a consequence of erosions or fissures. Rarely VLS may be asymptomatic and is an 
incidental finding on examination. In the women with itch, the itch may be difficult to withhold and 
can create embarrassment. The itch may be worse at night and may be sufficiently severe to disturb 
sleep. Dyspareunia occurs in the presence of erosions, fissures or introital narrowing. VLS may 
cause resorption of the labia minora, sealing of the clitoral hood, covering of the clitoris and 
narrowing of the vaginal introitus. The vagina and cervix are generally not involved (in contrast to 
lichen planus), unless there is a significant vaginal prolapse when the mucosa may become 
keratinised (Bhargava & Lewis, 2013; Corazza et al., 2021; Zendell & Edwards, 2013). Perianal 
lesions occur in women in about 30% of cases. There may be extension to the buttocks and 
genitocrural folds (Lewis et al., 2018). Squamous cell carcinoma in women has been associated 
with VLS. The risk of developing malignancy is approximately 3.5–5% (Micheletti et al., 2016).  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 19 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
VLS affects otherwise healthy individuals with a major impact on quality of life. A survey among 
1.492 patients with LS (1.421 adult women) showed that for 95% of the patients their quality of life 
was impacted “sometimes, frequently, or always” (for 93% of the patients this was also the case for 
impact on their sexual life). Overall, the impact of VLS was rated as moderate or severe on overall 
quality of life for approximately 85% of the patients. According to the same survey, one in ten 
women with VLS have considered suicide because of VLS (GlobalSkin, 2018). 
The aetiology of VLS is not well defined but available evidence indicates the role of two main 
pathomechanisms, i.e., immunological dysreactivity and chronic inflammation as well as abnormal 
collagen synthesis, which act on a susceptible genetic background and triggering factors (Corazza et 
al., 2021; Tran et al., 2019). One such triggering factor could be irritation from exposure to urine 
e.g., due to incontinence.  There is very little data on the role of urinary incontinence in VLS in 
women, but recent data found that the prevalence of urinary incontinence was 63% in LS women 
compared to 34% in non-LS women (Kirby et al., 2021). This may indicate an association between 
VLS in women and urinary incontinence.  
Urea, which is a degradation product excreted in urine, is via a slow equilibrium a source of 
formation of isocyanate. Isocyanate is a highly reactive electrophile that can quickly react with 
nucleophilic groups which in the body often is in the form of amino groups on e.g., proteins, 
peptides or free amino acids. The reaction between isocyanate and an amino group is irreversible 
and often referred to as “carbamylation”. The impact of carbamylation on protein properties is 
believed to be an important contributor to the development of a number of chronic diseases such as 
chronic kidney disease, cataract, atherosclerosis and rheumatoid arthritis (Jaisson et al., 2018). See 
IB Section 2.1 for further details. It is conceivable that carbamylation in the skin affects afferent 
small nerve fibres resulting in the sensation of itch. In addition, epidermal haemorrhagic bleedings, 
which are a typical finding in VLS, may be a result of mechanical ruptures of small blood vessels, 
where supporting connective tissues (collagen and elastin) have lost their elastic properties due to 
carbamylation (Adamolekun, 2011; Kimani et al., 2014). It is hypothesised that prolonged skin 
exposure to urea from urine may lead to formation of isocyanate and in turn increased protein 
carbamylation triggering skin changes characteristic for VLS in women genetically predisposed to 
develop LS. 
There are no treatments specifically approved for VLS in Europe or the UK. However, British and 
European guidelines recommend 3-month regimens with high potency topical corticosteroids. For 
many patients, long-term treatment, lasting for years or even life long, is often necessary, even if 
there are few signs and/or symptoms of LS (Kirtschig et al., 2015; Lewis et al., 2018). In women 
there is growing evidence that VLS under good control has a reduced risk of scarring and 
malignancy. However, the risk is not eliminated (Cooper et al., 2004; Lee et al., 2015). According 
to a survey including around 1400 women with VLS, only 21% of patients feel they are managing 
their VLS condition “Well” or “Very Well” and only half achieved remission for an average 
duration of 7 months (GlobalSkin, 2018). As such there is an unmet need for an approved safe and 
effective treatment for VLS. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 20 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
2.2.2 
MC2-25 cream  
The drug product MC2-25 cream consists of a cream base and the active dipeptide drug substance 
Alanyl-Glutamine (Ala-Gln). Ala-Gln is intended to scavenge isocyanate, a toxic degradation 
product from urea which is present in high concentrations in urine, and which may be an important 
triggering factor in VLS via carbamylation of proteins as described above.  
The carbamylation reaction is illustrated in Figure 1. Both free amino acids and proteins can be 
carbamylated. All free amino acids have an α-amino group, but in proteins the α-amino groups of 
amino acids are incorporated in the peptide bonds that link the amino acids and they are therefore 
not available for carbamylation. However, the essential amino acid lysine – whether free or 
incorporated in proteins – also has a positively charged ε-amino group side chain. The rate of the 
reaction between isocyanate and amino groups increases with decreasing pKa values, and this 
means that at pH 7 or below, the α-amino groups react about 100 times faster than the lysine ε-
amino groups (Gillery & Jaisson, 2013; Stark, 1965). The pH in the vulvar region (interior aspect of 
labia majora and perineum) is around 5.4-5.6 (Runeman, 2005). 
Figure 1: 
The reaction of isocyanic acid with protein amino groups (Jaisson et al., 2018) 
 
Free amino acids compete for isocyanate binding and thus act as natural scavengers for 
carbamylation (Kalim et al., 2014). However, long-term use of amino acids as isocyanate 
scavengers may pose problems due to formation of carbamylated amino acids, which may interfere 
with protein synthesis (Kraus & Kraus, 2001). As such, using peptides rather than amino acids as 
isocyanate scavengers may be a better alternative and in fact di- and oligopeptides have been 
demonstrated to be more efficient isocyanate scavengers than amino acids (Berg et al., 2013; Stark, 
1965). 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 21 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Considering these discoveries, MC2 undertook an in vitro screening assay of protein carbamylation 
with a range of different compounds including amino acids and peptides. Ala-Gln was demonstrated 
to be among the most efficient compounds in terms of preventing protein carbamylation through 
isocyanate scavenging, showing a ~65% inhibition of protein carbamylation, compared with e.g., 
Histidine which showed ~39% inhibition (see IB, Section 4.2.1.2). Furthermore, in another in vitro 
study in reconstructed human epidermis, Ala-Gln inhibited protein carbamylation in a dose-
dependent manner, resulting in ~89% inhibition at the highest concentration (3%) (see IB Section 
4.2.1.3). 
These data support the hypothesis that MC2-25 cream may be an efficient isocyanate scavenger and 
may thereby counteract the effects of carbamylation and potentially alleviate VLS. MC2-25 cream 
is being tested for the first time in VLS in this trial. It is currently being tested for the first time in 
humans in an ongoing clinical trial in Chronic Kidney Disease associated Pruritus (CKD-aP) 
patients (MC2-25-C1,  EUCT 2022-500044-38-01, NCT05482698). 
2.3 
Risk/benefit assessment 
2.3.1 
Known potential risks 
A summary of risks that may be associated with MC2-25 cream or specific trial 
procedures/circumstances and mitigation strategies to address these are provided in Table 2.  
Table 2: 
Summary of risks and mitigation strategies 
Risk 
MC2-25 cream 
Application site reaction  
Risk Description: No application site reactions were observed after topical 
(dermal) application of MC2-25 cream and MC2-25 vehicle to minipigs 
(twice daily for 2 weeks). In addition, in an ongoing randomised, double-
blind, vehicle controlled clinical trial in chronic kidney disease associated 
pruritus (CKD-aP) where MC2-25 cream (3%), or MC2-25 vehicle is applied 
twice daily to unlimited areas of CKD-aP skin for 12 weeks only 3 adverse 
events within the System Organ Class ‘Skin and subcutaneous tissue 
disorders’ (Preferred terms: pruritus, pruritus and alopecia) have been 
reported among 36 patients who completed 8–12 weeks treatment as of 
medio May 2023. All events were considered mild (Data on file). 
Consequently, the risk of application site reactions is considered low. 
However, in this trial MC2-25 cream will be applied topically in VLS for the 
first time. Therefore, at the present time application site reactions cannot be 
ruled out. 
Risk Mitigation: Adverse events will be evaluated more frequently during 
the first 2 weeks of the treatment phase (weekly visits) compared to the 
subsequent weeks of the treatment phase (bi-weekly visits). In addition, a 
patient may withdraw from the trial or discontinue trial treatment at any time 
at his/her own request or at the discretion of the investigator due to 
unacceptable adverse events.  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 22 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Use during Pregnancy  
Risk Description: The toxicological profile of the active product ingredient 
Ala-Gln has been evaluated as part of the approval of Dipeptiven® with no 
indications of teratogenic or other embryotoxic and peri-postnatal injuries 
observed up to an intravenous dosage of 1.6 g N(2)-L-alanyl-L-glutamine/kg 
body weight per day with resulting systemic safety margins even more 
favourable than those presented in Section 4.2. Reproductive toxicity studies 
have not been conducted with MC2-25 cream. 
Risk Mitigation: According to the (SmPC), Dipeptiven® should not be 
administered during pregnancy due to lack of experience. Therefore, patients 
can only be randomised in the trial if they are of either non-childbearing 
potential or of childbearing potential and have a negative pregnancy test at 
the Baseline visit and use a highly effective method of contraception 
throughout the trial.  
Risk 
Trial procedures/circumstances 
Use of MC2-25 vehicle  
Risk Description: Half of the patients will be treated with MC2-25 vehicle 
during the 12-week treatment period. This might result in deterioration of 
VLS. 
Risk Mitigation: No marketed products are approved for treatment of VLS. 
Therefore, patients will not miss out on approved treatment by participation 
in this trial. However, as described in Section 2.2.1, VLS has a significant 
impact on quality of life and therefore off-label treatments are not 
uncommon. Current UK and European guidelines are based on potent to 
ultrapotent topical corticosteroids. To limit the risk of VLS deterioration 
after entering the trial, all patients will be allowed to continue existing stable 
systemic treatments with a known or potential effect on VLS during the trial. 
Half of the patients will be randomised to receive the MC2-25 vehicle. There 
is no available data on the effect of MC2-25 vehicle in VLS patients, 
Consequently, it is currently not possible to establish an expected vehicle 
effect size, However, MC2-25 vehicle has emollient properties and as such is 
not strictly considered a placebo treatment. Patients are free to withdraw 
from the trial or discontinue trial treatment at any time at their own request 
or at the discretion of the investigator in case of unacceptable adverse events 
or lack of improvement. Withdrawal from the trial or discontinuation of trial 
treatment will not affect or prejudice the patient’s further care or treatment. 
2.3.2 
Known potential benefits 
There are currently no data on the clinical effect of MC2-25 cream in VLS. However, as described 
in Section 2.2.2 there are data to support the hypothesis that MC2-25 cream may be an efficient 
isocyanate scavenger and may potentially alleviate VLS. 
2.3.3 
Assessment of potential risks and benefits 
As described above, VLS is a serious disease and patients with VLS often suffer from a major 
impact on their quality of life. While the benefits of MC2-25 cream are not yet known, an effective 
isocyanate scavenger (Ala-Gln) may reduce the adverse effects resulting from carbamylation of skin 
proteins and amino acids and thereby alleviate itch and pain associated with VLS. 
This is the first clinical trial in VLS with MC2-25 cream, so no clinical data are available. MC2 is 
also developing MC2-25 cream for topical treatment of chronic kidney disease associated Pruritus 
(CKD-aP). The first clinical trial (Phase 2) with MC2-25 cream in patients with CKD-aP is 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 23 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
currently ongoing (MC2-25-C1, EUCT 2022-500044-38-01, NCT05482698). So far, only 3 adverse 
events within the System Organ Class ‘Skin and subcutaneous tissue disorders’ (Preferred terms: 
pruritus, pruritus and alopecia) have been reported among 36 patients who completed 8–12 weeks 
treatment as of medio May 2023. All events were considered mild (Data on file). As described in 
Section 4.2 below, the systemic safety margin for MC2-25 cream in this trial compared to the 
maximum recommended dose for IV infusion of Dipeptiven® ranges from 200 to 20.000 if 100% 
respectively 1% of Ala-Gln in the MC2-25-cream is absorbed to the systemic circulation. In view of 
these favourable systemic safety margins no safety laboratory samples are included in the trial. 
Furthermore, Ala-Gln is rapidly split into alanine and glutamine after reaching the systemic 
circulation. In man, half-lives of between 2.4 and 3.8 min (4.2 min in terminal renal insufficiency) 
and a plasma clearance of between 1.6 and 2.7 L/min were determined after IV infusion of Ala-Gln 
in the form of Dipeptiven® (see IB Section 5.2). So, any Ala-Gln which has not scavenged 
isocyanate in the skin after topical application of MC2-25 cream, may reach systemic circulation, 
but will rapidly be metabolised to the two respective amino acids and become part of the body’s 
amino acid homeostasis. In view of the rapid elimination of any systemically available Ala-Gln, the 
risk of systemic drug-drug interactions is considered negligible in this trial. Furthermore, any 
metabolite formed as a consequence of the isocyanate scavenging role of Ala-Gln in the skin, are 
presumably already present in VLS patients, given that Ala-Gln and its degradation products 
appears to be present endogenously in human skin, see ‘IB Section 1.3’.  
As also described in Section 4.2, MC2-25 cream was well tolerated when applied to the skin on a 
twice-daily basis for 2 weeks in minipigs and for 8–12 weeks in CKD-aP patients. Furthermore, 
Ala-Gln was well tolerated when applied in high doses to the peritoneal surface on a daily basis for 
8 weeks in patients with chronic renal failure. Therefore, the risk of local adverse effects (local 
application site reactions) is considered low in this trial. All excipients used in MC2-25 cream are 
known from topical use in other drug products.   
VLS prevalence increases with age as described in Section 2.2.1. Consequently, a considerable 
amount of elderly (>65 years of age) patients is expected to be enrolled. Elderly patients are 
considered a vulnerable population due to potential comorbidities and polypharmacy but not due to 
their VLS. In view of the favourable systemic and local safety profiles described above, there are no 
specific eligibility criteria for elderly patients. Likewise, there are no specific safety surveillance 
measures during the trial for elderly patients. Exclusion criterion 6, Section 5.2 ‘Any chronic or 
acute medical condition that, in the opinion of the investigator, may pose a risk to the safety of the 
patient or may interfere with the assessment of efficacy in this trial’ will ensure that elderly patients 
are not enrolled in the trial if they have significant comorbidities.  
In view of the major impact of VLS on patient’s quality of life, the potential benefits of MC2-25 
cream on VLS, and the benign safety profile of MC2-25 cream, the benefit-risk ratio for the current 
trial is considered positive. In view of the benign nature of the potential risks a Data Safety 
Monitoring Board is not considered necessary. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 24 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
3 
Objectives and endpoints 
Primary objective:  
To explore the efficacy 
of MC2-25 cream 
compared to MC2-25 
vehicle in vulvar lichen 
sclerosus (VLS). 
Primary endpoint: 
Mean change in weekly mean Worst Itch Numeric Rating Score (WI-NRS) 
recorded in the patient’s diary from Baseline to Week 12 for MC2-25 cream 
compared to MC2-25 vehicle. (Weekly mean WI-NRS is calculated as the 
average of WI-NRS values recorded in the patient’s diary for 7 days prior to 
the in-clinic visits). 
 
