Colorectal CancerPhase 2/3COLDFIRE-IIINCT06185556
COLDFIRE-III Trial: Efficacy of Irreversible Electroporation and Stereotactic Body Radiotherapy for Perivascular and Peribiliary Colorectal Liver Metastases
A Phase 2/3 study testing Irreversible electroporation and Stereotactic body radiotherapy in people with Colorectal Cancer and Liver Metastases, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
Trial summary
The primary objective of this phase IIb/III, prospective, randomized clinical trial is to compare the efficacy of irreversible electroporation (IRE) with stereotactic body radiotherapy (SBRT) in patients with perivascular or peribiliary colorectal liver metastases (CRLM), that are not amenable for surgical resection… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Cancer, Liver Metastases, Liver Metastasis Colon Cancer
- What is being tested?
- Irreversible electroporation and Stereotactic body radiotherapy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 1 siteNetherlands
- Study dates
- 20 Aug 2024to 1 Sep 2031
- Phase
- Phase 2/3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histological documentation of primary colorectal tumor is available;
- 1-3 CRLM visible on ceCT and/or MRI, size 0-5 cm and not eligible for resection or thermal ablation due to location close to a vessel or bile duct;
- Additional CRLM are allowed if considered either resectable or ablatable with a maximum of 10 CRLM. In patients with extrahepatic disease, a maximum of 5 additional CRLM is allowed;
- No or limited extrahepatic disease (1 extrahepatic lesion is allowed, with some exclusions mentioned in the exclusion criteria);
- Prior focal liver treatment is allowed;
- Subjects should preferably be treated with neo-adjuvant systemic therapy;
Show all 11Show fewer
- Subjects with recurrent (either local or distant-hepatic) CRLM after previous focal treatment who are unsuitable for (further) systemic therapy (further downsizing or conversion to resectable disease improbable);
- Adequate bone marrow, liver and renal function as assessed by laboratory requirements to be conducted within 7 days prior to definite inclusion;
- ASA classification 0 - 3;
- Age >18 years;
- Written informed consent;
Who cannot join
- Radical treatment unfeasible or unsafe (e.g. insufficient FLR);
- >10 CRLM; >5 CRLM when extra-hepatic disease is present;
- Positive para-aortal lymph nodes, celiac lymph nodes, adrenal metastases, pleural carcinomatosis or peritoneal carcinomatosis;
- Subjects who have progressive disease after neo-adjuvant systemic therapy;
- History of epilepsy;
- History of cardiac disease:
Show all 13Show fewer
- Uncontrolled hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen;
- Compromised liver function (e.g. signs of portal hypertension, INR > 1,5 without use of anticoagulants, ascites);
- Pregnant or breast-feeding subjects;
- Immunotherapy ≤ 2 weeks prior to the procedure;
- Chemotherapy and/or targeted therapy ≤ 2 weeks prior to the procedure;
- Severe allergy to contrast media not controlled with premedication;
- Any condition that is unstable or that could jeopardize the safety of the subject and their compliance in the study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Netherlands1 site, 1 recruiting
- Recruiting
Amsterdam UMC - location VUmc
Amsterdam, North Holland, 1081 HV
Danielle J. Vos, MD, 20-4444571 ext. +31, interventieradiologie@amsterdamumc.nl
Martijn R. Meijerink, Prof.
About this study
Official title: COLDFIRE-III Trial: Perivascular and Peribiliary Colorectal Liver Metastases (0-5cm): Irreversible Electroporation Versus Stereotactic Body Radiotherapy
The primary objective of this phase IIb/III, prospective, randomized clinical trial is to compare the efficacy of irreversible electroporation (IRE) with stereotactic body radiotherapy (SBRT) in patients with perivascular or peribiliary colorectal liver metastases (CRLM), that are not amenable for surgical resection or thermal ablation. Efficacy is assessed in terms of local control at 2 years.
Read the detailed description
Rationale: Currently, the gold standard for perivascular and peribiliary colorectal liver metastases (CRLM), that are not amenable for surgical resection or thermal ablation, is undetermined. Two non-thermal treatment modalities could provide a solution for these anatomically challenging CRLM: irreversible electroporation (IRE) and stereotactic body radiotherapy (SBRT).
