Does adding progesterone to dexamethasone in patients with brain swelling caused by cancer allow the use of lower doses of dexamethasone in the future?
| ISRCTN | ISRCTN16167828 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16167828 |
| EudraCT/CTIS number | 2021-003171-34 |
| IRAS number | 1004104 |
| Secondary identifying numbers | CPMS 51758, IRAS 1004104 |
- Submission date
- 21/02/2022
- Registration date
- 24/02/2022
- Last edited
- 20/08/2024
- Recruitment status
- Stopped
- Overall study status
- Stopped
- Condition category
- Cancer
Plain English summary of protocol
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-of-progesterone-for-cancer-spread-to-the-brain-prossper
Background and study aims
Corticosteroids, and in particular dexamethasone, remain central to the management of patients with brain tumours, despite their frequent and often serious side effects. Furthermore, there is increasing evidence that patients who remain on corticosteroids fare worse than those in whom steroids can be withdrawn and not simply because they have worse disease; possible explanations include a radio-protective effect and impaired immune response. The need for an alternative to corticosteroids has become increasingly recognised, but to date no such alternative has been identified. Progesterone is also a steroid, with neuroprotective and anti-inflammatory properties in pre-clinical models, but fewer side effects in patients. Progesterone warrants investigation as an alternative to corticosteroids for patients with brain tumour induced oedema. Unfortunately, pre-clinical models of brain tumours do not replicate the oedema (build-up of fluid) seen in patients, so laboratory studies are of limited value. In addition, the dose of progesterone to achieve optimal drug exposure is unclear. This trial in patients with brain tumours and oedema will investigate the pharmacokinetics (what the body does to the drug) of differing doses of oral progesterone. The researchers also hope to obtain preliminary evidence as to whether the addition of progesterone allows a greater reduction in the dose of dexamethasone for these patients. If successful, this trial will underpin a definitive trial studying the effectiveness of progesterone in patients with primary and metastatic brain tumours with oedema.
Who can participate?
Patients aged 18 years and over with secondary brain cancers with oedema
What does the study involve?
Stage 1: Participants will receive a single oral dose of 200 mg micronised progesterone on Day 1 and a second single 600 mg dose 5 -21 days later. Blood samples will be collected to measure drug levels after each dose of progesterone. Participants will also receive dexamethasone dose on Day 1 but this will be reduced as clinically indicated on other days.
Stage 2: Participants will receive oral micronised progesterone or placebo three times a day and a dose of dexamethasone. The progesterone or placebo will only be taken daily for 14 days. The daily dexamethasone dose will be the same on both sampling days, but can be adjusted as clinically indicated between the sampling days. The treating clinician will advise the dose to take each day. Blood samples will be collected to measure drug and hormone levels; participants will also be asked to complete questionnaires and an interview.
What are the possible benefits and risks of participating?
Benefits: Hopefully this study drug will help reduce the swelling in the brain caused by the brain tumour and will have few, or minor, side effects. It is also hoped that this may be a better treatment than the current medication that is routinely given to patients. It is hoped that this research will teach us more about this type of cancer and how it can be treated. This may enable us to improve the standard of treatment to help other patients with cancer in the future.
Risks:
Stage 1: Participants may be required to attend the clinic more often than people who are not in the study. This is because the research staff may want to see them more often to check on progress.
On two occasions participants will be asked to provide blood samples and given the option of staying overnight at the hospital for these blood samples to be collected. The researchers would expect most patients to be vaccinated against COVID-19 and all precautions will be in keeping with guidance at the time for hospital attendances.
Stage 2: Participants may be required to attend the clinic more often than people who are not in the study. This is because the research staff may want to see them more often to check on progress.
On up to four occasions participants will be asked to provide blood samples and given the option of staying overnight at the hospital for these blood samples to be collected. The researchers would expect most patients to be vaccinated against COVID-19 and all precautions will be in keeping with guidance at the time for hospital attendances. Before they start the trial, and on day 14, participants will have either a CT or an MRI scan of the brain. If participants have CT scans, this uses ionising radiation (x-rays). Ionising radiation may cause cancer many years or decades after the exposure but the chance of this happening is extremely small. If participants have the MRI scan, this can be noisy and claustrophobic. The MRI scan may require the injection of a contrast agent into a vein to allow the cancer to be better seen. This may cause side effects in a small minority of participants.
Where is the study run from?
Scottish Clinical Trials Research Unit (UK)
When is the study starting and how long is it expected to run for?
