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Trial registered on ANZCTR


Registration number
ACTRN12614000133639
Ethics application status
Approved
Date submitted
29/01/2014
Date registered
5/02/2014
Date last updated
5/02/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
The STRICT pilot study - Simvastatin Therapy for Reducing Inflammation in Colorectal cancer Trial
Scientific title
In metastatic colorectal cancer patients with systemic inflammation, is daily simvastatin feasible and safe to add to standard chemotherapy?
Secondary ID [1] 283994 0
Nil
Universal Trial Number (UTN)
Trial acronym
The STRICT pilot study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal cancer 290395 0
Systemic Inflammation 291066 0
Condition category
Condition code
Cancer 290785 290785 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Inflammatory and Immune System 291410 291410 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive standard first line chemotherapy, as chosen by their treating medical oncologist. In addition, participants will be asked to take a daily 40mg dose of simvastatin orally in the evening from the first day of chemotherapy until tumour progression or patient is withdrawn from treatment due to clinician or patient decision.

Adherence to medication will be conducted using patient diaries, completion of a monthly Medication Adherence Record Scale-5 questionnaire, and pharmacy records.
Intervention code [1] 288189 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 290780 0
Toxicity: Incidence of serious Grade 3 or 4 toxicity graded according to NCI CTCAE version 4.03
Timepoint [1] 290780 0
until tumour progression (anticipated to be <12 months)
Secondary outcome [1] 305278 0
Feasibility
- recruitment rates will be assessed using screening/enrollment logs collected at each recruitment site
- study drug adherence will be assessed using patient diaries, monthly Medicines Adherence Report Scale and pharmacy records.
Timepoint [1] 305278 0
6 months
Secondary outcome [2] 306610 0
Changes in inflammatory biomarkers
- IL-6 and IL-8 will be assessed by plasma ELISA assays
- WBC and differential will be assessed by full blood count
- Myeloid derived suppressor cell phenotype will be assessed by whole blood flow cytometry assays
- inflammatory plasma protein will be assessed by mass spectroscopy and western blot assays.
Timepoint [2] 306610 0
12 weeks
Secondary outcome [3] 306611 0
Quality of Life will be assessed by EuroQoL 5D and EORTC QolC30 questionnaires
Timepoint [3] 306611 0
12 weeks

Eligibility
Key inclusion criteria
Patients must fulfill ALL of the following criteria to be eligible for admission to the study:

* Radiological or pathologically confirmed metastatic colorectal cancer

* Measurable or evaluable disease

* Eligible for XELOX, mFOLFOX6, or FOLFIRI plus bevacizumab in accordance with local standards of care and pharmaceutical benefits scheme approvals

* Evidence of systemic inflammation - NLR > or = 5

* WHO performance status of 0, 1 or 2

* Adequately recovered from recent surgery. At least 4 weeks must have elapsed from major surgery.

* Life expectancy of > 3 months

* Hematology performed within 28 days of starting study treatment and with values within the ranges specified below
- Absolute granulocytes/neutrophils > 1.5 x 109 /L
- Platelets > 100 x 109/L
- Hemoglobin > 80g/L

* Biochemistry performed within 28 days of starting study treatment and with values within the ranges specified below
- Total bilirubin < 1.5 x institutional upper limit of normal (< 2.0 x with documented liver metastases)
- ALT < 2.5 x institutional upper limit of normal (< 5.0 x with documented liver metastases)
- AST < 2.5 x institutional upper limit of normal (< 5.0 x with documented liver metastases)
- Serum creatinine < 1.5 x institutional upper limit of normal or Creatinine Clearance > 50ml/min
- Magnesium > 0.5mM (1.2 mg/dL)
- Creatine phosphokinase < 2.5 x institutional upper limit of normal

* Patient must consent to provision of access to a representative formalin fixed paraffin block of tumour tissue for future research studies to be conducted. Where no previously resected or biopsied tumour tissue exists the patient may still be eligible for the study.

* Patient must consent to provision of blood samples.

* Age over 18 years

* Patient consent for trial participation must be obtained according to local Institutional Human Research Ethics Committee (HREC) requirements.

* Patients must be accessible for treatment and follow-up.

* The patient is not receiving therapy in a concurrent clinical study that involves systemic therapy or radiotherapy. The patient may enroll in biomarker studies and psychosocial studies.