IRE is a new, minimal-invasive image-guided treatment method for tumors not amenable for surgical resection or thermal ablation, due to vicinity near vital structures such as vessels and bile ducts. With IRE, multiple electrical pulses are applied to tumorous tissue. These pulses alter the existing transmembrane potential of the cell membranes, and create 'nanopores', after which the cell dies through loss of homeastasis. SBRT is another non-thermal ablation modality and has important advantages over conventional radiotherapy such as a more precise and greater biological dose delivery and hence less toxicity and presumably better outcome.
Study design: The COLDFIRE-III trial is a phase IIB/III, prospective randomized clinical trial. The primary conducting center will be the Amsterdam UMC (Amsterdam, the Netherlands). The purpose of this study is to assess and compare the efficacy of IRE and SBRT for perivascular or peribiliary CRLM in terms of local control at 2 years. Other objectives are overall survival, additional efficacy endpoints, safety, pain assessments and costs. For the sample size calculations, the log-rank test is used. The (2-year survival) proportion in group 1 (a treatment group) is 0.80. The proportion in group 2 (the alternative treatment group) is 0.55. The significance level of the test is 0.10. A total number of 78 patients will be randomized into one of two arms: arm A (IRE, n = 39) and arm B (SBRT, n = 39).
Study population: 78 patients with 1-3 perivascular and peribiliary lesions of 0-5 cm, ineligible for surgical resection and thermal ablation, suitable for both IRE and SBRT and no or limited extrahepatic disease (1 extrahepatic lesion is allowed, not including positive para-aortic lymph nodes, celiac lymph nodes, adrenal metastases, pleural carcinomatosis or peritoneal carcinomatosis) can be included. Supplementary resections for resectable lesions and thermal ablations for unresectable CRLM are allowed. A maximum number of 10 CRLM are allowed for patients with no extrahepatic disease and a maximum number of 5 lesions are allowed for patients with limited extrahepatic disease. Eligible patients will be stratified according to tumor size (≤3cm vs. 3-5 cm) and (induction) chemotherapy prior to local treatment.
Intervention: Patients will be randomized into one of two arms, arm A (IRE) and arm B (SBRT). The expert panel, consisting of at least two interventional radiologists, two radiation oncologists and two hepatobiliary surgeons, will appoint lesions that are ineligible for surgery of thermal ablation, and suitable for both IRE and SBRT, as target lesions.
- Conditions
- Colorectal Cancer, Liver Metastases, Liver Metastasis Colon Cancer, Unresectable Solid Tumor
- Being tested
- Irreversible electroporation, Stereotactic body radiotherapy
- Keywords
- Colorectal liver metastases, colorectal hepatic metastases
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Irreversible electroporationProcedure or surgery
Percutaneous (CT-guided) irreversible electroporation of 1-3 perivascular and peribiliary colorectal liver metastasis.
Stereotactic body radiotherapyRadiation
Stereotactic body radiotherapy (CT- or MRI-guided) of 1-3 perivascular and peribiliary colorectal liver metastases.
| Study group | Role | What they receive |
|---|---|---|
| A: Irreversible electroporation | Active comparator | Irreversible electroporation (IRE) is a primarily non-thermal, local ablative technique that utilizes electrical pulses to destroy tumor tissue. Theoretically, IRE only affects viable tumor tissue, leaving surrounding vital structures relatively intact. It is therefore considered to cause less morbidity than thermal ablative strategies. Receives: Procedure: Irreversible electroporation |
| B: Stereotactic body radiotherapy | Active comparator | Stereotactic body radiotherapy (SBRT) is a form of external beam radiation that has important advantages over conventional radiotherapy such as a more precise and greater biological dose delivery and hence less toxicity and presumably better outcome. Receives: Radiation: Stereotactic body radiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Local control
Local control is defined as no objectified signs for local tumor progression on imaging acquired 23-24 months following start of the initial study procedure, according to the RECIST criteria. Site recurrences within the first 12 months that are successfully retreated once using the same technique (re-IRE or re-SBRT), thermal ablation or surgical resection will not be regarded as an event for local control. Per patient analysis.