Secondary endpoints: 
• Mean change in weekly mean Worst Pain Numeric Rating Score (WP-NRS) 
recorded in the patient’s diary from Baseline to Week 12 for MC2-25 cream 
compared to MC2-25 vehicle. (Weekly mean WP-NRS is calculated as the 
average of WP-NRS values recorded in the patient’s diary for 7 days prior to 
the in-clinic visits.) 
• Percentage of patients obtaining a ≥4-point improvement in weekly mean 
WI-NRS recorded in the patient’s diary from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle.  
• Percentage of patients obtaining a ≥4-point improvement in weekly mean 
WP-NRS recorded in the patient’s diary from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle.  
• Percentage of patients obtaining a ≥3-point improvement in weekly mean 
WI-NRS recorded in the patient’s diary from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle.  
• Percentage of patients obtaining a ≥3-point improvement in weekly mean 
WP-NRS recorded in the patient’s diary from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle.  
• Change in Skindex-29 domains from baseline to week 12 for MC2-25 cream 
compared to MC2-25 vehicle. 
Other endpoints: 
• Percentage of patients obtaining a complete response (score ≤1) in weekly 
mean WI-NRS recorded in the patient’s diary from Baseline to Week 12 for 
MC2-25 cream compared to MC2-25 vehicle.  
• Percentage of patients obtaining a complete response (score ≤1) in weekly 
mean WP-NRS recorded in the patient’s diary from Baseline to Week 12 for 
MC2-25 cream compared to MC2-25 vehicle 
• Mean change in Worst Itch Numeric Rating Score (WI-NRS) recorded at in-
clinic visits from Baseline to Week 12 for MC2-25 cream compared to MC2-
25 vehicle. 
• Mean change in Worst Pain Numeric Rating Score (WP-NRS) recorded at in-
clinic visits from Baseline to Week 12 for MC2-25 cream compared to MC2-
25 vehicle. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 25 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
• Mean change in Worst Penetrative sex related Pain Numeric Rating Score 
(WPP-NRS) recorded at in-clinic visits from Baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle. 
• Percentage of patients obtaining a ≥3-point improvement in WI-NRS 
recorded at in-clinic visits from Baseline to Week 12 for MC2-25 cream 
compared to MC2-25 vehicle.  
• Percentage of patients obtaining a ≥3-point improvement in WP-NRS 
recorded at in-clinic visits from Baseline to Week 12 for MC2-25 cream 
compared to MC2-25 vehicle.  
• Percentage of patients obtaining a ≥3-point improvement in WPP-NRS 
recorded at in-clinic visits from Baseline to Week 12 for MC2-25 cream 
compared to MC2-25 vehicle.  
• Percentage of patients who reported ‘Very much better’, ‘Much better’ or ‘A 
little better’ in Patient’s Global Impression of Change (PGIC) for Worst Itch 
(WI), Worst Pain (WP) or Worst Penetrative sex related Pain (WPP) from 
baseline to week 12 for MC2-25 cream compared to MC2-25 vehicle. 
• Percentage of patients who reported an Important improvement in Patient’s 
Global Impression of Change (PGIC) for Worst Itch (WI), Worst Pain (WP) 
or Worst Penetrative sex related Pain (WPP) from baseline to week 12 for 
MC2-25 cream compared to MC2-25 vehicle. 
• Mean change in VQLI total score from baseline to week 12 for MC2-25 
cream compared to MC2-25 vehicle. 
• Mean change in Vulvar lichen sclerosus Area and Sign Severity Index 
(VASSI) from baseline to week 12 for MC2-25 cream compared to MC2-25 
vehicle 
• Mean change in VASSI Area scores from baseline to week 12 for MC2-25 
cream compared to MC2-25 vehicle 
• Mean change in VASSI Sign scores from baseline to week 12 for MC2-25 
cream compared to MC2-25 vehicle 
• Mean change in Clinician’s Global Assessment (CGA) of VLS from baseline 
to week 12 for MC2-25 cream compared to MC2-25 vehicle 
• Percentage of patients with a ≥2-point improvement in Clinician’s Global 
Assessment (CGA) of VLS from baseline to week 12 for MC2-25 cream 
compared to MC2-25 vehicle 
• Percentage of patients with an improvement in the Clinician’s Global 
Impression of Change (CGIC) assessment (i.e., ‘Very much better’, ‘Much 
better’ or ‘A little better’) from baseline to week 12 for MC2-25 cream 
compared to MC2-25 vehicle. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 26 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Secondary objectives: 
• To explore the safety 
of MC2-25 cream 
compared to MC2-25 
vehicle in VLS. 
 
Other endpoints: 
• Frequencies of treatment emergent adverse events (AEs), SAEs, adverse drug 
reactions, AEs leading to treatment discontinuation or trial withdrawal, Other 
important AEs and deaths during the trial for MC2-25 cream compared to 
MC2-25 vehicle. 
• Mean changes in Vital signs from Baseline to week 12 for MC2-25 cream 
compared to MC2-25 vehicle. 
• To explore the burden 
of VLS on women’s 
lives. 
• Burden of VLS on women’s lives as reported on the “VLS patient journey 
sheet”. 
 
 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 27 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
4 
Trial design 
4.1 
Description of trial design 
This is a multicentre, phase 2, randomised, double-blind, 2-arm, parallel-group and vehicle-
controlled trial in VLS. The trial consists of 3 consecutive periods adding up to a maximum trial 
duration for each patient of 18 weeks: 
• Screening period (up to 4 weeks) 
• Treatment period (12 weeks) and  
• Follow-up (FU) period: (2 weeks).  
33 patients will be randomised in a 1:1 ratio to MC2-25 cream or MC2-25 vehicle. During the 
treatment period, patients are treated for 12 weeks with MC2-25 cream or MC2-25 vehicle. In-clinic 
visits are planned at Screening 1, Baseline, Week 1, Week 4, Week 8 and Week 12 (End of 
Treatment). Phone visits are planned at Screening (Visit) 2, Week 2, Week 6, and Week 10. The 
week 14 visit may be either a phone visit on an in-clinic visit. 
A schematic overview of the trial is provided in Section 1.2 and a schedule of assessments and 
visits is provided in Section 1.3. 
 
4.2 
Rationale for trial design 
4.2.1 
Design 
This is a randomised, double-blind, and vehicle-controlled trial. By blinding, randomisation and 
inclusion of a group receiving MC2-25 vehicle (without the active ingredient), the trial design 
controls for potential influence on the results other than that arising from the pharmacological 
action of MC-25 cream (containing the active ingredient alanyl-glutamine [Ala-Gln])).  
4.2.2 
Comparator 
No marketed products are approved by regulatory authorities for treatment of VLS. Therefore, 
patients will not miss out on approved treatment by participation in this trial. MC2-25 vehicle has 
emollient properties. So, patients randomised to MC2-25 vehicle treatment will not receive active 
treatment, but they will receive emollient treatment during the treatment period. Available 
guidelines recommend the use of emollients and ultrapotent topical corticosteroids (Kirtschig et al., 
2015; Lewis et al., 2018). 
4.2.3 
Duration of trial 
The 12-week double-blind treatment duration is based on the assumption that if no differentiation to 
the MC2-25 vehicle is observed within this timeframe, then the treatment may be of less clinical 
relevance as current standard of care is a 12 weeks treatment with potent to ultrapotent topical 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 28 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
corticosteroids according to EU and UK guidelines (Kirtschig et al., 2015; Lewis et al., 2018). In 
addition, the 12-week treatment duration is supported by 13-weeks repeat dose toxicity studies in 
rats and dogs with Ala-Gln administered intravenously in form of Dipeptiven® (Fresenius, 2015). 
The double-blind treatment period is preceded by a screening period of up to 28 days duration 
allowing for wash out of other treatments and emollients before baseline as/if applicable and a 14-
day follow-up period, to ensure safety follow-up.  
4.2.4 
Trial population 
Traditional teaching is that there is a bimodal onset of VLS in prepubertal children and in post-
menopausal women. However, recent studies suggest that VLS prevalence is extremely low in 
childhood and increases steadily with age (Bleeker et al., 2016; Halonen et al., 2020; Melnick et al., 
2020). Consequently, the trial allows enrolment of adult women with no upper age limit. Children 
will not be enrolled as this is the first clinical trial with MC2-25 cream in VLS. As outlined in 
Section 2.2.1, chronic exposure to urine and from occlusion and moisture in the genitoanal area may 
be triggering factors for Lichen sclerosus. There is very little data on the role of urinary 
incontinence in VLS in women, but a recent cross-sectional analysis found that the prevalence of 
urinary incontinence was 63% in LS women compared to 34% in non-LS women (Kirby et al., 
2021). Consequently, women will be allowed to enter the trial regardless of their urinary 
incontinence status, but they will be screened for urinary incontinence when entering the trial so 
urinary incontinence status can be taken into account during analysis of trial data. According to a 
recent survey including around 1400 women with VLS, itch is the predominant symptom reported 
by >90% of the survey respondents and relief of itching was rated the most important efficacy 
parameter to be addressed in a future treatment (GlobalSkin, 2018). In a recent cross-sectional study 
including around 500 pre-menopausal women with VLS the most prevalent symptom was 
dyspareunia. However, pruritus prompted patients to seek medical attention at a frequency similar 
to dyspareunia (Krapf et al., 2022). Consequently, patients will be required to have a minimum 
Worst Itch Numeric Rating Score (WI-NRS) ≥ 4 (on a scale ranging from 0 [no itch] to 10 [worst 
imaginable itch) to ensure that trial patients suffer from itch and that it is at least of moderate 
intensity to ensure that there is room for improvement.   
4.2.5 
Dose strength 
Urea is in equilibrium with isocyanate which is a reactant in a process known as carbamylation. 
Carbamylation is believed to be an important contributor to the development of a number of chronic 
diseases including CKD. It is conceivable that carbamylation may also contribute to itch and dry 
skin associated with CKD, as well as the symptoms of itch and pain in VLS, as outlined in Section 
2.2.1. The concentration of urea in urine ranges from 9 to 23 g/L (Thomas, 2019). With a molar 
weight of 60.06 g/mole for urea, this corresponds to a urinary urea concentration ranging from 0.15 
to 0.38 mole/L. For the following calculation, an average urea concentration of 0.3 mole/L in urine 
is assumed.  
As mentioned above a recent cross-sectional analysis indicated that urinary incontinence is more 
frequent in women with VLS than in women without LS (Kirby et al., 2021). A previous trial  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 29 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
showed that the average pad weight gain in a one-hour pad test for incontinence was 16.5 g in 18 
women with proven genuine stress incontinence (Wall et al., 1990), which is classified as the lower 
end of moderate incontinence (Ferreira & Bo, 2015). Assuming a urine density of ~1 (i.e. 16.5 g 
~16.5 mL urine), this amount of urine contains ~4950 µmole of urea. The concentration of 
isocyanate in urine is not easy to calculate. The concentration of isocyanate in serum is very low 
due to high concentration of scavenging activity of amino and sulfhydryl groups of amino acids, 
peptides, and proteins (Nilsson et al., 1996). However, in the ultrafiltrate from the nephron, 
isocyanate will start accumulating. Kinetic data on the rate of formation of isocyanate depends on 
factors like temperature, pH of urine, and concentration of urea, but data suggest that equilibrium is 
reached fairly quickly (Dirnhuber & Schutz, 1948). Based on an accepted equilibrium ratio of urea 
to isocyanate of 99:1 (Jaisson et al., 2018; Nicolas et al., 2018), a urine amount containing 4950 
µmole of urea (the hourly urine leakage in patients with moderate incontinence) will contain up to  
49,5 µmole isocyanate. It is well known that urea is quickly absorbed into the skin (Gabard & 
Chatelain, 2003), thus the genital skin of LS patients with urinary incontinence is expected to have 
constant high levels of urea and isocyanate. 
To reduce the concentration of free isocyanate in the skin, the molar amount of scavenger (Ala-Gln) 
added via a cream should be higher than the molar concentration of isocyanate. At each treatment 
application one fingertip unit (FTU) (approximately 500 mg) should be used. It is generally 
accepted that one FTU covers 2% of the body surface area corresponding to appr. 358 cm2 (Sacco et 
al., 2010; Thomas & Finlay, 2007) which should be sufficient to cover the vulvar region which in 
the context of this trial includes the clitoris and periclitoral skin, interlabial sulci, labia minora, 
posterior fourchette and perineum, anal and perianal skin. There is 15 mg (0.015 gram) of Ala-Gln 
in 500 mg (1 FTU) of MC2-25 3% cream corresponding to 69 µmole dipeptide.  
Based on these calculations, administration of one FTU of MC2-25 cream in the vulvar region will 
provide a slight excess of scavenger (~69 µmole dipeptide scavenger vs 49,5 µmole isocyanate).  
Considering that the above calculations are based on average hourly urine leakage in patients with 
moderate urinary incontinence, the application of MC2-05 has to be repeated (see next section).  
4.2.6 
Dosing-regimen 
A FTU corresponding to 0.5 g of MC2-25 cream, or MC2-25 vehicle is to be applied on the vulvar 
region (i.e., the clitoris and periclitoral skin, interlabial sulci, labia minora, posterior fourchette and 
perineum, anal and perianal skin) after each toilet visit (during day and night) starting on the day of 
the Baseline visit. This dosing regimen has been chosen to ensure replenishment of Ala-Gln on the 
vulvar region (as the cream will likely be removed due to wiping after urination)  and to counteract 
any increase in urea concentration e.g., due to insufficient cleaning/wiping of urine residues after 
toilet visits. This will also counteract any increase in urea due to urinary leakage between toilet 
visits. Limited information is available on the normal range of urination frequencies in women. 
However, a recent survey investigating urination frequencies in 2534 healthy women reported 
reference ranges for urination frequencies between 2-10 times/day and 0-4 times/night (Wyman et 
al., 2022). Consequently, the maximum number of applications will be 12 per day. Assuming up to 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 30 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
12 toilet visits per day leads to a maximum total daily dose of 6.0 g of MC2-25 cream (3%) 
corresponding to 0.18 g Ala-Gln per day or 17 mg MC2-25 cream per cm2  skin per day (assuming 
that 6.0 g cream per day will be distributed on a skin area corresponding to two handprints or 358 
cm2).  
Systemic safety margin for Ala-Gln: Ala-Gln in the form of Dipeptiven® can safely be administered 
intravenously up to a maximum daily dose of 0.5 g Ala-Gln/kg/day. Under the assumption that an 
average adult woman weighs around 70 kg this corresponds to a maximum IV dose of 35 g Ala-Gln 
per day. If all Ala-Gln applied per day as MC2-25 cream was to penetrate into the systemic 
circulation this would correspond to a systemic safety margin of approximately 200. However, less 
than 1% of the topically applied Ala-Gln dose was recovered in the receptor fluid (a surrogate for 
absorption into the systemic circulation) in an in vitro whole human skin penetration trial with Ala-
Gln cream (see IB Section 4.3.1.2) which would correspond to a systemic safety margin of 
approximately 20,000. Whether whole human skin penetration data can be extrapolated to VLS or 
not can be debated as VLS skin could be argued both to be a deficient or an efficient skin barrier.  
Local tolerability of MC2-25 cream (3%) and Ala-Gln: In a local tolerability study, MC2-25 cream 
was well tolerated when applied topically on a twice-daily basis for 2 weeks in minipigs which is in 
accordance with regulatory requirements for ‘stand-alone’ local tolerance testing 
(EMA/CHMP/SWP/2145/2000 Rev. 1, Corr. 1). In this study the animals were treated with a total 
daily dose of 20 mg/cm2 of MC2-25 cream (i.e.10 mg/cm2 of MC2-25 cream per application, twice 
daily) under semi-occlusion to avoid that the cream was rubbed off. The total daily duration of local 
exposure to MC2-25 cream was 20 hours (divided in a 6-hour and a 14-hour exposure period), as 
the high dose volume results in residual cream on the skin. Thus, on average animals were exposed 
to 1 mg/cm2/hour over a 20-hour period. 
In the MC2-25-C3 trial patients are instructed to apply ~1.4 mg/cm2 of MC2-25 cream per 
application (i.e. 1 FTU ~0.5 g cream applied to an area corresponding to two handprints, or ~358 
cm2), after each toilet visit both day and night, and up to 12 times daily, resulting in a total daily 
dose of 16.8 mg/cm2 of MC2-25 cream. Thus, over a 24-hour period patients will on average be 
exposed to ~0.7 mg/cm2/hour (1.4 mg/cm2 x 12 applications per day : 24 hours per day), if they use 
the maximum number of 12 daily applications.  
The maximum total daily dose of cream per area, the amount of cream per area per application and 
the average hourly local exposure per area are therefore lower in the proposed clinical trial than in 
the minipig study.  
 
