Please note the ANZCTR will be unattended from Friday 20 December 2019 for the holidays. The Registry will re-open on Tuesday 07 January 2020. Submissions and updates will not be processed during that time.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12617001087347
Ethics application status
Approved
Date submitted
19/07/2017
Date registered
26/07/2017
Date last updated
21/10/2019
Date data sharing statement initially provided
21/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A clinical trial comparing Simvastatin to placebo, in addition to standard chemotherapy and radiotherapy, in preoperative treatment for patients with rectal cancer.
Scientific title
A randomized, placebo-controlled phase II trial of Simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer
Secondary ID [1] 292410 0
AG0115R/CTC0138
Universal Trial Number (UTN)
Trial acronym
SPAR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rectal Cancer 303991 0
Condition category
Condition code
Cancer 303330 303330 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The statin chosen for this trial, simvastatin (SIM), is a well-known and widely available 3-hydroxy-3-methyl-glutaryl-coenzyme (HMG-CoA) reductase inhibitor commonly used in the treatment of hypercholesterolaemia and ischaemic heart disease. Simvastatin or placebo is the trial intervention.

Simvastatin will be given as a 40 mg capsule taken daily for 90 days, starting 1 week prior to first radiation dose for standard Preoperative chemoradiation (pCRT).

capsules, Simvastatin will be encapsulated in Swedish orange size DB “AA” capsules, filled with microcrystalline cellulose powder. Patients will be asked to return unused drug and empty drug containers at the Week 13 visit (6 weeks post-pCRT). The number of capsules remaining will be counted by trial research staff and recorded to confirm adherence.
Intervention code [1] 298579 0
Treatment: Drugs
Comparator / control treatment
This study is placebo controlled. Placebo capsules will be level filled with Microcrystalline Cellulose Powder.
Control group
Placebo

Outcomes
Primary outcome [1] 302721 0
To compare rates of favourable (grades 1-2) MRI-based tumour regression grading (by central review) following preoperative chemoradiation (pCRT)with Simvastatin or placebo, considering MRI-based tumour regression grading in 4 ordered categories: 1, 2, 3, 4-5.
Timepoint [1] 302721 0
Based on MRI 6–8 weeks after preoperative chemoradiation, an analysis of inter-observer agreement on mrTRG between site radiologists and a central
radiologist will be repeated on all remaining patients at the conclusion of the trial or prior to any publication of results.
Secondary outcome [1] 336812 0
To compare between the Simvastatin (SIM) and placebo groups treated with pCRT: The rate of favourable (grades 1-2) Pathological tumour regression grading (pathTRG) in resected tumours by central review.
H&E-stained slides of formalin-fixed, paraffin-embedded tissue from the tumour and regional
nodes resected after completion of pCRT will be sent for central pathology scoring of pathTRG.
Timepoint [1] 336812 0
Collected at time of surgical resection.
Secondary outcome [2] 336814 0
To compare between the SIM and placebo groups treated with pCRT: The incidence of > grade 2 acute gastrointestinal (GI) and non-GI adverse events, assessed using NCI CTCAE version 4.03 (Composite secondary outcome)
Timepoint [2] 336814 0
Adverse events are assessed at week 3, 5, 7 and 13, then during annual follow up for 3 years.
Secondary outcome [3] 336815 0
To compare between the SIM and placebo groups treated with pCRT: The incidence of late GI adverse events.
Late GI adverse events will be recorded using the IBDQ-B questionnaire and the RTOG late GI toxicity scale.
Timepoint [3] 336815 0
Adverse events are assessed at week 3, 5, 7 and 13, then during annual follow up for 3 years.
Secondary outcome [4] 336816 0
To compare between the SIM and placebo groups treated with pCRT: Compliance with intended pCRT by review of eCRF data
Timepoint [4] 336816 0
Compliance will be assessed at completion of pCRT.
Secondary outcome [5] 336817 0
To compare between the SIM and placebo groups treated with pCRT: Compliance with trial medication
Timepoint [5] 336817 0
Percent compliance will be based on the formal count of capsules returned at the 6
weeks post-pCRT visit to estimate number of capsules consumed.
Secondary outcome [6] 336818 0
To compare between the SIM and placebo groups treated with pCRT: The proportion of patients undergoing surgical resection postpCRT by review of eCRF data
Timepoint [6] 336818 0
This will be calculated once recruitment had been completed and all patients have either undergone surgery or had reasons documented why surgery was not conducted.
Secondary outcome [7] 336819 0
To compare between the SIM and placebo groups treated with pCRT: 3-year local recurrence (LR) rate, disease-free survival (DFS) and cancer-specific survival (CSS) (composite secondary outcome)
Local recurrence (LR) is defined as any evidence of recurrent rectal cancer occurring within the pelvis at any point from the date of surgical resection onwards.
Disease-free survival (DFS) is defined as the interval from date of randomisation to the date of first evidence of disease relapse or death, whichever occurs first.
Cancer-specific survival (CSS) Cause of death data will be gathered from patient records, death certificates, and national databases.
Timepoint [7] 336819 0
LR will be assessed from the date of surgical resection up to 3 years
DFS and CSS will be assessed 3 years post randomisation
Secondary outcome [8] 336820 0
To compare between the SIM and placebo groups treated with pCRT: The pathological scores determined by the central pathologist for radiation colitis in irradiated rectum in the resected specimen
Timepoint [8] 336820 0
After last patient last visit

