Clinical Trial Results:
Altered tumor oxygenation by Metformin, a potential step in overcoming radiotherapy resistance in locally advanced cervical cancer.
|
Summary
|
|
EudraCT number |
2018-004119-36 |
Trial protocol |
NO |
Global end of trial date |
01 Nov 2024
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
15 Feb 2026
|
First version publication date |
15 Feb 2026
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
METOXY-LACC
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT04275713 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Oslo University Hospital
|
||
Sponsor organisation address |
Ullernchausseen 70, Oslo, Norway, 0379
|
||
Public contact |
Trial Manager, Oslo University Hospital, UXKJUH@ous-hf.no
|
||
Scientific contact |
Trial Manager, Oslo University Hospital, UXKJUH@ous-hf.no
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
06 Oct 2025
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
01 Nov 2024
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
01 Nov 2024
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The overall study objective is to investigate whether metformin can induce molecular changes, cell death and/or improved oxygenation in the tumor tissue, especially in hypoxic areas, and thereby improve tumor response with acceptable added acute toxicity.
|
||
Protection of trial subjects |
Routine care with weekly visits at the out-patient clinic for management of side effects and toxicity.
|
||
Background therapy |
Pelvic radiotherapy and weekly chemotherapy (cisplatin) followed by cervical brachytherapy. | ||
Evidence for comparator |
Tumor hypoxia is a prognostic factor, associated with poor radiotherapy response representing a valid, interventional target. This clinical trial investigated if the antidiabetic drug metformin, could decrease hypoxia according to established biomarkers. Metformin inhibits complex 1 of the mitochondrial respiratory chain, which results in reduced cellular oxidative phosphorylation . The subsequent reduction in cellular oxygen consumption has been shown to decrease tumor hypoxia in cervical cancer xenografts by making more oxygen available in initially hypoxic tumor areas. Moreover, metformin may improve tumor oxygenation by selectively killing hypoxic cells through the suppression of the mammalian target of rapamycin (mTOR) pathway and modulation of the unfolded protein response (UPR), both important for cell survival under hypoxic conditions. | ||
Actual start date of recruitment |
22 May 2020
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Norway: 41
|
||
Worldwide total number of subjects |
41
|
||
EEA total number of subjects |
41
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
31
|
||
From 65 to 84 years |
10
|
||
85 years and over |
0
|
||
|
||||||||||
|
Recruitment
|
||||||||||
Recruitment details |
Patients were recruited from Oslo University Hospital between May 2020 and July 2024. | |||||||||
|
Pre-assignment
|
||||||||||
Screening details |
Patients with newly diagnosed cervical cancer were screened after the initial diagnostic work-up, at the first visit to the Gynecologic outpatient clinic. Female patients ≥18 years of age with ECOG performance status 0–1 and histologically confirmed cervical cancer FIGO2018 stage IB2-IVa, planned for curative chemoradiotherapy were eligible. | |||||||||
|
Pre-assignment period milestones
|
||||||||||
Number of subjects started |
41 | |||||||||
Number of subjects completed |
41 | |||||||||
|
Period 1
|
||||||||||
Period 1 title |
overall trial (overall period)
|
|||||||||
Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
|
|||||||||
Blinding used |
Not blinded | |||||||||
|
Arms
|
||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||
|
Arm title
|
Intervention | |||||||||
Arm description |
Metformine 850 mg two times daily from one week before the start of radiotherapy and througout the treatment course. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
metformin
|
|||||||||
Investigational medicinal product code |
A10B A02
|
|||||||||
Other name |
Glucophage
|
|||||||||
Pharmaceutical forms |
Tablet
|
|||||||||
Routes of administration |
Oral use
|
|||||||||
Dosage and administration details |
Tablets taken orally 850 mg two times daily
|
|||||||||
|
Arm title
|
Control | |||||||||
Arm description |
Patients recieving standard treatment | |||||||||
Arm type |
No intervention | |||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
|
|||||||||
|
||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Intervention
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Metformine 850 mg two times daily from one week before the start of radiotherapy and througout the treatment course. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients recieving standard treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Subject analysis sets
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
Primary endpoint
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomized participansts with a signed informed concent form who has recieved allocated treatment, completed biopsy at baseline and after one week of study participation without major protcol deviations.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
Safety
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomized participants with assigned informed concent who had recieved allocated treatment
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
Secondary endpoints
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomized participants with assigned informed concent who had recieved allocated treatment and completed MRI at base line and after one week of participation without major protcol deviation.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Intervention
|
||
Reporting group description |
Metformine 850 mg two times daily from one week before the start of radiotherapy and througout the treatment course. | ||
Reporting group title |
Control
|
||
Reporting group description |
Patients recieving standard treatment | ||
Subject analysis set title |
Primary endpoint
|
||
Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
All randomized participansts with a signed informed concent form who has recieved allocated treatment, completed biopsy at baseline and after one week of study participation without major protcol deviations.
|
||
Subject analysis set title |
Safety
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All randomized participants with assigned informed concent who had recieved allocated treatment
|
||
Subject analysis set title |
Secondary endpoints
|
||
Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
All randomized participants with assigned informed concent who had recieved allocated treatment and completed MRI at base line and after one week of participation without major protcol deviation.
|
||
|
|||||||||||||||||
End point title |
Change in hypoxia related gene expression signature in tumour biopsies | ||||||||||||||||
End point description |
|||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Change in hypoxia related gene expression signature in tumour biopsies from baseline assessed after one week
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Change in hypoxia gene signature between arms | ||||||||||||||||
Statistical analysis description |
Change in hypoxia gene signature betwwen arms
|
||||||||||||||||
Comparison groups |
Intervention v Control
|
||||||||||||||||
Number of subjects included in analysis |
40
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.96 | ||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||
Confidence interval |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Change in MRI parameters | ||||||||||||||||
End point description |
Change in tumour volume
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Change in MRI volume from baseline to time of first brachytherapy
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Change in volume - baseline to first brachytherapy | ||||||||||||||||
Statistical analysis description |
Change in volume (%) - baseline to first brachytherapy
|
||||||||||||||||
Comparison groups |
Control v Intervention
|
||||||||||||||||
Number of subjects included in analysis |
41
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.025 | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From start of treatment to last follow-up (3-4 months after last radiotherapy treatment).
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Only AE Grade 3 or above, except renal toxicity (all grades).
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
CTCAE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Intervention arm
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients receiving chemoradiotherapy and metformin | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control group
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients recieving standard treatment (chemoradiotherapy). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
03 Apr 2023 |
Updated sample size calculations and up-dated allocation sequence accordingly. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/40105683 |
|||