In an ongoing randomised, double-blind, vehicle controlled clinical trial in chronic kidney disease 
associated pruritus (CKD-aP) where MC2-25 cream (3%), or MC2-25 vehicle is applied twice daily 
to unlimited areas of CKD-aP skin for 12 weeks only 3 adverse events within the System Organ 
Class ‘Skin and subcutaneous tissue disorders’ (Preferred terms: pruritus, pruritus and alopecia) 
have been reported among 36 patients who completed 8–12 weeks treatment as of medio May 2023. 
All events were considered mild (Data on file) (Data on file).  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 31 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
In view of the favourable systemic safety margin for Ala-Gln as well as the lack of local tolerability 
issues both after administration of MC2-25 cream on the skin in minipigs and CKD-aP patients, the 
proposed dosing regimen is considered safe.  
4.2.7 
Endpoints 
As described in the ‘Trial population’ section above, itch is an important symptom in VLS patients. 
In addition, according to a recent publication from the Core Outcomes for Research in Lichen 
sclerosus (CORALS) initiative, it is recommended that symptoms followed by lichen sclerosus 
specific quality of life and clinical signs of lichen sclerosus are evaluated in all clinical trials in 
lichen sclerosus (Simpson, 2022). Consequently, the primary endpoint the symptom itch which is 
evaluated by use of the clinical outcome assessment (COA), patient reported Worst Itch Numeric 
Rating Score (WI-NRS) with a 24-hour recall period. This COA was selected based on clinical 
relevance and regulatory acceptability precedent with two other extremely itchy diseases (namely 
Korsuva® for Chronic Kidney Disease associated Pruritus (CKD-aP) and Dupixent® for Atopic 
Dermatitis).  
Furthermore, in line with the above-mentioned CORALS initiative, the trial includes a number of 
other endpoints evaluating symptoms, lichen sclerosus specific quality of life and clinical signs 
reported by clinicians as follows. The trial includes endpoints evaluating patient reported outcomes 
such as Worst Pain- and Worst Penetrative sex related Pain Numeric Rating Scores (WP-NRS and 
WPP-NRS). To enable determination of minimum important difference (MID) in these patient-
reported numeric rating scores, the trial also includes endpoints evaluating Patient’s Global 
Impression of Change (PGIC) (on a verbal rating scale) for Worst Itch, Worst Pain and Worst 
Penetrative sex related Pain in accordance with recent Patient-Focused Drug Development (PFDD) 
Guidances1. Furthermore, patients will be asked to complete the VLS patient journey sheet at the 
Screening 1 visit. The VLS patient journey sheet seeks to understand what the most burdensome 
issues for VLS patients are. Also, patients will be asked to complete quality of life questionnaires 
(Skindex-29 and VQLI) throughout the trial to evaluate any effects of treatment on quality of life. 
The trial also includes a number of endpoints evaluating clinician reported outcomes to explore 
correlations with patient reported endpoints. 
4.3 
Start of trial and end of trial definition 
The start of trial is defined as the date of the first visit of the first patient. The end of trial is defined 
as the date of the last visit of the last patient. 
 