August 2019 to October 2025
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
PROSSPER trial manager, phs.prossper@phs.scot
Contact information
Public
SCTRU
1st Floor, Gyle Square
1 South Gyle Crescent
Edinburgh
EH12 9EB
United Kingdom
| Phone | +44 (0)131 275 7058 |
|---|---|
| phs.prossper@phs.scot |
Scientific
St James’ University Hospital
Bexley Wing, Level 4
Beckett Street
Leeds
LS9 7TF
United Kingdom
| Phone | +44 (0)113 206 8186 |
|---|---|
| C.J.Twelves@leeds.ac.uk |
Study information
| Study design | Interventional; Design type: Treatment, Drug, Randomized |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | PROgesterone as a Steroid SParing agent against oEdema occurring with secondary bRain cancers (PROSSPER) |
| Study acronym | PROSSPER |
| Study objectives | To establish the optimal dose of oral progesterone to give and to determine if such a dose is safe and well-tolerated by patients. |
| Ethics approval(s) |
Approved 16/12/2021, East of England - Cambridgeshire and Hertfordshire Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, United Kingdom; +44 (0)207 104 8096, +44 (0)207 104 8102, +44 (0)207 104 8265; cambsandherts.rec@hra.nhs.uk), ref: 21/EE/0262 |
| Health condition(s) or problem(s) studied | Oedema occurring with secondary brain cancers |
| Intervention | Current interventions as of 27/02/2024: Stage 1: Participants will receive a single oral dose of micronised progesterone 200 mg on Day 1 and a second single 600 mg dose 5 -21 days later. Blood samples will be collected to measure drug levels after each dose of progesterone. Participants will also receive dexamethasone as non IMP. The daily dexamethasone dose will be the same on both sampling days, but can be adjusted as clinically indicated between the sampling days. Stage 2: Participants will receive oral micronised progesterone/placebo three times a day (t.d.s.) and an 8 mg/day starting dose of dexamethasone. The progesterone or placebo will only be taken daily for 14 days. The dose of dexamethasone will be reduced over 14 days where possible. The treating clinician will advise the dose to take each day. Blood samples will be collected to measure drug and hormone levels; participants will also be asked to complete questionnaires and an interview. Previous interventions: Stage 1: Participants will receive a single oral dose of micronised progesterone 200 mg on Day 1 and a second single 600 mg dose 5 -10 days later. Blood samples will be collected to measure drug levels after each dose of progesterone. Participants will also receive an 8 mg dexamethasone dose on Day 1 but this will be reduced as clinically indicated on other days. Stage 2: Participants will receive oral micronised progesterone/placebo three times a day (t.d.s.) and an 8 mg/day starting dose of dexamethasone. The progesterone or placebo will only be taken daily for 14 days. The dose of dexamethasone will be reduced over 14 days where possible. The treating clinician will advise the dose to take each day. Blood samples will be collected to measure drug and hormone levels; participants will also be asked to complete questionnaires and an interview. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Progesterone |
| Primary outcome measure | Current primary outcome measure as of 27/02/2024: Stage 1: >4 of 6 patients achieve a serum progesterone exposure (area under the concentration/time curve) of 50 – 150% of the target exposure. This will be measured in each patient on two occasions (day 1 and another day between days 5-21) using liquid chromatography-triple quadrupole mass spectrometry (LC/MS/MS) to estimate drug concentrations in eight timed blood samples. Stage 2: 1. >13 of 18 patients able to tolerate micronised progesterone until the end of the 14-day treatment period at a dose predicted to achieve the target progesterone exposure. This will be measured in each patient on days 1, 8 and 14 using liquid chromatography-triple quadrupole mass spectrometry (LC/MS/MS) to estimate drug concentrations, each at a single timepoint (Ctrough). 2. Trough progesterone concentrations within 50 – 150% of target. This will be measured in each patient on days 1, 8 and 14 using liquid chromatography-triple quadrupole mass spectrometry (LC/MS/MS) to estimate drug concentrations, each at a single timepoint (Ctrough) Previous primary outcome measure: Stage 1: >4 of 6 patients achieve a serum progesterone exposure (area under the concentration/time curve) of 50 – 150% of the target exposure. This will be measured in each patient on two occasions (day 1 and another day between days 5-10) using liquid chromatography-triple quadrupole mass spectrometry (LC/MS/MS) to estimate drug concentrations in eight timed blood samples. Stage 2: 1. >13 of 18 patients able to tolerate micronised progesterone until the end of the 14-day treatment period at a dose predicted to achieve the target progesterone exposure. This will be measured in each patient on days 1, 8 and 14 using liquid chromatography-triple quadrupole mass spectrometry (LC/MS/MS) to estimate drug concentrations, each at a single timepoint (Ctrough). 2. Trough progesterone concentrations within 50 – 150% of target. This will be measured in each patient on days 1, 8 and 14 using liquid chromatography-triple quadrupole mass spectrometry (LC/MS/MS) to estimate drug concentrations, each at a single timepoint (Ctrough) |