* Patient agrees not to seek statin therapy during and/or after the completion of the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who fulfill any of the following criteria are not eligible for admission to the study:

* Prior chemotherapy for metastatic colorectal cancer or adjuvant chemotherapy completed in the last 6 months

* Radiotherapy within 28 days prior to enrolment or not recovered from a radiotherapy course

* A history of other malignancies with the exception of: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence for > 3 years.

* Evidence of bleeding diathesis or significant coagulopathy (in absence of therapeutic anticoagulation). History of a significant bleeding event or felt by the investigator to be at risk of such events.

* Significant vascular disease (e.g. aortic aneurysm requiring surgical intervention).

* Peripheral arterial thrombosis or other arterial thrombotic events within 6 months
prior to commencement of study treatment.

* Inadequately controlled hypertension (defined as values consistently 150/100 mmHg despite use of at least three standard antihypertensive medications).

* Prior history of hypertensive crisis or hypertensive encephalopathy.

* Clinically significant (i.e. active) cardiovascular disease (e.g. NYHA Class II or greater congestive heart failure).

* Pregnant or lactating females (a serum pregnancy test to be assessed within 7 days prior to study treatment, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment).

* Women of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) not using appropriate method of contraception and not willing to use an effective method of contraception during the study and for 6 months after the last dose of study medication. Oral or injectable contraceptive agents cannot be the sole method of contraception.

* Male patients must be surgically sterile or agree to use a barrier method of contraception.

* Any condition (e.g. psychological, geographical etc) that does not permit compliance with the protocol.

* Presence of active inflammatory bowel disease, infection or rheumatological condition.

* Previous history or current evidence of rhabdomyolsis or myopathy.

* Receipt of the investigational drug, simvastatin, or member of the statin class of drugs within the last 28 days

* Receipt of regular dosing of NSAIDs for a period of 2 weeks or more (excluding 8mg dexamethasone used for preventing hypersensitivity reactions) or corticosteroids (dose > 10 mg/day methylprednisolone equivalent).

* History of allergy to simvastatin or other statin drugs.

* Currently taking contraindicated medications of simvastatin (CYP3A4 or OATP1B1 inhibitors). Simvastatin is a CYP3A4 and OATP1B1 substrate that has demonstrated clinically relevant drug interactions with other known CYP3A4 and OATP1B1 substrates, inhibitors and inducers. Warfarin is a weak substrate for CYP3A4 and use of warfarin as anticoagulant should be undertaken only with caution and close monitoring of INR and consideration should be given to switching the patient to low molecular weight heparin for the duration of the study.

* Patients who are not able to swallow tablets.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The study population are untreated metastatic CRC patients with elevated NLR > or = 5. Patients will be included if they have radiologically or pathologically confirmed, metastatic CRC and meet the eligibility criteria of the study . A full blood count will be requested at the screening stage to determine whether patients have the required elevated systemic inflammation marker (NLR > or =5). If eligible for the study, the patient will be invited to participate in the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All endpoints are exploratory in nature and will not be corrected for multiple statistical testing, which will be noted in all publications.

* Recruitment rates for full study cohort and at each centre will be reported descriptively.

* Patient study drug adherence will be reported descriptively. Correlations between the 3 methods for drug adherence will be investigated using Spearman rank correlation statistics.

* Changes in NLR, CRP inflammatory cytokines, cells and proteins and lipid concentrations over the 12 weeks will be analysed using repeated measures ANOVA.

* Toxicities will be graded using the NCI CTCAE version 4.03 . The incidence of toxicities will be summarized by type of adverse event and severity in frequency tables. No formal statistical analysis will be conducted.

* Quality of life assessments on the EORTC QOLC30 and EQ-5D-3L will be used to derive pre-specified QoL scores according to the QoL manuals. Quality of life assessments and changes from baseline will be descriptively summarized by study visit.