1 https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-
series-enhancing-incorporation-patients-voice-medical - accessed 10 October 2022 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 32 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
5 
Trial population 
5.1 
Inclusion criteria 
Participants must meet all the following criteria to be eligible for participation in the trial: 
1. Women, of any race or ethnicity, who are ≥18 years of age at the time of Screening 1.  
2. Able to understand the trial and willing to comply with trial requirements. 
3. Has provided written informed consent. 
4. Clinical diagnosis of VLS (i.e., biopsy for histological confirmation not required except if 
needed to rule out malignancy or differential diagnosis of e.g., vulvar lichen planus) made by 
either a dermatologist or a gynaecologist familiar with VLS. 
5. Presence of at least one of the following signs of VLS: a. Hyperkeratosis (i.e., patches/plaques 
of bright white skin with a ‘powdery’ texture) and/or b. Sclerosis (i.e., areas of yellowish/ivory 
white skin with a smooth/waxy/firm texture. Sclerosis is often seen at the tips of the labia 
minora, or on periclitoral or perineal skin) in at least one of the following vulvar areas: Clitoris 
and/or periclitoral skin (C); Right interlabial sulcus and labium minus (R); Left interlabial 
sulcus and labium minus (L); Posterior Fourchette and/or perineum (P) (see protocol section 
8.5.1.2). 
6. First symptoms of VLS (e.g., itching and/or pain) noticed by the patient at least 6 months before 
baseline.  
7. At least four WI-NRS scores available in the diary for calculation of the average WI-NRS at the 
baseline visit. 
8. At least moderate itch defined as average WI-NRS ≥4 at the Baseline visit (average WI-NRS is 
calculated as the average of all available and at least four WI-NRS scores which are to be 
reported once daily by the patient in the diary for 7 days prior to the Baseline visit (7 days in 
total)).  
9. Women must be of either:  
a) Non-childbearing potential, i.e., post-menopausal* or confirmed sterile (e.g., hysterectomy, 
bilateral salpingectomy or bilateral oophorectomy) (*Note: a postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient) OR,  
b) Childbearing potential with a negative highly sensitive* urine pregnancy test at the Baseline 
visit (*Note: a highly sensitive urine pregnancy test must have a sensitivity down to at least 
25 mIU/ml for human chorionic gonadotropin (hCG)). 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 33 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
10. Women of childbearing potential must agree to use a highly effective method of contraception 
(i.e., a method with a failure rate of less than 1 % per year when used consistently and correctly) 
while receiving double-blind treatment. Highly effective contraception is defined as follows:  
a) combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: oral, intravaginal, transdermal 
b) progestogen-only hormonal contraception associated with inhibition of ovulation: oral, 
injectable, implantable 
c) intrauterine device (IUD) 
d) intrauterine hormone-releasing system (IUS)  
e) bilateral tubal occlusion  
f) vasectomised partner (provided that is the sole sexual partner of the patient and that the 
vasectomised partner has received medical assessment of the surgical success.) 
g) sexual abstinence if in line with the preferred and usual lifestyle of the patient and defined as 
refraining from heterosexual intercourse during the entire period of the trial. Periodic 
methods of abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
are not accepted methods of contraception). 
5.2 
Exclusion criteria 
Participants who meet any of the following criteria are ineligible for participation in the trial: 
Conditions/Diseases 
1. Pregnant, breast feeding, or planning to become pregnant during the trial.  
2. Any (other than VLS) ongoing localised or systemic disease involving the vulvar region – e.g., 
lichen planus, psoriasis, eczema, ulcerative colitis or known active infection (bacterial, viral or 
fungal). 
3. Ongoing symptomatic Urinary Tract Infection (UTI). Note: symptomatic is defined as recent 
start of pain (e.g., burning or stinging) with urination along with increased urination frequency. 
4. Ongoing or prior diagnosis of any genitoanal malignancy or pre-malignancy (e.g., differentiated 
intraepithelial neoplasia or squamous cell carcinoma). 
5. Any kind of ongoing cancer (or anti-cancer treatment within 3 months or 5 half-lives 
(whichever is longest) prior to the Baseline visit). Note: non-metastasising basal cell carcinoma 
which does not involve the genitoanal area is acceptable. 
6. Any chronic or acute systemic medical condition that, in the opinion of the investigator, may 
pose a risk to the safety of the patient or may interfere with the assessment of efficacy in this 
trial. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 34 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
7. Known history of allergic reaction to any ingredients in MC2-25 cream or MC2-25 vehicle (see 
Section 6.1.1.1). 
Treatments 
8. Start of a new or change of existing non-biologic systemic treatment, including but not limited 
to corticosteroids, cyclosporin, methotrexate and tacrolimus, within 21 days prior to the 
Baseline visit.  
9. Start of a new or change of existing biologic systemic treatment, including but not limited to 
etanercept, adalimumab, alefacept, infliximab, and ustekinumab within 3 months or 5 half-lives 
(whichever is longest) prior to the Baseline visit.  
10. Start of a new or change of existing systemic or intravaginal treatment with estrogen containing 
products, within 21 days prior to the Baseline visit 
11. Start of new or change of menstrual care routines within 21 days prior to the Baseline visit.  
12. Use of emollients (including but not limited to creams, ointments, oils, or soaps with emollient 
properties) on the vulvar region within 3 days prior to the Baseline visit. Note: Only water and, 
if necessary, a soap bar without emollient properties, may be used to wash the vulvar region 
(intimate hygiene) when bathing or showering from within 3 days prior to the Baseline visit. 
13. Use of any topical treatment on the vulvar region, including but not limited to calcineurin 
inhibitors, corticosteroids or anti-infectives within 14 days prior to the Baseline visit.  
14. Use of any light therapy on the vulvar region, including but not limited to UV-B, UV-A, and 
laser, within 28 days prior to the Baseline visit. 
15. Received a non-marketed or blinded drug within 28 days or 5 half-lives (whichever is longer) 
prior to the Baseline visit. 
Compliance/Administrative 
16. If in the opinion of the investigator, the patient is unlikely to comply with the clinical trial 
protocol. Note: Patient must be able to apply the IMP without need for assistance from e.g., 
spouse or caregiver. 
17. If previously randomised in this trial. 
5.3 
Inclusion of vulnerable populations 
A considerable number of elderly (>65 years of age) patients are expected to be enrolled in this 
trial. This is considered acceptable in view of the favourable safety profile of the trial and that no 
specific safety surveillance measures have been implemented for elderly patients specifically, see 
Section 2.3.3 for details. 
5.4 
Lifestyle considerations 
Not applicable 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 35 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
5.5 
Screen failures and re-screening 
Patients who fail screening because they do not meet the minimum WI-NRS criterion at baseline 
cannot be re-screened. Patients who fail screening for other reasons may be re-screened once. 
Reasons for screen failure must be recorded in the eCRF.  
5.6 
Strategies for recruitment and retention 
Patients may be identified from pre-existing databases, recruited in an outpatient setting or hospital 
environment.  Recruitment plans will be site specific with a common goal to create 
awareness/support for the trial among all site-affiliated staff working with this patient population. 
Due to the rarity of the disease, the identification of all potential patients for enrolment is critical. 
Advertising may be introduced to create awareness of the trial, e.g., at the enrolling centre as well 
as at any affiliates, referral clinics, or via patient organisations.  
To prevent patients from dropping out early, frequent visits are planned in the beginning of the trial 
and phone-visits will be conducted throughout the trial, and patients may also receive appointment 
reminders. 
A patient travel stipend sufficient to meet patients’ out-of-pocket travel costs will be available. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 36 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
6 
Trial intervention 
6.1 
Trial interventions administration  
6.1.1 
Trial intervention description 
6.1.1.1 
Investigational medicinal product (IMP) 
MC2-25 cream 
MC2-25 cream is a white oil-in-water, topical emulsion containing the active ingredient, Ala-Gln in 
the aqueous phase at a concentration of 30 mg/g. The formulation components are the following: 
L-alanyl-L-glutamine, triglycerides medium chain, paraffin liquid, glycerol, carbomer interpolymer 
type A, phenoxyethanol, macrogol lauryl ether (4), citric acid, sodium benzoate, polysorbate (20), 
sodium hydroxide, purified water. 
MC2-25 cream is not authorised in any markets. 
MC2-25 vehicle 
MC2-25 vehicle is identical to MC2-25 cream but without the active ingredient. 
6.1.2 
Dosing and administration 
MC2-25 cream, or MC2-25 vehicle must be applied after each toilet visit following urination 
(during day and night) starting on the day of the Baseline visit. The MC2-25 cream, or MC2-25 
vehicle should be applied by the patient in a thin saturating layer to the vulvar region (i.e., vulvar 
region includes clitoris and periclitoral skin, interlabial sulci, labia minora, posterior fourchette and 
perineum, anal and perianal skin). Approximately one fingertip-unit (FTU), roughly corresponding 
to 0.5 g cream is to be used after each toilet visit (during night and day). The vulvar region may be 
gently cleaned with water and dabbed dry with toilet paper or a clean cloth before each application 
of the trial treatment. Assuming, a maximum of 12 toilet visits are needed over a period of 24 hours, 
the maximum daily dose is expected to be around 6.0 g. A treatment application manual will be 
available for patients. 
Reference is made to Section 4.2 for the rationale behind the dosing-regimen. 
6.2 
Preparation/ handling/ storage/ accountability 
6.2.1 
Acquisition and accountability 
The IMP will be supplied by MC2’s designated vendor.    
The investigator is responsible for ensuring that all IMP received at the site is inventoried and 
accounted for throughout the trial. The IMP dispensed to the patient and returned to the site must be 
documented on the drug accountability form and in the eCRF. All IMP will be stored and disposed 
of according to the sponsor’s instructions.  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 37 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
IMP must be handled in strict accordance with the protocol and the label and must be stored at the 
trial site in a limited-access area. Used and unused IMP tubes returned by the patient must be 
available for verification by the trial monitor during on-site monitoring visits.  
IMP should be dispensed under the supervision of the investigator or a qualified member of the site 
staff, or by a hospital/clinic pharmacist. IMP will be supplied only to randomised patients. IMP 
cannot be relabelled or reassigned for use by other patients. The investigator agrees neither to 
dispense the IMP from, nor store it at, any site other than the trial sites agreed upon with the 
sponsor. 
Records of trial product used, and dosages administered will be kept during the trial. The trial 
monitor will note product accountability during site visits and at the completion of the trial. Patients 
will be asked to return all used and unused tubes in the accompanying box at each visit to ensure 
drug accountability. All returned tubes (used and unused) will be weighed to determine the amount 
of IMP used.  
6.2.2 
Formulation, appearance, packaging, and labelling 
Sponsor will provide Solural Pharma with the MC2-25 cream and MC2-25 vehicle. The tubes are 
identical in appearance and packaging.  
MC2-25 cream and MC2-25 vehicle will be labelled in accordance with applicable regulatory requirements 
and Good Manufacturing Practice Guidelines and delivered to the clinics in boxes.  
IMP for one patient consists of the following: One box containing 3 boxes with 8 tubes in each adding up to 
a total of 24 tubes per patient. Labels for the IMP will comply with the legal requirements of the 
country where the trial is performed and will be printed in the local language(s).  
6.2.3 
Product storage and stability 
The IMP must be stored securely at the site under the control of the investigator. The temperature 
will be monitored and documented. The IMP will be supplied to the clinical site(s) as tubes 
containing 60 g of product. The IMP is to be stored according to the label. At all times, the IMP 
tube should be protected from direct sunlight exposure. 
6.2.4 
Preparation and destruction 
No preparation of the IMP is needed.  
Destruction: IMP must only be destructed after sponsor’s approval. Unused IMP (i.e., both 
dispensed/returned as well as not dispensed IMP) should preferably be destructed locally at the site 
(to be documented on the IMP destruction form). If the IMP is not destructed at site but returned for 
destruction, to sponsor’s designated vendor, this must also be documented on the IMP return form. 
6.3 
Measures to minimise bias: randomisation and blinding 
 Randomization will be performed in a 1:1 ratio. Randomisation data will be kept strictly 
confidential, accessible only to authorised personnel, until the time of un-blinding. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 38 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
A patient who fulfils the trial eligibility requirements will be randomly assigned to treatment with 
IMP. 
An external statistician who is independent from the study team will prepare the randomization list 
using appropriate software tool ensuring equal allocation of patients into the two treatment arms. 
The external statistician will also prepare the emergency unblinding envelopes. The randomization 
list will be shared with Solural Pharma (who are responsible for labelling) and with PharmaLex 
(who are responsible for handling of SAEs) and will be kept strictly confidential, filed securely, and 
will be accessible only to authorized persons from Solural Pharma and PharmaLex until unblinding.  
This is a double-blind trial. The sponsor, sponsor representatives, and all patients, monitors, and site 
staff will be blinded throughout the trial. Instructions for emergency unblinding are provided in 
Section 10.2.1. The staff at the study treatment manufacturing site and the external statistician 
responsible for preparing the randomization list are not blinded. 
Each patient will be assigned a unique randomization number in ascending order determining which 
study treatment the patient will receive. These randomization numbers will be based on a supply list 
accompanying the IMP provided to the sites and the same randomization number (named as kit no.  
will also be listed to the applicable trial medication. At each dispense, this kit no. will be 
documented in the eCRF linking the trial medication to correct patient. No patient ID, other than the 
kit no. will be written on the trial medication. 
6.4 
Treatment compliance 
At all on-treatment visits, the patient will be asked if he/she has used the trial medication as 
prescribed. Any degree and nature of noncompliance will be specified. In addition, patients will be 
asked to complete an Application Diary during the treatment period as a measure of treatment 
compliance. Patients who are consistently noncompliant will be counselled. 
6.5 
Prohibited therapies 
6.5.1 
Prohibited therapies prior to baseline 
Several therapies are prohibited during the period leading up to baseline as outlined in Table 3. 
Therapies not listed in the table are allowed. 
Table 3: 
Prohibited therapies prior to baseline 
Prohibited Therapy 
Exclusion 
Criterion 
Applicable Wash-Out 
Period Prior to Baseline 
(Day 0) 
Use of anti-cancer treatment  
5 
3 months or 5 half-lives 
(whichever is longest)  
Start of a new or change of existing non-biologic systemic treatment, 
including but not limited to corticosteroids, cyclosporin and tacrolimus. 
8 
21 days 
Start of a new or change of existing biologic systemic treatment, 
including but not limited to etanercept, adalimumab, alefacept, 
infliximab, and ustekinumab 
9 
3 months or 5 half-lives 
(whichever is longest) 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 39 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Start of a new or change of existing systemic or intravaginal treatment 
with estrogen containing products 
10 
21 days 
Start of new or change of menstrual care routines  
11 
21 days 
Use of emollients (including but not limited to creams, ointments, oils, 
or soaps with emollient properties) on the vulvar region Note: Only 
water and, if necessary, a soap bar without emollient properties, may be 
used to wash the vulvar region (intimate hygiene) when bathing or 
showering.  
12 
3 days 
Use of any topical treatment on the vulvar region, including but not 
limited to calcineurin inhibitors, corticosteroids or anti-infectives. 
13 
14 days 
Use of any light therapy on the vulvar region, including but not limited 
to UV-B, UV-A and laser. 
14 
28 days 
Received a non-marketed or blinded drug. 
15 
28 days or 5 half-lives, 
whichever is longer 
6.5.2 
Prohibited therapies after Baseline 
Use of any therapies that would exclude the participant from participation in the trial (as specified 
in Section 5.2 Exclusion Criteria) is also prohibited during the treatment and follow-up periods, see 
Table 3. Therapies not listed in Table 3 are allowed. 
6.5.3 
Rescue therapies 
If prohibited therapies are used as rescue therapies during the screening period, the patient is not 
eligible for the trial. If prohibited therapies are used as rescue therapies during the treatment period, 
they must be recorded as concomitant therapies and reported as protocol deviations.  
 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 40 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
7 
Trial intervention discontinuation and participant discontinuation / 
withdrawal  
7.1 
Participant discontinuation / discontinuation of trial intervention 
In accordance with legal requirements and International Council for Harmonisation (ICH) – Good 
Clinical Practice (GCP) guidelines, every patient has the right to refuse further participation in this 
trial (withdrawal from trial) or refuse further treatment (discontinuation of treatment) at any time 
and without providing reasons. A patient’s refusal should be effectuated immediately upon her 
request.  
A patient will be withdrawn from the trial for any of the following reasons:  
• Lost to follow-up  
• Withdrawal of consent  
• Death  
• Trial terminated by sponsor  
In addition, a patient may be withdrawn from the trial or be discontinued from treatment at any time 
at the discretion of the investigator.  
Reasons for withdrawal from trial or discontinuation of treatment include (but are not necessarily 
limited to) lack of treatment effect, unacceptable AE(s), pregnancy, and protocol violations. 
In the case of trial withdrawal or treatment discontinuation, all assessments of the Week 12 (End of 
Treatment [EoT]) visit must be performed to the extent possible. The reasons for trial withdrawal or 
treatment discontinuation must be fully documented in the eCRF and the end of treatment form 
must be completed when treatment is permanently discontinued, and the end of trial form must be 
completed at end of the trial or in case of trial withdrawal. 
Patients who withdraw from the trial before randomisation will be considered screen failures. After 
randomisation, in case of treatment discontinuation, the patient should be encouraged to attend 
remaining trial visits in line with the schedule of assessments (SoA). If a patient is withdrawn from 
the trial due to an AE or treatment is discontinued due to an AE, the AE must be followed up as 
outlined in Section 8.8.4.1.  
7.2 
Lost to follow-up 
If a patient is lost to follow-up, every reasonable effort must be made by the site staff to contact the 
patient and determine the reason for discontinuation/withdrawal. The measures taken to follow-up 
must be documented. 
7.3 
End-of-treatment visit  
Unless a patient withdraws consent for trial participation, or is lost to follow-up, an End-of-
Treatment Visit should be performed as soon as possible (no later than 30 days) after the treatment 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 41 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
has been discontinued. Every effort should be made to conduct the End-of-Treatment Visit before 
the patient starts subsequent therapy. If a patient is unable to return to the site for the End-of-
Treatment Visit, then the patient should be contacted (e.g., by phone) to collect information on AEs 
and concomitant therapies and other EOT visit assessments (in particular PROs) to the extent 
possible that occurred within 30 days after the last treatment. Additional information on reporting of 
AEs can be found in Section 8.8.4.1. 
Patients who permanently discontinue treatment at some point after the administration of the first 
dose of trial medication will not be replaced. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 42 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
8 
Trial assessments and procedures 
8.1 
Visit schedule 
The schedule of assessments (SoA) is provided in Table 1. 
The following order of assessments must always be adhered to:  
• At Visit 1, the informed consent process must be completed before Patient Reported Outcomes 
or any other clinical assessment or procedure.  
• At all visits, Patient Reported Outcomes should be assessed before all other clinical assessments 
or procedures. 
8.2 
Screening 
Up-front waivers for inclusion or exclusion criteria are not allowed. Any deviation from inclusion 
or exclusion criteria identified post-randomisation, will be reported as a protocol deviation, patients 
shall continue in the trial as planned unless discontinuation of IMP treatment is warranted for safety 
reasons. 
8.3 
Demographics and medical history 
The following demographic and medical history must be collected:  
• Age  
• Height  (can be self-reported) 
• Weight (can be self-reported) 
• Race 
• Ethnic origin 
• Complete VLS history (year of first VLS symptoms, year of VLS diagnosis, diagnosis made by 
gynaecologist, dermatologist or other [specify], diagnosis confirmed by biopsy, any family 
members with VLS, currently seeing a VLS treating physician regularly, current VLS treating 
physician is gynaecologist, dermatologist or other [specify]) 
• All other current and past medical/surgical conditions within the previous 12 months. 
8.4 
Prior and concomitant therapies 
All medications and treatments (i.e., prescription drugs [including COVID-19 vaccination 
programs, see Table 3], over the counter [OTC] drugs and vitamins, herbal and dietary supplements, 
and lubricants used with sex), hereafter referred to as therapies, taken within 30 days prior to 
screening will be recorded as prior therapies at the Screening 1 visit.  
All therapies used after the screening 1 visit will be recorded as concomitant therapies.  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 43 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Information about the total daily dose, route of administration, start and discontinuation dates, and 
indication are to be recorded in the eCRF. 
8.5 
Efficacy assessments 
8.5.1 
 Clinician reported outcomes (ClinRO) assessments 
8.5.1.1 
Imaging of VLS  
Imaging of the vulvar region (i.e., clitoris and periclitoral skin, interlabial sulci, labia minora, 
posterior fourchette and perineum, anal and perianal skin), must be obtained by the investigator 
(preferably the same investigator at all visits for a specific patient) at Screening 1, Baseline, Week 
1, Week 4, Week 8 and Week 12 (or Early Termination) for all patients. Imaging of VLS should 
preferably be performed BEFORE the scoring of the VASSI. 
Detailed description of the imaging procedure will be provided in a separate imaging manual. Steps 
will be taken to ensure that the images are pseudonymised.  
8.5.1.2 
Vulvar lichen sclerosus Area and Sign Severity Index (VASSI) 
The Vulvar lichen sclerosus Area and Sign Severity Index (VASSI) evaluates the severity of 3 non-
permanent signs of VLS in 5 different vulvar areas. It must be performed by the investigator 
(preferably the same investigator at all visits for a specific patient) at Screening 1, Baseline, Week 
1, Week 4, Week 8 and Week 12 (or Early Termination) for all patients. It should preferably be 
performed AFTER Imaging of VLS and BEFORE scoring of the CGA. 
Areas: The 5 different vulvar areas are Clitoris and periclitoral skin (C), Right interlabial sulcus and 
labium minus (R), Left interlabial sulcus and labium minus (L), Posterior fourchette and perineum 
(P), Anus and perianal skin (A)), see Figure 2. 
Signs: The 3 non-permanent signs of VLS are Fissures/erosions (longitudinal/patchy ruptures of 
the skin surface), Ecchymoses (bleedings within the skin) and Hyperkeratoses (patches/plaques of 
bright white skin with a ‘powdery’ texture). IMPORTANT: Hyperkeratoses must be distinguished 
from Sclerosis (areas of yellowish/ivory white skin with a smooth/waxy/firm texture) and Pallor 
(areas of pale whitish skin that differ from hyperkeratosis in that they are not “powdery”). Sclerosis 
and pallor are permanent signs of VLS.  
Severity: The severity must be scored on a 4-point scale from 0-3 ( i.e., 0 (no lesion), 1 (length of 
lesion ≤5 mm), 2 (length of lesion > 5mm and ≤ 10 mm) or 3 (length of lesion > 10 mm)) for each 
non-permanent sign in each vulvar area (i.e., the light grey cells in Table 4). Note: The measure 
included in the photocard used for imaging of VLS must be used as reference when assigning 
severity scores. In case a non-permanent sign extends from one vulvar area into another, then it 
must be scored in both areas according to the length of the lesion in the particular area. In contrast, 
if a non-permanent sign involves the border between two areas, it should only be scored for the area 
that is most involved/affected to avoid scoring the same lesion twice.  
A scoring manual will be available. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 44 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
For endpoint analyses, the VASSI Area scores, VASSI Sign scores and Total VASSI score (i.e., the 
white cells in Table 4) will be calculated as follows: 
1. A VASSI Area score (VASSIC, -R, -L, -P, -A) is calculated by summing up the 3 severity scores 
for Fissures/erosions, Ecchymoses and Hyperkeratoses in the particular vulvar area [range 0-
9].  
2. A VASSI Sign score (VASSIF, -E, -H) is calculated by summing up the severity scores for a 
particular sign across all 5 vulvar areas [range 0-15] 
3. The Total VASSI (VASSI) score is calculated by summing the 5 VASSI Area scores or 
VASSI Sign scores [range 0-45] 
 
Table 4: 
Vulvar lichen sclerosus Area and Sign Severity Index (VASSI) 
         Vulvar  
            areas 
 
Signs  
Clitoris and 
periclitoral 
skin 
(C) 
Right 
interlabial 
sulcus and 
labium minus 
(R) 
Left 
interlabial 
sulcus and 
labium minus 
(L) 
Posterior 
fourchette and 
perineum 
(P) 
Anus and 
perianal skin 
(A) 
VASSI Sign 
scores 
Fissures /  
erosions (F) 
 
 
 
 
 
VASSI F = 
Ecchymoses (E) 
 
 
 
 
 
VASSI E = 
Hyperkeratoses 
(H)* 
 
 
 
 
 
VASSI H = 
VASSI Area 
scores  
VASSI C = 
VASSI R = 
VASSI L = 
VASSI P = 
VASSI A = 
Total VASSI 
score = 
Light grey cells must be filled in by the investigator with severity scores. The severity must be scored on a 4-point scale (i.e., 0 (no 
lesion), 1 (length of lesion ≤5 mm), 2 (length of lesion > 5mm and ≤ 10 mm) or 3 (length of lesion > 10 mm) for each non-permanent 
sign in each vulvar area; White cells will be calculated. 
*IMPORTANT: Hyperkeratoses (patches/plaques of bright white skin with a ‘powdery’ texture) is a non-permanent sign of VLS and 
must be distinguished from Sclerosis (areas of yellowish/ivory white skin with a smooth/waxy/firm texture) and Pallor (areas of pale 
whitish skin that differ from hyperkeratosis in that they are not “powdery”). Sclerosis and pallor are permanent signs of VLS. 
 