Measured: 2 years
Secondary outcomes (10)
Overall survival (OS) per patient
Overall survival is defined as the time from randomization to the time of death due to any cause or to the last day of follow up (censored).
Measured: Assessed up to 5 years
Local tumor progression-free survival (LTPFS) per patient and per tumor.
Local tumor progression-free survival is defined as the time from randomization to the time of unequivocal local tumor progression.
Measured: Assessed up to 5 years
Distant tumor progression-free survival (DPFS) per patient
Distant tumor progression-free survival is defined as the time from randomization to the time of unequivocal distant tumor progression.
Measured: Assessed up to 5 years
Time to progression (TTP) per patient
Time to progression is defined as the time from randomization to the time of local disease progression, new metastases (events). The date of death from any cause is considered to be a competing risk
Measured: Assessed up to 5 years
Safety per procedure and per patient
Rate of adverse events and serious adverse event, graded from I to V according to the standard classification of surgical complications.
Measured: Assessed up to 5 years
Assessment of pain per patient
Pain assessment using visual analogue scale questionnaires (VAS; per procedure analysis: Assessed prior to, directly after and every three months after local treatment.
Measured: Assessed up to 1 year
Quality of life (QoL) per patient as assessed by EORCT QLQ-C30 questionnaires
The quality of life is assessed in both treatments using EORCT QLQ-C30 questionnaire (per procedure analysis), prior to, and every three months after treatment during a total follow-up time of 1 year.questionnaires: Assessed prior to, and every three months after local treatment.
Measured: Assessed up to 1 year
Quality of life (QoL) per patient as assessed by EQ-5D questionnaires
The quality of life is assessed in both treatments using EQ-5D questionnaire (per procedure analysis), prior to, and every three months after treatment during a total follow-up time of 1 year.questionnaires: Assessed prior to, and every three months after local treatment.
Measured: Assessed up to 1 year
Quality of life (QoL) per patient as assessed by PRODISQ questionnaires
The quality of life is assessed in both treatments using PRODISQ questionnaire (per procedure analysis), prior to, and every three months after treatment during a total follow-up time of 1 year.questionnaires: Assessed prior to, and every three months after local treatment.
Measured: Assessed up to 1 year
Cost-effectiveness ratio (ICER) per patient
Direct and indirect total costs of care, and incremental cost-effectiveness ratio (ICER).
Measured: Assessed up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Dec 2023
- Study start20 Aug 2024
- Primary completion1 Sep 2029 (estimated)
- Study completion1 Sep 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colorectal CancerStudies of the same condition, open and under way.
- More trials run by Amsterdam UMC, location VUmcThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A prospective, randomized clinical trial.
- Masking
- None (open label)
- Enrolment
- 78 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Collaborators
- Angiodynamics, Inc.
- Responsible party
- Principal investigator, M.R. Meijerink, Amsterdam UMC, location VUmc
- Investigators
- Martijn R. Meijerink, Prof., Principal investigator, Amsterdam UMC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06185556
- Sponsor's protocol ID
- NL83557.018.23
- Acronym
- COLDFIRE-III
- Status last verified
- Aug 2024
- First submitted
- 17 Nov 2023
- Last updated
- 23 Aug 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- COLDFIRE-III Trial: Perivascular and Peribiliary Colorectal Liver Metastases (0-5cm): Irreversible Electroporation Versus Stereotactic Body Radiotherapy
- ClinicalTrials.gov ID
- NCT06185556
- Acronym / sponsor ID
- COLDFIRE-III / NL83557.018.23
- Conditions
- Colorectal Cancer, Liver Metastases, Liver Metastasis Colon Cancer, Unresectable Solid Tumor
- Keywords
- Colorectal liver metastases, colorectal hepatic metastases
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 78 participants (estimated)
- Lead sponsor
- Amsterdam UMC, location VUmcUniversity, hospital or other
- Collaborators
- Angiodynamics, Inc.
