Clinical Trial Results:
Mesenchymal stem cells for radiation-induced hyposalivation and xerostomia in previous head and neck cancer patients (MESRIX-II)
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Summary
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EudraCT number |
2018-000348-24 |
Trial protocol |
DK |
Global end of trial date |
22 Feb 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Jun 2025
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First version publication date |
27 Jun 2025
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CVB2018-1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04776538 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Rigshospitalet
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Sponsor organisation address |
Inge Lehmannsvej 7, København Ø, Denmark, 2100 Købehavn
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Public contact |
Christian Von Buchwald, Rigshospitalet, Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, 0045 35452370, christian.von.buchwald@regionh.dk
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Scientific contact |
Christian Von Buchwald, Rigshospitalet, Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, 0045 35452370, christian.von.buchwald@regionh.dk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Jun 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Feb 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Feb 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The objective is to examine whether enrichment of the submandibular glands with injections of allogeneic ASCs will improve the salivary function in radiation-induced salivary damage.
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Protection of trial subjects |
Description of Measures to Protect Trial Subjects:
To ensure the safety and well-being of participants in this trial investigating adipose-derived mesenchymal stem/stromal cell (ASC) therapy for radiation-induced xerostomia, several protective measures were implemented:
• Direct Access to Clinical Oversight: All participants were provided with a direct phone number to the principal investigator, ensuring they had 24/7 access to medical guidance or assistance throughout the trial period.
• Minimization of Pain and Distress: All injections were performed under ultrasound guidance to enhance precision and minimize discomfort or procedural complications. The procedure was conducted by trained personnel in a controlled clinical setting.
• Blinding and Randomization: The study employed a double-blind, placebo-controlled design to prevent bias and protect participants from psychological distress associated with knowing their treatment allocation.
• Monitoring and Follow-up: Participants were closely monitored for adverse events and treatment outcomes, with structured follow-up visits at 4 months and again at 1 year post-treatment. These follow-ups included clinical assessments, patient-reported outcomes, and blood sample analysis to detect potential immune responses.
• Adverse Event Recording: A structured protocol was in place for the documentation and evaluation of adverse events, allowing prompt identification and management of any treatment-related complications.
• Ethical Oversight: The study protocol received approval from an independent ethics committee, and all patients provided informed consent prior to enrollment, ensuring they were fully aware of the procedures, potential risks, and their right to withdraw at any time.
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Background therapy |
In this trial, no additional treatments beyond the investigational product (adipose-derived mesenchymal stem/stromal cells, ASCs) and the placebo comparator were systematically administered across all arms or groups. All participants continued with their usual standard of care for radiation-induced xerostomia as prescribed by their treating clinicians, but no specific supportive therapies (e.g., sialogogues, saliva substitutes, or other interventions) were mandated or applied as part of the trial protocol. | ||
Evidence for comparator |
The comparator used in this trial was a placebo consisting of CryoStor10 (BioLifeSolutions) supplemented with 10% dimethyl sulfoxide (DMSO), which served as the vehicle solution for the adipose-derived mesenchymal stem/stromal cells (MSCs). This specific formulation was chosen to match the composition of the investigational product, minus the active cellular component. By using the same vehicle solution as the treatment arm, the design ensured that any observed therapeutic differences could be attributed specifically to the MSCs. | ||
Actual start date of recruitment |
19 Jan 2021
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Safety | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 120
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Worldwide total number of subjects |
120
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EEA total number of subjects |
120
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
80
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From 65 to 84 years |
40
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients are accessible for inclusion if they have been treated with radiotherapy for a head and neck cancer in Denmark. Patients will be recruited from the Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet, by referral from other departments, e.g. Oncology Departments or can be self-referred | |||||||||
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Pre-assignment
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Screening details |
Patients were initially contacted by phone to assess interest and answer questions. Those interested received written study information and were invited to a screening visit, where informed consent was obtained. Eligibility was assessed through clinical exams, labs, sialometry, and questionnaires. Only eligible patients were randomized. | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
The sponsor, investigators, study staff (except for staff involved in stem cell preparation and staff involved in bioanalytical analyses), and patients will be blinded to treatment assignment. A project nurse will thaw the frozen suspension of ASCs or placebo just before injection, and the syringes are covered in sterile green tape to ensure that neither the patients nor the study staff can see the suspension injected.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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adipose-derived mesenchymal stem cell (ASC) | |||||||||
Arm description |
adipose-derived mesenchymal stem cell (ASC) injection to the submandibular gland | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
adipose-derived mesenchymal stem cell (ASC)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Dispersion for injection
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Routes of administration |
Injection
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Dosage and administration details |
A total of 0.5 mL of ASCs or placebo was injected without anaesthesia into each submandibular gland, and for the patients receiving ASCs, this corresponded
to a dose of approximately 25 106 cells per gland.