Figure 2: 
Vulvar areas 
 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 45 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
 
 
8.5.1.3 
Clinician’s Global Assessment (CGA) of VLS 
The Clinician’s Global Assessment (CGA) of VLS evaluates the global (overall) severity of VLS in 
the entire vulvar region (i.e., including the clitoris, periclitoral skin, interlabial sulci, labia minora, 
posterior fourchette and perineum, anal and perianal areas). It should preferably be performed 
AFTER the scoring of the VASSI and BEFORE scoring of the CGIC. 
The CGA must be evaluated by the investigator (preferably the same investigator at all visits for a 
specific patient) on a 5-point scale ranging from Clear to Severe at Screening 1, Baseline, Week 1, 
Week 4, Week 8, and Week 12 or Early Termination using Table 5 below : 
 
Table 5: 
Clinician’s Global Assessment (CGA) of VLS 
CGA score 
Description 
    
   
   
C
L
A
P
R

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 46 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Clear 
No visible Non-permanent signs* of VLS (Fissures/Erosions, Ecchymoses or 
Hyperkeratoses) in the vulvar region. 
Note: Permanent signs# of VLS may be present 
Almost clear 
Barely visible Non-permanent signs* of VLS (Fissures/Erosions, Ecchymoses 
or Hyperkeratoses) in the vulvar region. 
 
Mild 
 Slightly visible Non-permanent signs* of VLS (Fissures/Erosions, Ecchymoses 
or Hyperkeratoses) in the vulvar region. 
 
Moderate 
Easily visible Non-permanent signs* of VLS (Fissures/Erosions, Ecchymoses 
or Hyperkeratoses) in the vulvar region. 
 
Severe 
Markedly visible Non-permanent signs* of VLS (Fissures/Erosions, 
Ecchymoses or Hyperkeratoses) in the vulvar region. 
 