- Study start
- 20 Aug 2024 (actual)
- Primary completion
- 1 Sep 2029 (estimated)
- Study completion
- 1 Sep 2031 (estimated)
- First posted
- 29 Dec 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of this phase IIb/III, prospective, randomized clinical trial is to compare the efficacy of irreversible electroporation (IRE) with stereotactic body radiotherapy (SBRT) in patients with perivascular or peribiliary colorectal liver metastases (CRLM), that are not amenable for surgical resection or thermal ablation. Efficacy is assessed in terms of local control at 2 years.
Detailed description
Rationale: Currently, the gold standard for perivascular and peribiliary colorectal liver metastases (CRLM), that are not amenable for surgical resection or thermal ablation, is undetermined. Two non-thermal treatment modalities could provide a solution for these anatomically challenging CRLM: irreversible electroporation (IRE) and stereotactic body radiotherapy (SBRT).
IRE is a new, minimal-invasive image-guided treatment method for tumors not amenable for surgical resection or thermal ablation, due to vicinity near vital structures such as vessels and bile ducts. With IRE, multiple electrical pulses are applied to tumorous tissue. These pulses alter the existing transmembrane potential of the cell membranes, and create 'nanopores', after which the cell dies through loss of homeastasis. SBRT is another non-thermal ablation modality and has important advantages over conventional radiotherapy such as a more precise and greater biological dose delivery and hence less toxicity and presumably better outcome.
Study design: The COLDFIRE-III trial is a phase IIB/III, prospective randomized clinical trial. The primary conducting center will be the Amsterdam UMC (Amsterdam, the Netherlands). The purpose of this study is to assess and compare the efficacy of IRE and SBRT for perivascular or peribiliary CRLM in terms of local control at 2 years. Other objectives are overall survival, additional efficacy endpoints, safety, pain assessments and costs. For the sample size calculations, the log-rank test is used. The (2-year survival) proportion in group 1 (a treatment group) is 0.80. The proportion in group 2 (the alternative treatment group) is 0.55. The significance level of the test is 0.10. A total number of 78 patients will be randomized into one of two arms: arm A (IRE, n = 39) and arm B (SBRT, n = 39).
Study population: 78 patients with 1-3 perivascular and peribiliary lesions of 0-5 cm, ineligible for surgical resection and thermal ablation, suitable for both IRE and SBRT and no or limited extrahepatic disease (1 extrahepatic lesion is allowed, not including positive para-aortic lymph nodes, celiac lymph nodes, adrenal metastases, pleural carcinomatosis or peritoneal carcinomatosis) can be included. Supplementary resections for resectable lesions and thermal ablations for unresectable CRLM are allowed. A maximum number of 10 CRLM are allowed for patients with no extrahepatic disease and a maximum number of 5 lesions are allowed for patients with limited extrahepatic disease. Eligible patients will be stratified according to tumor size (≤3cm vs. 3-5 cm) and (induction) chemotherapy prior to local treatment.
Intervention: Patients will be randomized into one of two arms, arm A (IRE) and arm B (SBRT). The expert panel, consisting of at least two interventional radiologists, two radiation oncologists and two hepatobiliary surgeons, will appoint lesions that are ineligible for surgery of thermal ablation, and suitable for both IRE and SBRT, as target lesions.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- A prospective, randomized clinical trial.