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Arm title
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Placebo | |||||||||
Arm description |
Placebo consisted of CryoStor10 (BiolifeSolutions) supplemented with 10% DMSO | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Dispersion for injection/infusion
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Routes of administration |
Injection
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Dosage and administration details |
0.5 mL of placebo was injected without anaesthesia into each submandibular gland,
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Baseline characteristics reporting groups
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Reporting group title |
adipose-derived mesenchymal stem cell (ASC)
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Reporting group description |
adipose-derived mesenchymal stem cell (ASC) injection to the submandibular gland | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo consisted of CryoStor10 (BiolifeSolutions) supplemented with 10% DMSO | ||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ASC injection
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set includes all randomized participants who were allocated to the adipose-derived mesenchymal stem/stromal cell (ASC) injection group and received one injection of the investigational product. Data from these 60 subjects were analyzed according to the intention-to-treat principle, meaning all participants were analyzed in the group to which they were originally assigned
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Subject analysis set title |
Placebo
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set includes all randomized participants who were allocated to the placebo group and received one injection of the placebo solution (CryoStor10 supplemented with 10% DMSO). Data from these 60 subjects were analyzed according to the intention-to-treat principle, meaning all participants were included in the analysis based on their original randomization assignment
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End points reporting groups
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Reporting group title |
adipose-derived mesenchymal stem cell (ASC)
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Reporting group description |
adipose-derived mesenchymal stem cell (ASC) injection to the submandibular gland | ||
Reporting group title |
Placebo
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Reporting group description |
Placebo consisted of CryoStor10 (BiolifeSolutions) supplemented with 10% DMSO | ||
Subject analysis set title |
ASC injection
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set includes all randomized participants who were allocated to the adipose-derived mesenchymal stem/stromal cell (ASC) injection group and received one injection of the investigational product. Data from these 60 subjects were analyzed according to the intention-to-treat principle, meaning all participants were analyzed in the group to which they were originally assigned
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Subject analysis set title |
Placebo
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set includes all randomized participants who were allocated to the placebo group and received one injection of the placebo solution (CryoStor10 supplemented with 10% DMSO). Data from these 60 subjects were analyzed according to the intention-to-treat principle, meaning all participants were included in the analysis based on their original randomization assignment
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End point title |
Unstimulated saliva flow rate | ||||||||||||||||||||
End point description |
The primary efficacy objective: To compare the effect of ASC injection, relative to placebo, on changes in unstimulated salivary gland function from baseline to month 4, in patients with previous head and neck cancer. i.e., effectiveness: change in salivary gland function is measured by 4 months change in unstimulated whole saliva flow rate between ASC and placebo (consisting of CryoStor10 (BiolifeSolutions), the freeze media for ASCs).
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End point type |
Primary
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End point timeframe |
4 months
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Attachments |
Unstimulated salivary flow rate |
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Statistical analysis title |
Change in unstimulated salivary flow rate | ||||||||||||||||||||
Statistical analysis description |
Effectiveness: Saliva gland function measured as the change in unstimulated whole saliva flow rate in the group receiving ASCs compared with the group of participants receiving placebo. Timeframe: 4 months. The saliva flow rate will be measured as ml/min.
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Comparison groups |
adipose-derived mesenchymal stem cell (ASC) v Placebo v ASC injection v Placebo
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Number of subjects included in analysis |
240
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Confidence interval |
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End point title |
1. Effectiveness: Stimulated salivary gland function measured by 4 months change in stimulated whole saliva flow rate. | ||||||||||||||||||||
End point description |
Effectiveness: Stimulated salivary gland function measured by 4 months change in stimulated whole saliva flow rate.
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End point type |
Secondary
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End point timeframe |
4 months
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Attachments |
Stimulated salivary flow rate |
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Statistical analysis title |
Change in saliva flow rate | ||||||||||||||||||||
Statistical analysis description |
The change in saliva flow rate from baseline to the four-month follow-up visit will be presented as ml/min. Continuous outcome measures (change from baseline) will be analysed using an analysis of covariance (ANCOVA) model with randomised treatment group as a class variable and the baseline value as a continuous covariate.
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Comparison groups |
ASC injection v Placebo
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Confidence interval |
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End point title |
Patient-Reported Outcome of xerostomia - XQ | ||||||||||||||||||||
End point description |
Key secondary objectives are: To compare the effect of ASC injection, relative to placebo, from baseline to month 4 on all of the following outcome measures:
Patient-Reported Outcome of xerostomia: Xerostomia Questionnaire (XQ).
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End point type |
Secondary
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End point timeframe |
4 months
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Attachments |
Table 2 |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Patient-Reported Outcome of xerostomia: The European organisation for research and treatment of cancer quality of life questionnaire, head and neck-35 (EORTC QLQ-H&N35) | ||||||||||||
End point description |
To compare the effect of ASC injection, relative to placebo, from baseline to month 4 on all of the following outcome measures: Patient-Reported Outcome of xerostomia: The European organisation for research and treatment of cancer quality of life questionnaire, head and neck-35 (EORTC QLQ-H&N35):
a. Domains for dry mouth (HNDR)
b. Domains for sticky saliva (HNSS)
c. Domains for swallowing (HNSW)
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End point type |
Secondary
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End point timeframe |
The primary endpoint, as well as the key secondary outcomes will all be evaluated based on the 4 months assessment.
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Attachments |
Untitled (Filename: Tabel 2.docx) |
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Statistical analysis title |
Change in symptom score | ||||||||||||
Comparison groups |
Placebo v ASC injection
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Number of subjects included in analysis |
117
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Safety was monitored throughout the study period of 4 months
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Adverse event reporting additional description |
Safety was evaluated by registration of treatment-related adverse events, serious adverse events (SAE), or death. Evaluation of the immune response to ASC was measured by the development of de novo HLA antibodies
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTC AE 5.0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
5.0
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Reporting groups
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Reporting group title |
Mesenchymal stem cells
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Reporting group description |
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Reporting group title |
Placebo
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/37658468 |
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