*Non-permanent signs of VLS include fissures/erosions (longitudinal/ respectively patchy ruptures of the skin surface), 
ecchymoses (bleedings inside the skin) and hyperkeratoses (patches/plaques of bright white skin with a ‘powdery’ 
texture). Hyperkeratoses must be distinguished from Sclerosis (areas of yellowish/ivory white skin with a 
smooth/waxy/firm texture) and pallor (areas of pale whitish skin that differ from hyperkeratosis in that they are not 
“powdery”) 
# Permanent signs of VLS include e.g., atrophy, sclerosis, pallor, scarring or fusion. 
A scoring manual will be available.  
8.5.1.4 
Clinician’s Global Impression of Change (CGIC) of VLS 
Clinician’s Global Impression of Change (CGIC) in non-permanent signs of VLS including 
fissures/erosions (longitudinal/respectively patchy ruptures of the skin surface), ecchymoses 
(bleedings inside the skin) and hyperkeratoses (patches/plaques of bright white skin with a 
‘powdery’ texture) must be assessed by the investigator (preferably the same investigator at all 
visits for a specific patient) at Week 1, Week 4, Week 8, and Week 12 or Early Termination visits 
using the below 7-item verbal rating scale. It should preferably be performed AFTER the scoring of 
the CGA: 
Please choose the response below that best describes the overall change in the patient's non-
permanent signs of vulvar lichen sclerosus since the trial medication was started at baseline, based 
on the baseline image of VLS (see Section 8.5.1.1 ‘Imaging of VLS’): 
• Very much better 
• Much better 
• A little better 
• No change 
• A little worse 
• Much worse 
• Very much worse 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 47 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
8.5.2 
Patient reported outcomes (PRO) assessments 
8.5.2.1 
Worst Itch Numeric Rating Score (WI-NRS) of VLS 
The patient’s WI-NRS score must be recorded by the patient in a diary once daily (i.e., every day 
around the same timepoint, e.g. morning, afternoon or evening ) for a total of 7 days (i.e. starting 7 
days before the next in-clinic visit and ending on the day before the next in-clinic visit) leading up 
to each in-clinic visit day at Baseline, Week 1, Week 4, Week 8, and Week 12 (or Early 
Termination) using an 11-point numeric rating scale ranging from 0 to 10: 
Please score the intensity of the Worst Itch associated with your lichen sclerosus, that you have 
experienced in the past 24 hours: 0 (no itch), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (worst imaginable itch). 
In addition, the patient’s WI-NRS score must be reported to the clinical staff at in-clinic visits at 
Screening 1, Baseline, Week 1, Week 4, Week 8, and Week 12 or Early Termination using the 
11-point numeric rating scale above. 
8.5.2.2 
Worst Pain Numeric Rating Score (WP-NRS) of VLS 
The patient’s WP-NRS score must be recorded by the patient in a diary once daily (i.e., every day 
around the same timepoint, e.g. morning, afternoon or evening) for a total of 7 days (i.e. starting 7 
days before the next in-clinic visit and ending on the day before the next in-clinic visit) leading up 
to each in-clinic visit day at Baseline, Week 1, Week 4, Week 8, and Week 12 (or Early 
Termination) using an 11-point numeric rating scale ranging from 0 to 10: 
Please score the intensity of the Worst Pain* associated with your lichen sclerosus, that you have 
experienced in the past 24 hours: 0 (no pain), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (worst imaginable pain). 
*Pain includes sensations such as Burning, Stinging, Soreness and Irritation. 
In addition, the patient’s WP-NRS score must be reported to the clinical staff at in-clinic visits at 
Screening 1, Baseline, Week 1, Week 4, Week 8, and Week 12 or Early Termination using the 
11-point numeric rating scale above. 
8.5.2.3 
Worst Penetrative sex related Pain Numeric Rating Score (WPP-NRS) of VLS 
At Screening 1, Baseline, Week 4, Week 8, and Week 12 or Early Termination visit all patients 
must indicate whether they are sexually active or not by answering Question 1 below. Patients who 
answer No to Question 1, must subsequently answer only Question 2. Patients who answer Yes to 
Question 1 must subsequently answer Questions 2, 3, and 4, and finally in Question 5 report their 
Worst Penetrative sex related Pain on an 11-point numeric rating scale ranging from 0 to 10 as also 
described below: 
1. Have you had penetrative sex during the past 4 weeks? (Yes/No) 
If No, please answer Question 2 only. If Yes, please answer Questions 2, 3, 4 and 5. 
2. Have you abstained from penetrative sex during the past 4 weeks due to your vulvar lichen 
sclerosus? (Yes/No) 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 48 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
3. How many times have you had penetrative sex during the past 4 weeks? (X times)    
4. Have you used lubricants during penetrative sex during the past 4 weeks? (Yes/No)   
5. Please score the intensity of the Worst Penetrative sex related Pain* you have experienced due 
to your lichen sclerosus in the past 4 weeks: 0 (no penetrative sex related pain), 1, 2, 3, 4, 5, 6, 
7, 8, 9, 10 (worst imaginable penetrative sex related pain). 
*Pain includes sensations such as Burning, Stinging, Soreness and Irritation.  
8.5.2.4 
Patient’s Global Impression of Change (PGIC) of VLS 
PGIC in Worst Itch (WI), Worst Pain (WP) and Worst Penetrative sex related Pain (WPP) must be 
reported to the clinical staff at Week 4, Week 8, and Week 12 or Early Termination visits using a 
7-item verbal rating scale: 
Please choose the response below that best describes the overall change in your [Worst Itch*] 
associated with your lichen sclerosus since you started applying the trial medication: 
• Very much better 
• Much better 
• A little better 
• No change 
• A little worse 
• Much worse 
• Very much worse 
*Repeat with Worst Pain and Worst Penetrative sex related Pain. 
8.5.2.5 
Patient’s rating of importance of improvements of VLS 
Patients reporting an improvement in PGIC (i.e., ‘Very much better’, ‘Much better’ or ‘A little 
better’) must report the Importance of the improvement to the clinical staff at Week 4, Week 8, and 
Week 12 or Early Termination visits using a 2-item Importance Questionnaire: 
Question 1: You have reported an improvement in your [Worst Itch*] associated with your lichen 
sclerosus since you started applying the trial medication. Was the improvement important to you? 
(Yes/No).  If yes, please proceed to question 2. 
Question 2: In which way(s) was the improvement in your [Worst Itch*] associated with your 
lichen sclerosus important to you? (Free text). 
*Repeat with Worst Pain and Worst Penetrative sex related Pain. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 49 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
8.5.2.6 
International Consultation on Incontinence Questionnaire Urinary Incontinence 
Short Form (ICIQ-UI-SF)  
Incontinence status must be evaluated by the patient at Baseline and Week 12 or Early termination 
visits using the ICIQ-UI-SF questionnaire. 
The ICIQ-UI-SF is a validated questionnaire with a recall period of 4 weeks comprising a total of 
4 questions about when, how often and how much urine is leaked and how much urine leaking 
interferes with everyday life. The ICIQ-UI-SF score ranges from a maximum score of 21 indicating 
maximum burden) and a minimum score of 0 (indicating no burden). A score ≥ 1 indicates urinary 
incontinence (Avery et al., 2004). 
8.5.2.7 
Menopausal status and Menstrual cycle status 
Menopausal status (Pre-menopausal or Menopausal) in accordance with inclusion criterion 9, 
Section 5.2 must be recorded for all women at Baseline and Week 12 (or Early Termination) visits.  
Menstrual cycle status (i.e., whether the patient is menstruating or not, reason in case of no 
menstruation, number of days since the first day of the latest menstruation period, average duration 
of menstruation period in days, regularity of menstrual cycle) must be evaluated by all pre-
menopausal women at Baseline, and Week 12 (or Early Termination) visits. 
8.5.2.8 
Skindex-29 
Skindex-29 is a skin specific multidimensional quality-of-life instrument. It must be evaluated by 
the patient at Baseline, Week 4, Week 8, and Week 12 or Early Termination visits using the 
Skindex-29 Quality of Life Index questionnaire. It inquires how often (1. Never, 2. Rarely, 3. 
Sometimes, 4. Often, 5. All the time) during the previous 4 weeks the patient experienced the effect 
described in each item. Seven items address the Symptoms domain, ten items the Emotional 
domain, and twelve items the Functioning domain. All responses are transformed to a linear scale of 
100, varying from 0 (no effect) to 100 (effect experienced all the time). Skindex-29 scores are 
reported as three scale scores, corresponding to the three domains; a scale score is the average of a 
patient’s responses to items in a given domain (Chren et al., 1997). 
8.5.2.9 
VQLI 
The Vulvar Quality of Life Index (VQLI) questionnaire is a vulvar specific quality-of-life 
instrument which was validated in cohorts of women including 40-50% Lichen Sclerosus patients. 
It must be evaluated by the patient at Baseline, Week 4, Week 8, and Week 12 or Early Termination 
visits using the Vulvar Quality of Life Index (VQLI) questionnaire. In the context of this trial, the 
vulvar region includes clitoris and periclitoral skin, interlabial sulci, labia minora, posterior 
fourchette and perineum, anal and perianal skin.  
The questionnaire comprises a total of 15 questions with a recall period of 1 month under the 
following domains: Symptoms (Questions 1–2); Feelings and Emotions (Questions 3–5); Activities 
of daily living (Questions 6–10); Relationships (Question 11); Sexual function (Questions 12–13); 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 50 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Future health concerns (Question 14); and Treatment (Question 15). Each of the questions are 
graded zero to three on a Likert scale, with 0 representing no symptom or complaint (‘Not at all’ or 
‘Not applicable’), 1 (‘A little’), 2 (‘A lot’) and 3 (‘Very much’), resulting in a maximum score of 
45/45 and a minimum score of 0/45 (Saunderson et al., 2020). 
8.5.2.10 
VLS patient journey sheet 
The Burden of living with VLS before entering the trial must be described by the patient by filling 
in the ‘VLS patient journey sheet’ at the Screening 1 visit. The patient journey sheet is a 
questionnaire which collects information about: 
• which issues the VLS patient has experienced in relation to VLS 
•  which issues experienced in relation to VLS the patient has found most burdensome. 
8.6 
Safety and other assessments 
8.6.1 
Physical examination 
A complete (i.e., including all organ systems as well as the vulvar region) physical examination is 
required at Screening 1 and Week 12 (EoT or Early Termination) visits.  
An abbreviated physical examination (including the vulvar region as minimum; other organ systems 
may be included depending on present signs, symptoms, or investigation outcomes) is required at 
the Baseline visit (and if judged necessary by the investigator) at the FU visit.  
Any abnormalities must be assessed as “clinically significant” or “not clinically significant” by the 
investigator. Abnormalities classified as “clinically significant” must be recorded in the eCRF as 
AEs. 
8.6.2 
Vital signs 
Vital signs (Systolic Blood Pressure, Diastolic Blood Pressure, Heart rate and Temperature) will be 
recorded by trained clinical staff at Baseline and Week 12 (or Early termination) visits. Vital signs 
are also recorded at Week 14 (Follow-up) if judged necessary by the investigator. 
Any abnormalities must be assessed as “clinically significant” or “not clinically significant” by the 
investigator. Abnormalities classified as “clinically significant” must be recorded in the eCRF as 
Aes. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 51 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
8.6.3 
Urine pregnancy test 
A highly sensitive urine pregnancy test (i.e., with a sensitivity down to at least 25 mIU/ml for 
human chorionic gonadotrophin (hCG) will be collected from women of childbearing potential (see 
inclusion criterion 9, Section 5.1) by trained clinical staff at all in-clinic visits and must be recorded 
in the eCRF. Urine pregnancy test samples will be destroyed after the results of the test have been 
recorded. 
If there is suspicion of pregnancy at any time during the trial, an additional urine sample will be 
obtained and analysed. Should a participant become pregnant during the trial, treatment must be 
discontinued, and the patient must be withdrawn from the trial.  
All pregnancies (occurring before or after start of IMP administration) should be immediately 
reported to MC2 or designee and followed through to resolution (i.e., delivery, miscarriage, or 
elective abortion). The report should be submitted within the same timelines as an SAE (within 24 
hours of knowledge), although a pregnancy per se is not considered an SAE.  
8.7 
Laboratory assessments 
8.7.1 
Analysis of laboratory samples 
There will be no scheduled sampling for clinical laboratory analyses in this trial.  
If there is a suspicion of a medical condition (considered related or not to the IMP), relevant 
laboratory samples may be taken and analysed at the discretion of the investigator. No samples will 
be stored for future analysis. 
8.8 
Adverse events and serious adverse events 
8.8.1 
Definition of adverse events (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered an investigational or non-investigational medicinal product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign, symptom, or disease temporally associated with the use of a 
medicinal product, whether considered related to the medicinal product or not. Such unfavourable 
signs, symptoms or diseases may be discovered via any trial assessment (e.g., laboratory findings, 
PRO questionnaires, physical examination). 
8.8.2 
Definition of serious adverse events (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 52 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Other serious or important medical event 
Any important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered an SAE when, based on appropriate medical judgment, they may 
jeopardise the participant or the participant may require medical or surgical intervention to prevent 
one of the outcomes listed in the above definitions.  
The death of a participant enrolled in a trial is per se not an event, but an outcome. Any event 
resulting in a fatal outcome must be fully documented and reported, regardless of the causality 
relationship to the IMP. 
Any pre-planned hospitalisations or procedures that are known at the time of signing the informed 
consent form will not be recorded as SAEs but will be recorded as AEs only. 
All SAEs will be assessed for expectedness by the sponsor or designee. An SAE is considered 
“unexpected” if its nature or severity is not included in the IB, Section 6.2.12. 
8.8.3 
Classification of an adverse event 
8.8.3.1 
Severity of adverse events 
The investigator is to classify the severity (intensity) of an AE according to the following 
definitions: 
• Mild – The patient was aware of the signs and symptoms, but the signs and symptoms were 
easily tolerated and does not interfere with daily activity. 
• Moderate – The signs and symptoms were sufficient to restrict, but did not prevent, usual daily 
activity for the patient. The patient is still able to function. 
• Severe – The patient was unable to perform usual daily activities. 
The maximum severity recorded during the course of an AE (mild, moderate, or severe) will be 
considered the final severity. 
8.8.3.2 
Relationship of adverse events to trial treatment 
The investigator is responsible for assessing the relationship of an AE to the IMP treatment using 
good clinical judgment and the following definitions: 
• Not related – The AE is clearly explained by another cause not related to the IMP 
administration; the temporal relationship of the AE to IMP administration makes a causal 
relationship clearly improbable or concomitant medication, therapeutic interventions, or 
underlying condition provide a sufficient explanation for the observed AE. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 53 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
• Unlikely related – The AE is most likely related to aetiology other than the IMP administration; 
the temporal relationship of the AE to IMP administration makes a causal relationship unlikely, 
and other concomitant medication, therapeutic interventions or underlying disease provide 
plausible explanations for the observed AE. 
• Possibly related – The AE and administration of IMP are temporally related, but the AE can be 
explained equally well by causes other than the IMP administration. A causal relationship is 
conceivable and cannot be dismissed. 
• Probably related – The AE and use of IMP are temporally related, and the AE is more likely 
explained by IMP administration than by other causes. Good reason and sufficient 
documentation to assume a causal relationship. 
The last relationship recorded during the course of an AE will be considered the final relationship as 
the investigator is assumed to have had the most information to perform the relationship assessment 
at that time. 
8.8.3.3 
Outcome of adverse events 
The outcome of an AE will be classified as:  
• Recovered/resolved 
• Recovered/resolved with sequelae (note: in case of sequelae, the sequelae must be reported as a 
comment in the eCRF) 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal 
• Unknown 
8.8.4 
Time period and frequency for event assessment and follow-up 
8.8.4.1 
Adverse event reporting 
The investigator or designee (as per site delegation log) is responsible for obtaining, assessing, and 
documenting all AEs during the trial.   
Adverse event information will be collected from individual trial patients from signature of the 
informed consent form until the last trial visit.  
All AEs will be documented in the eCRF, including a description of each AE, AE relationship to 
IMP, start and stop dates, seriousness, severity, action taken (with the IMP and other actions taken) 
and outcome.   
If the event is reported as an SAE, the timelines for SAE reporting apply (see Section 8.8.4.2). If the 
event is reported as non-serious AE, it should be reported on the appropriate eCRF page.  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 54 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Throughout the trial, the occurrence of AEs should be monitored by nondirective questioning of the 
patient at each visit. Information on AEs can also be obtained from signs and symptoms detected 
during examinations, observations made by the site staff, or spontaneous reports from patients. Pre-
existing conditions that worsen during the trial should also be recorded as AEs. This will also 
include worsening of the disease as judged by the investigator.  
AEs requiring therapy must be treated in accordance with recognised standards of medical care to 
protect the health and well-being of the patient. Treatment due to an AE will be recorded in the 
patient’s records and on the appropriate eCRF. 
All SAEs and related non-serious AEs must be followed by the investigator until they are resolved 
or until judged by the investigator to be stable/needing no further follow-up. Unrelated non-serious 
AEs must be followed by the investigator until the patient’s last trial visit. All relevant follow-up 
information will be reported in the eCRF (and to PharmaLex if it qualifies as an SAE, see Section 
8.8.9.1). 
8.8.4.2 
Serious adverse event reporting 
Any SAE, whether by the investigator considered IMP-related or expected or not, must be reported 
immediately to PharmaLex as soon as it becomes known to the investigator and not later than 
within 24 hours of his/her knowledge of the occurrence of an SAE (see Section 8.8.9.1). For each 
SAE, the investigator will complete a Serious Adverse Event Report Form and assess the 
relationship of each SAE to trial treatment.  
Follow-up report forms regarding the status of the SAE and the participant’s subsequent course 
should be submitted to PharmaLex immediately and not later than 24 hours of follow up 
information awareness and until the SAE has resolved, is stabilised or needing no further follow-up 
(in the case of persistent impairment) or the patient dies. 
The forms and acknowledgment of receipt will be retained by both the site and PharmaLex. For 
contact details for reporting SAEs, pregnancies and other safety concerns, refer to Section 8.8.9.1. 
The investigator will document such events in the best possible detail on the SAE Report Form.  
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that is both unexpected (not 
listed in the Reference Safety Information (RSI) Section 6.2.12 of the IB, and for which there is 
evidence to suggest a causal relationship between the IMP and the SAE. The National Competent 
Authorities (NCA), Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be 
informed of SUSARs and other safety issues according to local requirements, via Eudravigilance. 
All investigators participating in the trial will also be notified of SUSARs and other safety issues as 
applicable.  
Investigator instructions for reporting SAEs and contact information are provided in Section 8.8.9.1. 
SAEs occurring after a patient has completed the trial and deemed IMP-related by the investigator 
should be reported to the sponsor within 24 hours from the investigator’s awareness. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 55 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
8.8.5 
Reporting events to participants 
Not applicable 
8.8.6 
Events of special interest 
Not Applicable 
8.8.7 
Reporting of pregnancy 
Any pregnancy occurring from the date of the informed consent signature until trial completion 
must be recorded in the eCRF and reported to PharmaLex as soon as possible, but no later than 24 
hours from the investigator’s awareness of the pregnancy (see Section 8.8.9.1).  
The investigator must actively follow-up, document, and report to PharmaLex the progress of the 
pregnancy until outcome is reached.   
8.8.8 
Trial medication overdose and trial medication errors 
An overdose of the IMP is a dose that is higher than the highest dose under clinical investigation.  
In the event of a clinically significant overdose, as judged by the investigator, the event should be 
reported as an AE and supportive treatment or discontinuation of the IMP may be instigated as 
judged by the investigator. In view of the high systemic safety margin (see Section 4.2), the 
administered dose may be several folds higher than the highest dose under clinical investigation 
without necessarily qualifying as a clinically significant overdose. 
A trial medication error is when the trial medication is used outside the dosing regimen specified in 
the protocol. In the event of a clinically significant trial medication error, as judged by the 
investigator, the event should be reported as an AE and supportive treatment or discontinuation of 
the IMP may be instigated as judged by the investigator. 
8.8.9 
Reporting of serious adverse events and pregnancies 
8.8.9.1 
Contact person(s) and number(s) 
SAEs and pregnancies must be reported immediately (i.e., not later than 24 hours after first 
knowledge). The SAE or pregnancy report should be e-mailed or faxed to PharmaLex using the 
following e-mail or fax-number:  
Email: PV-nordic@pharmalex.com    
Fax number: +45 74 44 19 37 
  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 56 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
9 
Statistical considerations 
9.1 
Statistical hypotheses 
On the primary and all secondary endpoints, treatment groups will be compared for superiority of 
MC2-25 cream over MC2-25 vehicle. The null hypothesis is of no difference between the two 
treatment groups. For further details see Section 9.4.1. 
9.2 
Sample size determination 
Sixty two (62) patients will be screened. 33 patients will be randomised in a 1:1 ratio of MC2-25 
cream to MC2-25 vehicle. For a two-sided test with a 5% level of significance and an effect size of 
1 standard deviation, this sample size will provide adequate power (≥78%) to compare mean change 
in mean weekly WI-NRS from Baseline to Week 12 between MC2-25 cream and MC2-25 vehicle 
with 16 to 17 patients per treatment group. 
9.3 
Populations for analyses 
The analysis populations are defined as follows: 
Screened set (SS): all patients who sign the informed consent form. 
Safety analysis set (SAS): all patients who are randomised and dispensed the trial medication at 
Randomisation/Day 0, excluding patients to whom trial medication is not dispensed or who return 
all the trial medication unused. Patients will be analysed according to the actual treatment. 
Full analysis set (FAS): all patients who are randomised. Patients will be analysed according to the 
randomised treatment.  
Modified full analysis set (MFAS): all patients who are randomised and returned for at least one 
post-baseline scheduled visit with data on weekly mean WI-NRS. Patients will be analysed 
according to the randomised treatment. 
Per-protocol set (PPS): a subset of the MFAS patients who completed the trial with WI-NRS data 
for Week 12 and are deemed to have no important protocol deviations that could interfere with the 
objectives of this trial. Important deviations of eligibility criteria and other deviations from the 
protocol will be assessed. Important deviations from the protocol may lead to exclusion of a patient 
or data points from the PPS, which could have interfered with the administration of the treatment or 