| Arm | Type | Receives |
|---|---|---|
| A: Irreversible electroporation | Active comparator | Procedure: Irreversible electroporationIrreversible electroporation (IRE) is a primarily non-thermal, local ablative technique that utilizes electrical pulses to destroy tumor tissue. Theoretically, IRE only affects viable tumor tissue, leaving surrounding vital structures relatively intact. It is therefore considered to cause less morbidity than thermal ablative strategies. |
| B: Stereotactic body radiotherapy | Active comparator | Radiation: Stereotactic body radiotherapyStereotactic body radiotherapy (SBRT) is a form of external beam radiation that has important advantages over conventional radiotherapy such as a more precise and greater biological dose delivery and hence less toxicity and presumably better outcome. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Histological documentation of primary colorectal tumor is available;
- 1-3 CRLM visible on ceCT and/or MRI, size 0-5 cm and not eligible for resection or thermal ablation due to location close to a vessel or bile duct;
- Additional CRLM are allowed if considered either resectable or ablatable with a maximum of 10 CRLM. In patients with extrahepatic disease, a maximum of 5 additional CRLM is allowed;
- No or limited extrahepatic disease (1 extrahepatic lesion is allowed, with some exclusions mentioned in the exclusion criteria);
- Prior focal liver treatment is allowed;
Key exclusion criteria (13 listed)
- Radical treatment unfeasible or unsafe (e.g. insufficient FLR);
- >10 CRLM; >5 CRLM when extra-hepatic disease is present;
- Positive para-aortal lymph nodes, celiac lymph nodes, adrenal metastases, pleural carcinomatosis or peritoneal carcinomatosis;
- Subjects who have progressive disease after neo-adjuvant systemic therapy;
- History of epilepsy;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Irreversible electroporationPercutaneous (CT-guided) irreversible electroporation of 1-3 perivascular and peribiliary colorectal liver metastasis. | Procedure or surgery | A: Irreversible electroporation |
| Stereotactic body radiotherapyStereotactic body radiotherapy (CT- or MRI-guided) of 1-3 perivascular and peribiliary colorectal liver metastases. | Radiation | B: Stereotactic body radiotherapy |
Primary outcome
Local control
Time frame: 2 years
Local control is defined as no objectified signs for local tumor progression on imaging acquired 23-24 months following start of the initial study procedure, according to the RECIST criteria. Site recurrences within the first 12 months that are successfully retreated once using the same technique (re-IRE or re-SBRT), thermal ablation or surgical resection will not be regarded as an event for local control. Per patient analysis.
10 secondary outcomes
Overall survival (OS) per patient
Time frame: Assessed up to 5 years
Local tumor progression-free survival (LTPFS) per patient and per tumor.
Time frame: Assessed up to 5 years
Distant tumor progression-free survival (DPFS) per patient
Time frame: Assessed up to 5 years
Time to progression (TTP) per patient
Time frame: Assessed up to 5 years
Safety per procedure and per patient
Time frame: Assessed up to 5 years
Assessment of pain per patient
Time frame: Assessed up to 1 year
Quality of life (QoL) per patient as assessed by EORCT QLQ-C30 questionnaires
Time frame: Assessed up to 1 year
Quality of life (QoL) per patient as assessed by EQ-5D questionnaires
Time frame: Assessed up to 1 year
Quality of life (QoL) per patient as assessed by PRODISQ questionnaires
Time frame: Assessed up to 1 year
Cost-effectiveness ratio (ICER) per patient
Time frame: Assessed up to 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Aug 2024.
- Individual participant dataSharing planned: No
Related trials for Colorectal Cancer
Active, not recruitingPhase 1/2
Phase I/II Study of the Anti-Programmed Death Ligand-1 Durvalumab Antibody (MEDI4736) in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Can...
Colorectal Neoplasms, Breast Neoplasms
RecruitingPhase 1
A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC)
Metastatic Colorectal Cancer
Active, not recruiting
Streamlined Geriatric and Oncological Evaluation Based On IC Technology
Breast Cancer, Comorbidities and Coexisting Conditions
RecruitingPhase 2
At-Home Cancer Directed Therapy Versus in Clinic for the Treatment of Patients With Advanced Cancer
Advanced Anal Carcinoma, Advanced Biliary Tract Carcinoma
Not yet recruitingPhase 2
SAMe in Prevention of Oxaliplatin-associated Liver Injury
Colorectal Cancer, Liver Metastases
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Martijn R. Meijerink, Prof. principal investigator
Amsterdam UMC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Irreversible electroporation and Stereotactic body radiotherapy in people with Colorectal Cancer and Liver Metastases, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 23 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Danielle J. Vos, M.D. (+3120-4444571, interventieradiologie@vumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Local control (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Aug 2024; AzTrials last refreshed its copy on 8 Nov 2026.