| Secondary outcome measures | Secondary outcome measures: 1. Compliance with the structured dexamethasone dose reduction guidelines at 75% of decision points in at least 13 of 18 patients in line with protocol guidelines and as clinically appropriate. This will be measured by comparing the actual timing of dexamethasone dose reduction to that planned in the protocol at the specified timepoints after each patient has completed stage 2 (22 days duration) 2. Description of dexamethasone-related symptoms and quality of life measured by completion of a patient diary (days 1-22) and the quality of life (QoL) questionnaires DSQ-C, EORTC QLQ-C30 and EORTC BN20 (day 1 and day 14) 3. Percentage of patients achieving a >50% reduction in dexamethasone dose taken on Day 14 , measured by comparing dexamethasone dose at Day 1 and Day 14 in the two patient groups (progesterone and placebo) 4. Comparison of final dexamethasone dose on Day 14 measured by comparing dexamethasone dose at Day 1 and Day 14 in the two patient groups (progesterone and placebo) Tertiary outcome measures: 1. Confirmation that patients on micronised progesterone have no additional clinically significant changes in their endocrine, liver function or lipid profile. This will be measured by comparison of laboratory data on Days 1, 8, 14 and 22 2. Description of changes on CT/MRI in patients on micronised progesterone compared to those on placebo. CT/MRI will be conducted at screening and Day 14 3. Acceptability/feasibility of PROMs and future trial design, including randomisation, established through patient interviews. This will be measured after each patient has completed stage 2 (22 days duration) |
| Overall study start date | 22/08/2019 |
| Completion date | 01/10/2025 |
| Reason abandoned (if study stopped) | Participant recruitment issue |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 42; UK Sample Size: 42 |
| Total final enrolment | 6 |
| Key inclusion criteria | Current participant inclusion criteria as of 27/02/2024: 1. Patients ≥18 years old 2. Capable of giving informed consent 3. ECOG performance status 0, 1 or 2 4. Diagnosis of cerebral metastases 5. Receiving dexamethasone for control of brain tumour symptoms 6. Ability to swallow oral medication Previous participant inclusion criteria: 1. Patients ≥18 years old 2. Capable of giving informed consent 3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 4. Clinical and/or radiological diagnosis of cerebral metastases with peri-tumoural oedema on CT/MRI in the last 14 days 5. Responding symptomatically to dexamethasone for control of brain tumour symptoms at a dose of >8 mg for >48 hours 6. Ability to swallow oral medication |
| Key exclusion criteria | Current participant exclusion criteria as of 27/02/2024: 1. Patients who are unable or unwilling to give informed consent 2. History of unexplained vaginal bleeding 3. Concurrent meningioma 4. On HRT medication 5. History of cholestasis in the last 6 months 6. History of allergy to either progesterone or other ingredients of the trial drug including peanut allergy 7. Pregnant or lactating (all female patients of childbearing age will undergo pregnancy testing enrolment (Stage 1)/ randomisation (Stage 2) 8. Clinically significant co-morbidities that in the opinion of the investigator would preclude study participation 9. * Planned surgery, chemotherapy, or radiotherapy within the study treatment period *Stage 2 only. In Stage 1 there is no tumour assessment so the second micronized progesterone dose (with dexamethasone and pharmacokinetic sampling) can be after any local treatment provided the interval between trial dosing days is no more than 21 days 10. Patients participating in Stage 1 will not be eligible for Stage 2 Previous participant exclusion criteria: 1. Patients who are unable or unwilling to give informed consent 2. History of unexplained vaginal bleeding 3. Concurrent meningioma 4. On HRT medication 5. History of venous thromboembolic disease, myocardial infarction or stroke in last 12 months 6. History of cholestasis in the last 6 months 7. History of allergy to either progesterone or other ingredients of the trial drug including peanut allergy. 8. Pregnant or lactating (all female patients of childbearing age will undergo pregnancy testing prior to randomisation) 9. Clinically significant co-morbidities that in the opinion of the investigator would preclude study participation 10. Planned surgery, chemotherapy or radiotherapy within the 14-day study treatment period 11. Patients participating in Stage 1 will not be eligible for Stage 2 |
| Date of first enrolment | 20/10/2022 |
| Date of final enrolment | 01/07/2025 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Leeds
LS9 7TF
United Kingdom
Liverpool
L7 8YA
United Kingdom
Sponsor information
Government
PHS 1 South Gyle Crescent
Edinburgh
EH12 9EB
Scotland
United Kingdom
| Phone | +44 (0)131 275 7058 |
|---|---|
| phs.prossper@phs.scot | |
| Website | https://www.publichealthscotland.scot/ |
"ROR" |
https://ror.org/023wh8b50 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 15/10/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
20/08/2024: The following changes were made to the trial record:
1. The total final enrolment was added.
2. The study was stopped on 31/07/2024 due to several issues:
• We anticipated recruitment being more challenging than other trials as the patient population comes from different disease sites and is a group of underrepresented patients who are frequently excluded from clinical trials.