the evaluation of treatment effect. All such decisions will be identified and documented before the 
final trial database is unblinded. Important protocol deviations may include, but are not limited to, 
medication non-compliance, missing consecutive application days, and intake of prohibited 
concomitant therapies, which may have an impact on the primary endpoint. 
The SAS will be used for all safety analyses. FAS, MFAS, and PPS will be used for efficacy 
analyses. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 57 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
9.4 
Statistical analyses 
9.4.1 
General approach 
The methodology presented below represents a brief overview of the statistical methods that will be 
fully detailed in the statistical analysis plan (SAP). The SAP will be finalised before the database is 
locked. Any changes to the methods described in the final SAP will be described and justified in the 
clinical trial report. All statistical analyses will be performed using SAS statistical software 
(Version 9.4 or higher).  
Statistical significance will be tested at the two-sided 5% significance level unless otherwise 
specified. Superiority is concluded if a p-value of statistical hypothesis testing is below the 
significance level and the estimate of treatment difference is in favourable direction for MC2-25 
cream. Estimates of treatment effects and differences at timepoints other than Week 12 will be 
reported exploratively. 
Categorical variables will be described by summary tables of frequencies (counts and percentages) 
per treatment group, continuous parameters by displaying arithmetic mean, median, minimum and 
maximum values, standard deviation, and, where applicable, interquartile ranges. 
All collected and derived data will be presented in individual patient data listings. 
9.4.2 
Analysis of efficacy 
On the FAS, all efficacy endpoints will be analysed, the primary endpoint also on the MFAS and 
the PPS. All endpoints, including PROs and HRQoL questionnaires, will be summarised as 
observed. For statistical analyses of primary and secondary endpoints, missing values will be 
imputed by different approaches described below. Further details will be given in the SAP. 
9.4.2.1 
Analysis of the primary efficacy endpoint 
The primary endpoint, mean change in weekly mean WI-NRS from baseline to Week 12 for MC2-
25 cream compared to MC2-25 vehicle, will be analysed by a mixed model of repeated measures 
(MMRM) including all post-baseline assessments. The model will include the fixed effects of 
treatment, visit, treatment-by-visit interaction, menopausal status at baseline, ICIQ-UI-SF score at 
baseline, and weekly mean WI-NRS at baseline. The mean change in WI-NRS at Week 12, as well 
as the treatment difference will be estimated using LS-means and reported together with the 
associated standard error, 95% confidence intervals and p-values based on F-statistics. 
On the FAS, for the primary analysis assuming missingness at random, missing data will be 
imputed 20 times and summarised following Rubin’s rule. Following a treatment policy approach, 
all data will be considered.  
Applying the same statistical model, in sensitivity analyses MMRM will be applied to observed 
cases on the FAS, MFAS and PPS, respectively, without imputation. In a while-on-treatment 
approach, in another sensitivity analysis on the FAS, only data up to the week of treatment 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 58 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
discontinuation will be considered. As detailed in the SAP, further sensitivity analyses may 
consider assumption of missingness not at random and other potential intercurrent events.  
9.4.2.2 
Analysis of the secondary endpoints 
Secondary endpoints include mean changes in weekly mean WP-NRS and in Skindex-29 domain 
scores as well as percentages of participants obtaining a ≥3-point or a ≥4-point improvement in in 
weekly mean WI-NRS and weekly mean WP-NRS, respectively.  
Mean changes in weekly mean WP-NRS and in Skindex-29 domain scores on the FAS will be 
analysed as described in Section 9.4.2.1 for primary and sensitivity analyses on mean changes in 
weekly mean WI-NRS. On the FAS, percentages of participants obtaining a ≥3-point or a ≥4-point 
improvement in weekly mean WI-NRS and weekly mean WP-NRS will be analysed by means of 
logistic regression adjusting for respective NRS scores at baseline. If the endpoint is missing, no 
improvement is assumed. 
9.4.3 
Safety analyses 
9.4.3.1 
Safety analyses – General 
On the SAS, safety will be analysed by means of incidences of AEs, changes in vital signs and 
physical examination. 
9.4.3.2 
Adverse events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. Treatment-emergent adverse events (TEAEs), related TEAEs, non-serious TEAEs, 
serious TEAEs, related serious TEAEs, TEAEs leading to treatment discontinuation and deaths will 
be summarised by the overall incidence of at least one event, incidence by body system, and 
incidence by body system and preferred term. Each patient will contribute only once (e.g., the first 
occurrence) to each of the rates, regardless of the number of occurrences (events) the patient 
experiences. The number of occurrences will also be displayed.  
Treatment-emergent AEs will be summarised by severity (mild, moderate, or severe), and by 
relationship to trial product (not related, unlikely, possibly, or probably). In summaries of severity 
and relationship, patients who report more than one event that are mapped to the same preferred 
term will be counted only once under the strongest severity and last relationship, accordingly. An 
AE is treatment-emergent if its date of onset is on or after the day of start of trial medication. An 
AE is related if relationship to trial product is not assessed as unrelated. 
9.4.4 
Baseline descriptive statistics 
For the FAS (and MFAS if it differs from the FAS) and the SAS, summary tables will describe the 
trial population by treatment group and overall, regarding demographic and other baseline 
characteristics. Demographics include age, sex, race, and ethnicity (see Section 8.2). Baseline 
characteristics include medical history, and relevant history/details of VLS related information 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 59 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
(VLS history, VLS patient journey, VLS treatment history, and NRS and other scores at screening 
and/or baseline).   
9.4.5 
Planned interim analyses 
The current trial is a phase 2 trial and is powered to detect statistical significance on the primary 
endpoint and to inform further clinical development. The expected recruitment period is relatively 
short, and the double-blind treatment period is only 12 weeks. Thus, no interim analysis is planned. 
9.4.6 
Sub-group analyses 
In descriptive summary tables, results on the primary endpoints will be displayed per site and per 
country. If deemed appropriate, sub-group analyses may be conducted as detailed in the SAP. 
9.4.7 
Tabulation of individual participant data 
9.4.7.1 
Trial medication/exposure 
Descriptive statistics will be used to summarise trial medication exposure for the SAS. Measures of 
IMP exposure will include the total duration of treatment, the total weight of trial medication used, 
the average weight of trial medication used and the total number of applications.   
9.4.7.2 
Prior and concomitant therapies 
For the SAS, prior and concomitant therapies (as defined in Section 6.5) will be summarised by 
treatment. Separate summaries will be given for prior therapies, for prior therapies ongoing at 
baseline, and for concomitant therapies. 
9.4.7.3 
Further tabulation of individual participant data 
As collected and derived, all individual participant data will be listed in individual participant data 
listings. 
9.4.8 
Exploratory analyses 
Exploratory endpoints include complete responders, WI-NRS, WP-NRS and WPP-NRS recorded at 
in-clinic visits, PGIC, Importance of improvements in PGIC, VQLI total score, VASSI, CGA, 
CGIC and burden of living with VLS.  
Exploratory endpoints will be described in summary tables as observed in the FAS. If deemed 
appropriate, statistical hypothesis testing may be conducted on exploratory endpoints to compare 
treatment groups as detailed in the SAP. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 60 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
10 Supporting documentation and operational considerations 
10.1 
Regulatory, ethical, and trial oversight considerations 
10.1.1 
Ethical considerations and conduct of the trial 
There are no marketed products approved for the treatment of VLS. Therefore, patients will not 
miss out on approved treatment by participation in this trial. VLS has a significant impact on quality 
of life and therefore off-label treatments are not uncommon. Current UK and European guidelines 
are based on potent to ultrapotent topical corticosteroids. To limit the risk of VLS deterioration 
during the trial, the patients are allowed to continue existing stable systemic treatments with a 
known or potential effect on VLS. Furthermore, patients are free to withdraw from the trial or 
discontinue treatment in case of unacceptable adverse events or lack of improvement. 
The active ingredient included in the MC2-25 cream is approved for use in an already marketed 
product (Dipeptiven®), which is given intravenously in considerably higher concentration than used 
in this trial. There are no known undesirable effects for this marketed product when used as 
prescribed. No application site reactions were observed after topical (dermal) application of MC2-
25 cream and MC2-25 vehicle to minipigs (twice daily for 2 weeks). Furthermore, the excipients 
used in MC2-25 cream are known from topical use in other approved drug products. Therefore, the 
risk of local side effects on the skin is considered low in this trial. 
There is no blood drawing or other procedures considered to introduce risks involved in the trial. 
Women of childbearing potential not using adequate contraception are excluded from the trial to 
avoid potential risks related to pregnancy or breastfeeding. 
The use of MC2-25 cream during the trial may improve VLS in individual participants. However, 
the effectiveness of the MC2-25 cream has not yet been proven and half of the participants will 
receive the vehicle cream. This might result in deterioration of VLS. It should be noted however, 
that MC2-25 vehicle has emollient properties and as such is not strictly considered a placebo.  
In view of the major impact of VLS on quality of life, the benign risk profile of MC2-25 cream, and 
MC2-25 vehicle are considered outweighed by the potential benefits of MC2-25 cream. The results 
of the trial may, if they are favourable, help bring a new treatment for VLS on the market in the 
future. In conclusion, based on the above considerations conduct of the trial is considered ethical. 
This trial must be carried out in compliance with the protocol, with regulation (EU) No 536/2014, 
and with the applicable laws and regulatory requirements of the appropriate regulatory agency. The 
trial must be conducted in accordance with the ethical principles originating from the Declaration of 
Helsinki and amendments and applicable ICH-GCP guidelines.  
10.1.2 
Institutional review board (IRB) or independent ethics committee (IEC) 
This protocol, the proposed informed consent form, and other information for patients must be 
reviewed and approved by an IRB or IEC, before the start of the trial, in compliance with local 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 61 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
regulations. This committee must also approve any amendments to the protocol, other than 
administrative ones, before initiation of the amendment procedures. 
10.1.3 
Informed consent process 
Before participation in the trial, each patient is required to provide written consent to participate in 
the trial. Each patient will receive oral and written information of the trial. The patient should be 
given every opportunity to ask for clarification of any point she does not understand and, if 
necessary, ask for more information. At the end of the interview, the patient should be given all the 
time she needs to consider the trial. No trial-specific procedures will be performed before a patient’s 
informed consent is obtained. 
10.1.4 
Trial completion, discontinuation, and closure 
The trial will be considered completed when the last patient has completed the last visit. Trial 
completion must be distinguished from premature termination of the trial and temporary suspension 
of the trial.  
The sponsor (MC2 Therapeutics) reserves the right to prematurely terminate or temporarily suspend 
trial sites or the trial at any time for any reason. The sponsor may terminate one or several 
sites/investigators at any time, provided there is reasonable cause and sufficient notice is given in 
advance of the intended termination.  
Reasons for the early termination of a trial site or the trial by the sponsor or investigator may 
include but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the investigator 
• Discontinuation of further IMP development 
If the trial is prematurely terminated or suspended, the sponsor (or designee) shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) (CRO) used in the trial of the reason(s) for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the patients and 
should assure appropriate patient therapy and/or follow-up. 
10.1.5 
Confidentiality and privacy 
10.1.5.1 
Confidentiality of trial documentation 
By signing the protocol, the investigator agrees to keep all information provided by the sponsor in 
strict confidence and to request similar confidentiality from his/her staff and the IRB/IEC. Trial 
documents provided by the trial sponsor (i.e., protocols, Investigators’ Brochures, eCRFs and other 
material) will be stored appropriately to ensure their confidentiality. The information provided by 
the sponsor to the investigator may not be disclosed to others without direct written authorisation 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 62 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
from the sponsor, except to the extent necessary to obtain informed consent from patients who wish 
to participate in the trial. 
10.1.5.2 
Privacy of individual health information  
The investigator, site staff, sponsor and any third parties working for sponsor and involved in the 
clinical trial will undertake to protect the privacy of all individually identifiable health information 
and personalised information (“Personal Data”) as per the applicable data protection rules in each of 
the countries, where the trial is being conducted. All Personal Data will be processed in accordance 
with the appropriate legal basis as described in the Informed Consent document. While all data 
records will be identified by the corresponding patient number, the identity of the patient will be 
held in confidential source documents at the trial site. Any Personal Data will be pseudonymised 
before leaving the sites and will be encrypted while at transfer, and appropriately protected at rest. 
All site staff, monitors, auditors and health authorities with access to this information are legally or 
contractually bound not to disclose such information. The sponsor and all involved parties will 
comply with the respective data protection rules. 
Data handling and record keeping will be performed in compliance with the applicable data 
protection rules. 
All parties involved in this clinical trial will be obliged by law, as well as by contractual 
arrangements to process any Personal Data in compliance with the EU GDPR and all other related 
laws and regulations. The parties involved undertake to instruct and supervise their employees 
regarding the requirements and compliance with EU GDPR and with all related laws and 
regulations. 
The Sponsor will put in place and make sure that anyone involved in the clinical trial puts in place 
appropriate technical and organisational measures such as:  
(a) the pseudonymisation and encryption of personal data 
(b) the ability to ensure the ongoing confidentiality, integrity, availability and resilience of 
processing systems and services 
(c) the ability to restore the availability and access to personal data in a timely manner in the event 
of a physical or technical incident 
(d) a process for regularly testing, assessing and evaluating the effectiveness of technical and 
organisational measures for ensuring the security of the processing. 
If one of the parties involved in the clinical trial deviates or observes a deviation from the agreed 
security measures, a notification will be promptly sent to the sponsor's data protection responsible, 
and the sponsor will assess whether a personal data security breach has occurred and act 
accordingly. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 63 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
10.1.5.3 
Patient involvement in the design of the clinical trial 
Two VLS patients (facilitated by the Danish lichen sclerosus association) have reviewed and 
provided comments to the protocol before finalisation. 
10.1.6 
Future use of stored specimens and data 
There is no scheduled sampling for clinical laboratory analyses in this trial. No samples or 
specimens will be stored for future analysis. 
10.1.7 
Safety oversight 
In view of the benign nature of the potential risks (see Section 2.3.3) a Data Safety Monitoring 
Board is not implemented in the trial. 
10.1.8 
Quality assurance and quality control 
10.1.8.1 
Direct Access to source documents 
As specified in the investigator’s agreement, the investigator agrees to allow trial-related 
monitoring, audit(s), IRB/IEC review(s) and regulatory inspection(s), with direct access to all the 
required source records, and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any issues. 
10.1.8.2 
Monitoring procedures 
The Clinical Trial Monitor will contact and/or visit the investigator site periodically to verify the 
adherence to the protocol, the maintenance of trial-related source records, and the completeness and 
accuracy of all eCRF entries compared to source data. 100% SDV is selected for this trial. The 
investigator will cooperate with the trial monitor to ensure that any discrepancies that may be 
identified are resolved. 
10.1.8.3 
Audit and inspection 
The investigator will make all the trial-related source data and records available to a quality 
assurance auditor mandated by the sponsor, or to domestic or foreign regulatory inspectors, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the rights and 
well-being of the patients have been adequately protected, and that all data relevant for the 
evaluation of the IP have been processed and reported in compliance with GCP/ICH and applicable 
regulatory requirements. 
The investigator is to notify the MC2 or designee immediately of any inspection by regulatory 
authorities or IRBs. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 64 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
10.1.9 
Data handling and record keeping 
10.1.9.1 
Recording of data 
Data handling and record keeping will be performed in compliance with any applicable law 
including applicable data protection rules. Personal data will be handled in accordance with chapter 
V of the of the General data Protection Rules (GDPR). 
10.1.9.2 
Source documents 
Source data are all the information in original records and copies of original records of clinical 
findings, observations, or other activities in the trial that are necessary for the reconstruction and 
evaluation of the trial.  
Trial data collection procedures must ensure that each data element can be traced with a high level 
of confidence from its originator or recorder to its representation in the trial database and then to its 
place in the analysis and report of trial results. Once recorded, the trial data must be protected from 
unauthorised modification or deletion, and all authorised modifications and deletions must be 
securely linked in the permanent record with their author, time of change, and reason for change 
(i.e., the audit trail must be maintained). Applicable data protection regulations must be followed to 
protect the privacy of trial patients. 
The investigator will permit trial-related monitoring, audit(s), IRB/IEC review(s) and regulatory 
inspection(s), with direct access to all the required source records. 
The Principal Investigator will certify the trial data to be accurate and complete and will release the 
trial data for transmittal to MC2 or designee. 
Source records need to be preserved for the minimum period permitted by local regulations (see 
Section 10.1.9.4). For each patient screened, the investigator will indicate in the source record(s) 
that the patient participated in the trial. 
10.1.9.3 
Case report forms 
The primary data collection tool for the trial is an eCRF designed specifically for the trial. For each 
patient screened in the trial, an eCRF will be completed by the site staff and signed by the 
investigator or his/her designate. Any data recorded on source documents and required to be 
captured in the database will be entered in the eCRFs using a validated a 21 CFR Part 11-compliant 
electronic data capture (EDC) system. 
The investigator will be responsible for ensuring the accuracy of all data entered in the eCRFs. All 
eCRFs are to be completed in a timely manner. 
Errors occurring in the eCRFs will be queried. Queries raised by data reviewers must be addressed 
by site staff. 
On request, the investigator will provide MC2 with additional data relating to the trial, or copies of 
relevant source records, duly pseudonymised (i.e., patient’s name is redacted). 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 65 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Any transfer of personal data to third countries will be in accordance with Chapter V of the General 
Data Protection Regulation (GDPR) 
10.1.9.4 
Retention of documents 
The investigator shall take responsibility for maintaining adequate and accurate source documents 
of all observations and data generated during this trial, including any data clarification forms 
received from MC2 or designee. Such documentation is subject to inspection by the sponsor or its 
agents, the European Medicines Agency (EMA), and/or other regulatory agencies. The investigator 
is responsible for retention of essential documents including the Investigator Trial File for 25 years 
in accordance with the Clinical Trials Regulation (Regulation (EU) No 536/2014). 
10.1.10 
Protocol deviations 
Protocol deviations will be reported. Important deviations related to study inclusion or exclusion 
criteria, conduct of the trial, patient management or patient assessment will be reported in the CSR. 
as per the Clinical Study Reporting Guideline (CPMP/ICH/137/95). 
10.1.11 
Publication and data sharing policy 
The clinical trial will be registered, and results will be posted at least on https://euclinicaltrials.eu 
and in accordance with applicable local regulations.  
All publications (e.g., manuscripts, abstracts, oral/slide presentations, book chapters) based on this 
trial must be submitted to MC2 for review, as specified in the Clinical Trial Agreement between the 
institution, investigator and MC2 or its designee. 
10.1.12 
Conflict of interest policy 
The investigators should provide a curriculum vitae or equivalent documentation of suitability to be 
responsible for the trial, including valid GCP training, documentation of current licensure (as 
applicable), and should sign a financial disclosure on conflict of interests.  
10.2 
Additional considerations 
10.2.1 
Emergency unblinding  
Patient safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator may contact the sponsor prior to 
unblinding a patient’s intervention assignment unless this could delay emergency treatment of the 
patient. Emergency unblinding envelopes will be available at all clinical trial sites. If a patient’s 
intervention assignment is unblinded, the sponsor must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and case report form, as applicable. Emergency unblinding envelopes will also be 
available at the external pharmacovigilance provider (Pharmalex) responsible for handling of SAEs 
and reporting of SUSARs. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 66 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
10.3 
Insurance 
MC2 has taken out appropriate insurance policies covering the subjects in the clinical trial in 
accordance with applicable laws and regulations. 
10.4 
Protocol amendments 
All substantial changes to this clinical trial protocol require a written protocol amendment that must 
be approved by the IRB/IEC, and if applicable the regulatory authorities, before implementation.  
These requirements for approval should in no way prevent any immediate action from being taken 
by the investigator or MC2 in the interests of preserving the safety of all patients included in the 
trial. If an immediate change to the protocol is felt to be necessary by the investigator and is 
implemented for safety reasons, MC2 or designee should be notified, and the IRB/IEC should be 
informed according to their reporting requirements. 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 67 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Signature page for principal investigator 
Investigational Medicinal Product: MC2-25 cream 
Protocol number: MC2-25-C3 
Protocol title: A parallel group (2-arm), randomised, double-blind, 12-week trial to explore the 
efficacy and safety of MC2-25 cream and MC2-25 vehicle in women diagnosed with vulvar lichen 
sclerosus (VLS) 
 