Eligibility
Key inclusion criteria
1. Males or females with biopsy proven rectal adenocarcinoma, or high-grade dysplasia with radiological evidence of invasive tumour
2. Distal border of the tumour is below the peritoneal reflection as assessed by MRI scan
3. Age more than or equal to 18 years
4. Clinical TNM tumour staging is T2-4 N0-2 M0 after staging investigations including CT scan of chest, abdomen and pelvis and pelvic MRI scan
5. Planned for concurrent long-course pCRT using fluoropyrimidine-based chemotherapy
6. Radiologically-measureable disease on baseline pelvic MRI scan
7. Adequate bone marrow function (e.g. platelets >100 x 109/L, neutrophils >1.5 x 109/L)
8. Adequate liver function (e.g. ALT/AST <3 x ULN, bilirubin <1.5 x ULN)
9. Adequate renal function (e.g. estimated creatinine clearance >50 ml/min)
10. Trial treatment planned to start within 28 days of randomisation
11. Diagnostic biopsy of rectal tumour is available for histological substudies
12. Willing and able to comply with all trial requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments (e.g. able to have IV contrast if this is required for tumour assessments)
13. Signed, written informed consent for the main trial
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindications or hypersensitivity to statins, fluoropyrimidine chemotherapy or radiotherapy
2. Patients planned to receive oxaliplatin or biological agents (e.g. cetuximab) as part of pCRT
3. Taking statins in the 6 weeks before planned start of pCRT
4. Predicted life expectancy of less than 3 years
5. Prior pelvic or rectal radiotherapy
6. History of another malignancy within 5 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment
7. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
8. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol
9. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 8525 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [2] 11625 0
Lake Macquarie Private Hospital - Gateshead
Recruitment hospital [3] 11626 0
Bankstown-Lidcombe Hospital - Bankstown
Recruitment hospital [4] 11627 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [5] 11628 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [6] 11629 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [7] 11630 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [8] 15016 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [9] 15017 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [10] 15018 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment hospital [11] 15019 0
Mater Adult Hospital - South Brisbane
Recruitment postcode(s) [1] 16619 0
2298 - Waratah
Recruitment postcode(s) [2] 23671 0
2290 - Gateshead
Recruitment postcode(s) [3] 23672 0
2200 - Bankstown
Recruitment postcode(s) [4] 23673 0
5011 - Woodville
Recruitment postcode(s) [5] 23674 0
2444 - Port Macquarie
Recruitment postcode(s) [6] 23675 0
4029 - Herston
Recruitment postcode(s) [7] 23676 0
2050 - Camperdown
Recruitment postcode(s) [8] 28301 0
2065 - St Leonards
Recruitment postcode(s) [9] 28302 0
3550 - Bendigo
Recruitment postcode(s) [10] 28303 0
4215 - Southport
Recruitment postcode(s) [11] 28304 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 21937 0
New Zealand
State/province [1] 21937 0
Waikato
Country [2] 21938 0
New Zealand
State/province [2] 21938 0
Palmerston North
Country [3] 21939 0
New Zealand
State/province [3] 21939 0
Christchurch
Country [4] 21940 0
New Zealand
State/province [4] 21940 0
Bay of Plenty