All statistical tests will be conducted using SPSS Version 20 (IBM) and using two-tailed significance level of 0.05.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2014
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 1629 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 1631 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 1632 0
North Shore Private Hospital - St Leonards
Recruitment hospital [4] 1633 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [5] 2009 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 7516 0
2139 - Concord Repatriation Hospital
Recruitment postcode(s) [2] 7517 0
2050 - Camperdown
Recruitment postcode(s) [3] 7518 0
2065 - Royal North Shore Hospital
Recruitment postcode(s) [4] 7519 0
2065 - St Leonards
Recruitment postcode(s) [5] 7520 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 288183 0
Government body
Name [1] 288183 0
Northern Translational Cancer Research Unit Seed
Funding
Country [1] 288183 0
Australia
Funding source category [2] 288184 0
University
Name [2] 288184 0
Bosch Institute (University of Sydney) Translational Grant in Aid
Country [2] 288184 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
University of Sydney, NSW 2006
Country
Australia
Secondary sponsor category [1] 287330 0
None
Name [1] 287330 0
Address [1] 287330 0
Country [1] 287330 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290479 0
Sydney Local Area Health Distict HREC - CRGH
Ethics committee address [1] 290479 0
Concord Repatriation General Hospital
Hospital Road
Concord, NSW 2139
Ethics committee country [1] 290479 0
Australia
Date submitted for ethics approval [1] 290479 0
23/09/2013
Approval date [1] 290479 0
31/10/2013
Ethics approval number [1] 290479 0
HREC/13/CRGH/214
Ethics committee name [2] 290481 0
North Shore Private Hospital HREC
Ethics committee address [2] 290481 0
North Shore Private Hospital
3 Westbourne Street
St Leonards, NSW 2065
Ethics committee country [2] 290481 0
Australia
Date submitted for ethics approval [2] 290481 0
05/11/2013
Approval date [2] 290481 0
28/11/2013
Ethics approval number [2] 290481 0
NSPHEC 2013-009

Summary
Brief summary
The aim of this study is to assess the safety and feasibility of adding simvastatin to standard first-line chemotherapy regimens in untreated, metastatic colorectal cancer (CRC) patients with elevated inflammatory biomarkers.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with metastatic colorectal cancer with evidence of systemic inflammation. You must also be eligible for standard first-line chemotherapy regimens in accordance with local standards of care and pharmaceutical benefits scheme approvals.

Study details
All participants in this study will receive standard first line therapy, as chosen by their treating medical oncologist. In addition, participants will be asked to take a daily 40mg dose of simvastatin orally in the evening from the first day of chemotherapy until tumour progression or patient is withdrawn from treatment due to clinician or patient decision.

Participants will be monitored for treatment toxicity and inflammation, and will also be asked to complete a questionnaire at 6 months to evaluate quality of life. The feasibility of the trial methods will also be evaluated in order to determine whether they could be used in a larger randomised clinical trial (RCT).
Trial website
Trial related presentations / publications
KA Charles, SJ Clarke, M Michael, L Horvath, D Goldstein, C Diakos, P Blinman, AJ McLachlan, M Molloy, DC McMillan (2013). The STRICT (Simvastatin Therapy for Reducing Inflammation in Colorectal cancer Trial) Study: A Phase II randomized, placebo-controlled clinical trial in metastatic colorectal cancer patients with elevated markers of inflammation. New Concepts Symposium at the Australasian Gastro-Intestinal Trial Groups Annual Scientific Meeting (Melbourne, Nov 2013).
Public notes

Contacts
Principal investigator
Name 43938 0
Dr Kellie Charles
Address 43938 0
Cancer Pharmacology Laboratory School of Medical Sciences (Pharmacology) Room 306, Blackburn Building DO6 University of Sydney NSW 2006
Country 43938 0
Australia
Phone 43938 0
+61 2 9036 5239
Fax 43938 0
Email 43938 0
[email protected]
Contact person for public queries
Name 43939 0
Dr Kellie Charles
Address 43939 0
Cancer Pharmacology Laboratory School of Medical Sciences (Pharmacology) Room 306, Blackburn Building DO6 University of Sydney NSW 2006
Country 43939 0
Australia
Phone 43939 0
+61 2 9036 5239
Fax 43939 0
Email 43939 0
[email protected]
Contact person for scientific queries
Name 43940 0
Dr Kellie Charles
Address 43940 0
Cancer Pharmacology Laboratory School of Medical Sciences (Pharmacology) Room 306, Blackburn Building DO6 University of Sydney NSW 2006
Country 43940 0
Australia
Phone 43940 0
+61 2 9036 5239
Fax 43940 0
Email 43940 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
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