The signature of the principal investigator below constitutes his/her approval of this protocol and 
provides the necessary assurances that this trial will be conducted according to all stipulations, 
clinical and administrative, as detailed in the protocol. The trial will not be initiated without the 
approval of an Institutional Review Board and/or Independent Ethics Committee. 
 
 
 
Principal Investigator’s printed name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Site Address 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator’s signature 
 
 
 
Date (dd-mmm-yyyy) 
 
 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 68 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Appendices 
Appendix 1 
Overall data flow of the clinical data 
 

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 69 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
11 References 
 
REFERENCE LIST 
 
Adamolekun, B. (2011). Neurological disorders associated with cassava diet: a review of putative 
etiological mechanisms. Metab Brain Dis, 26(1), 79-85. https://doi.org/10.1007/s11011-011-
9237-y  
Avery, K., Donovan, J., Peters, T. J., Shaw, C., Gotoh, M., & Abrams, P. (2004). ICIQ: a brief and 
robust measure for evaluating the symptoms and impact of urinary incontinence. Neurourol 
Urodyn, 23(4), 322-330. https://doi.org/10.1002/nau.20041  
Berg, A. H., Drechsler, C., Wenger, J., Buccafusca, R., Hod, T., Kalim, S., Ramma, W., Parikh, S. 
M., Steen, H., Friedman, D. J., Danziger, J., Wanner, C., Thadhani, R., & Karumanchi, S. A. 
(2013). Carbamylation of serum albumin as a risk factor for mortality in patients with 
kidney failure. Sci. Transl. Med, 5(175), 175ra129. 
http://www.ncbi.nlm.nih.gov/pubmed/23467560 (Not in File)  
Bhargava, K., & Lewis, F. M. (2013). Lichen sclerosus occurring on vaginal mucosa secondary to 
uterine prolapse. J Obstet Gynaecol, 33(3), 319-320. 
https://doi.org/10.3109/01443615.2012.738720  
Bleeker, M. C., Visser, P. J., Overbeek, L. I., van Beurden, M., & Berkhof, J. (2016). Lichen 
Sclerosus: Incidence and Risk of Vulvar Squamous Cell Carcinoma. Cancer Epidemiol 
Biomarkers Prev, 25(8), 1224-1230. https://doi.org/10.1158/1055-9965.Epi-16-0019  
Chren, M. M., Lasek, R. J., Flocke, S. A., & Zyzanski, S. J. (1997). Improved discriminative and 
evaluative capability of a refined version of Skindex, a quality-of-life instrument for patients 
with skin diseases. Arch Dermatol, 133(11), 1433-1440. 
https://www.ncbi.nlm.nih.gov/pubmed/9371029 
https://jamanetwork.com/journals/jamadermatology/article-abstract/559466  
Cooper, S. M., Gao, X. H., Powell, J. J., & Wojnarowska, F. (2004). Does treatment of vulvar 
lichen sclerosus influence its prognosis? Arch Dermatol, 140(6), 702-706. 
https://doi.org/10.1001/archderm.140.6.702  
Corazza, M., Schettini, N., Zedde, P., & Borghi, A. (2021). Vulvar Lichen Sclerosus from 
Pathophysiology to Therapeutic Approaches: Evidence and Prospects. Biomedicines, 9(8). 
https://doi.org/10.3390/biomedicines9080950  
Dirnhuber, P., & Schutz, F. (1948). The isomeric transformation of urea into ammonium cyanate in 
aqueous solutions. Biochem. J, 42(4), 628-632. 
http://www.ncbi.nlm.nih.gov/pubmed/16748342 (Not in File)  
Ferreira, C. H., & Bo, K. (2015). The Pad Test for urinary incontinence in women. J Physiother, 
61(2), 98. https://doi.org/10.1016/j.jphys.2014.12.001  
Fresenius. (2015). Dipeptiven SmPC.  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 70 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Gabard, B., & Chatelain, E. (2003). Concentration of urea in the stratum corneum and moisturizing 
effect (N. R. Wohlrab J, Wohlrab, Ed. Vol. 2). Shaker Verlag, Aachen.  
Gillery, P., & Jaisson, S. (2013). Usefulness of non-enzymatic post-translational modification 
derived products (PTMDPs) as biomarkers of chronic diseases. J Proteomics, 92, 228-238. 
https://doi.org/10.1016/j.jprot.2013.02.015  
GlobalSkin. (2018). Lichen  Sclerosus Survey Results.  
Goldstein, A. T., Marinoff, S. C., Christopher, K., & Srodon, M. (2005). Prevalence of vulvar 
lichen sclerosus in a general gynecology practice. J Reprod Med, 50(7), 477-480.  
Halonen, P., Jakobsson, M., Heikinheimo, O., Gissler, M., & Pukkala, E. (2020). Incidence of 
lichen sclerosus and subsequent causes of death: a nationwide Finnish register study. Bjog, 
127(7), 814-819. https://doi.org/10.1111/1471-0528.16175  
Jaisson, S., Pietrement, C., & Gillery, P. (2018). Protein Carbamylation: Chemistry, 
Pathophysiological Involvement, and Biomarkers. Adv Clin Chem, 84, 1-38. 
https://doi.org/10.1016/bs.acc.2017.12.001  
Kalim, S., Karumanchi, S. A., Thadhani, R. I., & Berg, A. H. (2014). Protein carbamylation in 
kidney disease: pathogenesis and clinical implications. Am. J. Kidney Dis, 64(5), 793-803. 
http://www.ncbi.nlm.nih.gov/pubmed/25037561 (Not in File)  
Kimani, S., Moterroso, V., Morales, P., Wagner, J., Kipruto, S., Bukachi, F., Maitai, C., & Tshala-
Katumbay, D. (2014). Cross-species and tissue variations in cyanide detoxification rates in 
rodents and non-human primates on protein-restricted diet. Food Chem Toxicol, 66, 203-
209. https://doi.org/10.1016/j.fct.2014.01.047  
Kirby, L., Gran, S., Orekoya, F., Owen, C., & Simpson, R. (2021). Is urinary incontinence 
associated with vulval lichen sclerosus in women? A cross-sectional study. Br J Dermatol, 
185(5), 1063-1065. https://doi.org/10.1111/bjd.20583  
Kirtschig, G., Becker, K., Günthert, A., Jasaitiene, D., Cooper, S., Chi, C. C., Kreuter, A., Rall, K. 
K., Aberer, W., Riechardt, S., Casabona, F., Powell, J., Brackenbury, F., Erdmann, R., 
Lazzeri, M., Barbagli, G., & Wojnarowska, F. (2015). Evidence-based (S3) Guideline on 
(anogenital) Lichen sclerosus. J Eur Acad Dermatol Venereol, 29(10), e1-43. 
https://doi.org/10.1111/jdv.13136  
Krapf, J. M., Smith, A. B., Cigna, S. T., & Goldstein, A. T. (2022). Presenting Symptoms and 
Diagnosis of Vulvar Lichen Sclerosus in Premenopausal Women: A Cross-Sectional Study. 
J Low Genit Tract Dis, 26(3), 271-275. https://doi.org/10.1097/LGT.0000000000000679  
Kraus, L. M., & Kraus, A. P., Jr. (2001). Carbamoylation of amino acids and proteins in uremia. 
Kidney Int Suppl, 78, S102-107. https://doi.org/10.1046/j.1523-1755.2001.59780102.x  
Lee, A., Bradford, J., & Fischer, G. (2015). Long-term Management of Adult Vulvar Lichen 
Sclerosus: A Prospective Cohort Study of 507 Women. JAMA Dermatol, 151(10), 1061-
1067. https://doi.org/10.1001/jamadermatol.2015.0643  
Leibovitz, A., Kaplun, V. V., Saposhnicov, N., & Habot, B. (2000). Vulvovaginal examinations in 
elderly nursing home women residents. Arch Gerontol Geriatr, 31(1), 1-4. 
https://doi.org/10.1016/s0167-4943(00)00059-5  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 71 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Lewis, F. M., Tatnall, F. M., Velangi, S. S., Bunker, C. B., Kumar, A., Brackenbury, F., Mohd 
Mustapa, M. F., & Exton, L. S. (2018). British Association of Dermatologists guidelines for 
the management of lichen sclerosus, 2018. Br J Dermatol, 178(4), 839-853. 
https://doi.org/10.1111/bjd.16241  
Melnick, L. E., Steuer, A. B., Bieber, A. K., Wong, P. W., & Pomeranz, M. K. (2020). Lichen 
sclerosus among women in the United States. Int J Womens Dermatol, 6(4), 260-262. 
https://doi.org/10.1016/j.ijwd.2020.05.001  
Micheletti, L., Preti, M., Radici, G., Boveri, S., Di Pumpo, O., Privitera, S. S., Ghiringhello, B., & 
Benedetto, C. (2016). Vulvar Lichen Sclerosus and Neoplastic Transformation: A 
Retrospective Study of 976 Cases. J Low Genit Tract Dis, 20(2), 180-183. 
https://doi.org/10.1097/LGT.0000000000000186  
Nicolas, C., Jaisson, S., Gorisse, L., Tessier, F. J., Niquet-Leridon, C., Jacolot, P., Pietrement, C., & 
Gillery, P. (2018). Carbamylation is a competitor of glycation for protein modification in 
vivo. Diabetes Metab, 44(2), 160-167. https://doi.org/10.1016/j.diabet.2017.05.006  
Nilsson, L., Lundquist, P., Kagedal, B., & Larsson, R. (1996). Plasma cyanate concentrations in 
chronic renal failure. Clin Chem, 42(3), 482-483. 
http://clinchem.aaccjnls.org/content/clinchem/42/3/482.full.pdf  
Runeman. (2005). The Vulvar Skin Microenvironment: Impact of Tight-fittingUnderwear on 
Microclimate, pH and Microflora.  
Sacco, J. J., Botten, J., Macbeth, F., Bagust, A., & Clark, P. (2010). The average body surface area 
of adult cancer patients in the UK: a multicentre retrospective study. PLoS One, 5(1), e8933. 
https://doi.org/10.1371/journal.pone.0008933  
Saunderson, R. B., Harris, V., Yeh, R., Mallitt, K. A., & Fischer, G. (2020). Vulvar quality of life 
index (VQLI) - A simple tool to measure quality of life in patients with vulvar disease. 
Australas J Dermatol, 61(2), 152-157. https://doi.org/10.1111/ajd.13235  
Simpson, R. (2022). Core outcome domains for lichen sclerosus: a CORALS initiative consensus 
statement. British Journal of Dermatology  
Smith, Y. R., & Haefner, H. K. (2004). Vulvar lichen sclerosus : pathophysiology and treatment. 
Am J Clin Dermatol, 5(2), 105-125. https://doi.org/10.2165/00128071-200405020-00005  
Stark, G. R. (1965). Reactions of Cyanate with Functional Groups of Proteins. III. Reactions with 
Amino and Carboxyl Groups*. Biochemistry, 4(6), 1030-1036. 
http://dx.doi.org/10.1021/bi00882a008 (Not in File)  
Thomas, C. L., & Finlay, A. Y. (2007). The 'handprint' approximates to 1% of the total body surface 
area whereas the 'palm minus the fingers' does not. Br J Dermatol, 157(5), 1080-1081. 
https://doi.org/10.1111/j.1365-2133.2007.08183.x  
Thomas, L. (2019, 27 Feb 2019). Urine Composition: What’s Normal? news-medical.net. Retrieved 
16 June from https://www.news-medical.net/health/Urine-Composition-Whats-Normal.aspx 
Tran, D. A., Tan, X., Macri, C. J., Goldstein, A. T., & Fu, S. W. (2019). Lichen Sclerosus: An 
autoimmunopathogenic and genomic enigma with emerging genetic and immune targets. Int 
J Biol Sci, 15(7), 1429-1439. https://doi.org/10.7150/ijbs.34613  

 
Clinical Trial Protocol 
Clinical Trial No.: MC2-25-C3 
 
 
 
 
Confidential 
  
Page 72 of 72 
MC2-25 cream 
Version: 4.0 31-Jul-2024 
Walkden, V., Chia, Y., & Wojnarowska, F. (1997). The association of squamous cell carcinoma of 
the vulva and lichen sclerosus: implications for management and follow up. J Obstet 
Gynaecol, 17(6), 551-553. https://doi.org/10.1080/01443619768588  
Wall, L. L., Wang, K., Robson, I., & Stanton, S. L. (1990). The Pyridium pad test for diagnosing 
urinary incontinence. A comparative study of asymptomatic and incontinent women. J 
Reprod Med, 35(7), 682-684.  
Wallace, H. J. (1971). Lichen sclerosus et atrophicus. Trans St Johns Hosp Dermatol Soc, 57(1), 9-
30.  
Wyman, J. F., Cain, C. H., Epperson, C. N., Fitzgerald, C. M., Gahagan, S., Newman, D. K., 
Rudser, K., Smith, A. L., Vaughan, C. P., & Sutcliffe, S. (2022). Urination Frequency 
Ranges in Healthy Women. Nurs Res. https://doi.org/10.1097/NNR.0000000000000595  
Zendell, K., & Edwards, L. (2013). Lichen sclerosus with vaginal involvement: report of 2 cases 
and review of the literature. JAMA Dermatol, 149(10), 1199-1202. 
https://doi.org/10.1001/jamadermatol.2013.4885