Funding & Sponsors
Funding source category [1] 296961 0
Government body
Name [1] 296961 0
Cancer Council NSW
Address [1] 296961 0
153 Dowling St, Woolloomooloo NSW 2011
Country [1] 296961 0
Australia
Funding source category [2] 296973 0
Government body
Name [2] 296973 0
Cancer Australia
Address [2] 296973 0
Level 14,
300 Elizabeth Street
Surry Hills NSW 2000
Country [2] 296973 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The Australasian Gastro-Intestinal Trials Group (AGITG)
Address
Locked Bag 77
Camperdown
NSW 1450
Country
Australia
Secondary sponsor category [1] 295965 0
None
Name [1] 295965 0
Address [1] 295965 0
Country [1] 295965 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298166 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 298166 0
c/- Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 298166 0
Australia
Date submitted for ethics approval [1] 298166 0
10/04/2017
Approval date [1] 298166 0
04/07/2017
Ethics approval number [1] 298166 0
X17-0108 & HREC/17/RPAH/158
Ethics committee name [2] 301173 0
Northern A Health and Disability Ethics Committee
Ethics committee address [2] 301173 0
133 Molesworth St
Ministry of Health, Health & Disability Ethics Committee
Wellington
NA
New Zealand
6011
Ethics committee country [2] 301173 0
New Zealand
Date submitted for ethics approval [2] 301173 0
Approval date [2] 301173 0
25/05/2018
Ethics approval number [2] 301173 0
18/NTA/7

Summary
Brief summary
The primary purpose of this trial is to compare the effect of simvastatin with placebo on the effectiveness and side effects of pre-operative chemoradiotherapy treatment prior to rectal cancer surgery, and on the body's inflammatory response to cancer.

Who is it for?
You may be eligible to enroll in this trial if you are aged 18 or over and have been diagnosed with rectal adenocarcinoma or high grade dysplasia with radiological evidence of invasive tumour, for which pre-operative chemoradiotherapy treatment is planned.

Study details
All participants enrolled in this trial will be randomly allocated (by chance) to receive either the active simvastatin treatment in addition to their planned chemoradiotherapy treatment, or to receive an inactive placebo in addition to their planned chemoradiotherapy treatment. Participants will take the allocated treatment capsule once daily for 90 days starting one week before chemoradiotherapy. The study will last 3 years and participants will be asked to visit the clinic on nine occasions for clinical examinations and they will also have blood tests and magnetic resonance imaging (MRI) scans. Tumour tissue removed at the time of surgery will be assessed in the laboratory.

It is hoped that if the study showed a positive outcome, then it may ultimately lead to patients in the future benefiting from adding simvastatin to chemoradiotherapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76198 0
A/Prof Michael Jameson
Address 76198 0
C/o NHMRC Clinical Trials Centre
92-94 Parramatta Road
Camperdown NSW 2050
Country 76198 0
Australia
Phone 76198 0
+61-2-9562-5000
Fax 76198 0
Email 76198 0
spar@ctc.usyd.edu.au
Contact person for public queries
Name 76199 0
Ms Amy Zhong
Address 76199 0
NHMRC Clinical Trials Centre
92-94 Parramatta Road
Camperdown NSW 2050
Country 76199 0
Australia
Phone 76199 0
+61-2-9562-5000
Fax 76199 0
Email 76199 0
spar@ctc.usyd.edu.au
Contact person for scientific queries
Name 76200 0
A/Prof Michael Jameson
Address 76200 0
C/o NHMRC Clinical Trials Centre
92-94 Parramatta Road
Camperdown NSW 2050
Country 76200 0
Australia
Phone 76200 0
+61-2-9562-5000
Fax 76200 0
Email 76200 0
spar@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results