• Recruitment to the original Stage 1 protocol was initially delayed by six months due to issues with import of study drug that were out with the control of the research team and study sponsor.
• Once open, recruitment was then slow primarily due to the vast majority of patients with brain metastases and taking dexamethasone not being eligible to the original entry criteria. Since we were keen for the patients recruited to Stage 1 to be representative of patients that would be recruited to Stage 2, we had initially applied the same eligibility criteria, however, on reflection we realised that since Stage 1 is purely a pharmacokinetics (PK) study we could have collected the PK information perfectly reasonably on those patients that were excluded on the basis of Stage 2 criteria.
• Substantial amendment to widen eligibility criteria was submitted on 31 May 2023 then, following significant delays at MHRA for review and confirmation of approval, the new version of protocol was implemented at site on 23 August 2024.
• Despite more eligible patients being identified following implementation of the amendment the patient uptake was then negatively impacted by doctors strikes and the significant disruptions to oncology clinics. Once normal clinical services were resumed an immediate improvement in recruitment was observed and a further five patients were recruited to the study within the six week period between 26 October and 06 December 2023 when we were obliged to halt recruitment to Stage 1 due to the planned closure of Public Health Scotland (PHS) CTU and withdrawal of sponsor responsibilities.
• While five patients were enrolled within the narrow recruitment window only four of these patients were fit and well enough to provide the paired sets of PK samples required to complete Stage 1 while one patient provided a single set of samples.
• A redesigned Stage 2 protocol was submitted to NIHR in February 2024 for approval in principle for a costed extension including a change in sponsor to Glasgow and delivery with the Glasgow Oncology CTU. NIHR rejected this proposal in March 2024 stating that their decision was primarily based on the extent of changes to the study design, despite initial discussions with NIHR having suggested this was a viable approach, and the associated increase in cost. NIHR requested that the study be closed down.
• A request was then submitted for NIHR agreement to submit a different, abbreviated proposal for a no-cost extension to submit a protocol amendment to change sponsor to University of Leeds to recruit the remaining evaluable patients required to complete Stage 1. NIHR agreed to submission of options appraisal for consideration, which was submitted to NIHR in April2024, however, NIHR rejected this proposal and requested that the study be closed down.
• Chief Investigators (CIs) requested a meeting at that time to discuss this decision directly with NIHR EME Programme Director (PD); it was not, however, feasible for NIHR to host the meeting until 10 July 2024. The CIs delivered a presentation to EME PD and Consultant Advisor who confirmed that they were supportive in that they recognised the clinical need for the research question, and the value in completing Stage 1, but raised concerns related to potential delays for a Deed of Novation to change study sponsor and stated they required to discuss further internally.
• Final confirmation was then received from EME PD on 16 July 2024 that due to a number of ongoing concerns, the final decision was for the NIHR/ PHS contract for PROSSPER to terminate on the current planned date of 31 July 2024.
27/02/2024: The following changes were made and the plain English summary was updated to reflect those changes:
1. The interventions were changed.
2. The primary outcome measures were changed.
3. The participant inclusion criteria were changed.
4. The participant exclusion criteria were changed.
5. The recruitment end date was changed from 01/07/2024 to 01/07/2025.
04/01/2024: The overall end date was changed from 31/07/2024 to 01/10/2025.
14/02/2023: Cancer Research UK plain English summary link added to plain English summary field.
08/11/2022: The recruitment start date was changed from 01/11/2022 to 20/10/2022.
17/10/2022: The following changes have been made:
1. The recruitment start date has been changed from 30/10/2022 to 01/11/2022.
2. One of the public contacts has been removed.
14/09/2022: The recruitment start date was changed from 30/09/2022 to 30/10/2022.
10/08/2022: One of the public contacts has been updated.
09/08/2022: The recruitment start date has been changed from 15/09/2022 to 30/09/2022.
04/08/2022: The recruitment start date has been changed from 15/08/2022 to 15/09/2022.
12/07/2022: The recruitment start date was changed from 15/07/2022 to 15/08/2022.
15/06/2022: The recruitment start date was changed from 01/06/2022 to 15/07/2022.
21/02/2022: Trial's existence confirmed by the NIHR.
