StAtins for Venous Event Reduction in Patients With Venous Thromboembolism Pilot Study

Phase 2

• Conditions: Venous Thromboembolism
• Interventions: Drug: Rosuvastatin

• Registration Number: NCT02679664
• Lead Sponsor: Ottawa Hospital Research Institute

Brief Summary

The SAVER pilot is a randomized, open-label pilot study to determine the feasibility of recruitment. In addition to feasibility data, the investigators will carefully collect clinical data to determine if rosuvastatin can reduce post-thrombotic syndrome (PTS) in venous thromboembolism (VTE) patients.

Eligible consenting patients who developed acute, symptomatic, and objectively confirmed proximal leg deep vein thrombosis (DVT) and/or PE will be randomized and equally allocated to 2 trial arms, either the treatment group (rosuvastatin tablet (20 mg/day) or the control group (usual care). The pilot trial consists of up to 4 study contacts over 6 months: screening, randomization, telephone follow-up (90 days), and final study visit (180 days).

Detailed Description

The SAVER pilot is a randomized, open-label pilot study to determine the feasibility of recruitment. In addition to feasibility data, the investigators will carefully collect clinical data to determine if rosuvastatin can reduce post-thrombotic syndrome (PTS) in venous thromboembolism (VTE) patients.

* SCREENING: Research coordinators at each pilot site will screen patients for eligibility and will complete detailed logs of all patients meeting inclusion (both enrolled and excluded). After providing informed consent, eligibility will be confirmed by the following tests : a lipid profile, A1C test/ CBC, transaminase (ALT) levels, Creatinine and pregnancy test (if a female of child bearing potential). Consenting participants who (following screening) do not meet eligibility criteria will be followed up to establish feasibility outcomes.

* RANDOMIZATION: Randomization will be conducted using an Interactive Web based Randomization System in a 1:1 ratio for treatment (20mg rosuvastatin od) or control (no study drug).

* STUDY DRUG DISPENSING: Participants randomized to the treatment arm will be dispensed x 200 20mg tablets of rosuvastatin along with a medication diary.They will be educated on study drug dosing regimen (20mg tablet od), how to complete their medication diary and on the possible side-effects of rosuvastatin. They will be advised to contact either the study coordinator, investigator or go directly to the emergency department should they experience any symptoms in particular anything muscle related.

* BASELINE. Assessments include;

* Demographic data;

* Concomitant medications (antiplatelet, anti-inflammatories, anticoagulation);

* Type of index VTE;

* PTS Villalta leg assessment conducted by both the participant (Patient Reported Villalta \[PRV\] questionnaire) and a qualified blinded independent observer (The Villalta scale is the most extensively validated tool and is recommended by the ISTH) - (Primary Outcome);

* Risk factors for recurrent VTE, bleeding and arterial vascular events;

* Medical history including prior VTE, Arterial disease, Liver disease and Glucose Intolerance.

* 90 DAY FOLLOW UP \[Treatment arm only\]: Participants randomized to treatment will be followed up via telephone or email at 90 days (+/- 21 days);

* Participants will be asked questions to screen for;

* Study outcomes: Suspected VTE, Arterial, Bleeding and/ or Muscle Events Patients who report any unexplained muscle symptoms will be asked to have their Creatine kinase (CK) levels tested within 2 weeks of reporting the symptoms. Study drug will be discontinued if CK levels are markedly elevated (\> 10 x ULN).;

* Study Drug compliance

* Adverse events.

* Concomitant medication will be reviewed in case of any contraindications. Changes or additions in concomitant anticoagulation therapy, anti-platelet or anti - inflammatory medication will also be recorded.

* Study coordinators will log all follow up contact attempts.

* FINAL STUDY VISIT (180 days (+/- 21 days): All study participants will be asked to attend an in person study visit at 180 days (+/-21) for;

* Follow-up of study outcomes; VTE, Arterial, Bleeding and Muscle events;

* Study drug compliance;

* Relevant (S)AE(s).

* Repeat PTS leg assessment (using the Villalta scale) both by a qualified independent observer and the participant (Primary outcome);

* Study drug compliance: Medication Diaries and used medication bottles will be collected by the study coordinator. Coordinator will perform a pill count and reconcile with the participants medication diary. Coordinator will also ask participant reasons for any missed doses.

ADJUDICATION OF STUDY OUTCOMES: All Bleeding, VTE and Arterial Suspected Events as well as deaths will be recorded on a suspected event CRF along with any diagnostic imaging/ tests and will trigger a more in-depth evaluation, and review by an independent adjudication committee.

ADVERSE EVENTS: AEs will be elicited, monitored and recorded throughout the study.

All events meeting the definition of an SAE (as per ICH-GCP) must be reported to the SAVER Trial Office in Ottawa, Canada within 24 h of awareness.

Study Timeline

• Study First Submitted: 2016-02-01
• Study First Submitted QC: 2016-02-05
• Study First Posted: 2016-02-10
• Study Start: 2016-11
• Primary Completion: 2020-01-13
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-25
• Last Update Posted: 2020-02-27
• Study Completion: 2020-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 312

Inclusion Criteria

1. Symptomatic objectively confirmed proximal leg DVT (above the trifurcation of the popliteal vein) and/or PE (segmental or greater) diagnosed in the last 30 days.

Exclusion Criteria

1. Unable or unwilling to provide written informed consent

2. ≤ 18 years of age

3. Currently prescribed a statin

4. A medical history or current diagnosis of any of the following:

   • Abdominal aortic aneurysm,
   • Peripheral arterial disease,
   • Stroke,
   • Transient ischemic attack (TIA),
   • Myocardial infarction (MI),
   • Acute coronary syndromes,
   • Stable angina,
   • Coronary or other arterial revascularization

5. LDL-C >4.91 mmol/L

6. LDL-C between 1.81mmol/L to 4.9mmol/L AND 10 ASCVD risk score >10%

7. Diabetes mellitus or pre-diabetes

8. Contraindication to rosuvastatin;

   • Hypersensitivity or intolerance to statins;
   • History of muscle disorders or statin-related muscle pain;
   • Liver disease (active liver disease or unexplained elevations of serum transaminases exceeding 3 times the upper limit of normal);
   • Chronic kidney disease (Creatinine clearance < 30ml/min)
   • Currently pregnant or breast feeding;
   • Taking cyclosporine.

9. Life expectancy less than 3 months, as judged by the investigator

10. Unstable medical or psychological condition that would interfere with trial participation.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment group	Rosuvastatin	20 mg tablet of rosuvastatin PO once-a-day starting at the time of randomization until the completion of follow-up at 6 months.

Primary Outcome Measures

Name	Time	Method
Number of participants recruited per center per month - [Study Feasibility]	3 years	Study feasibility as indicated by the number of participants recruited per center per month.
Incidence of PTS	180 days (+/- 21 days)	Incidence of post thrombotic syndrome (PTS), as measured by the Villalta scale at 6 months by both an 'Blinded Independent Assessor' and self reported by the participant.

Secondary Outcome Measures

Name	Time	Method
Non-major VTE	180 days (+/- 21 days)	1. Distal DVT(distal to the trifurcation of the popliteal vein); 2. Isolated sub-segmental PE; 3. Superficial phlebitis \> 5 cm; 4. Superficial phlebitis ≤ 5 cm
Muscle Toxicity	180 days (+/- 21 days)	Participants reporting symptoms of muscle toxicity will have their CK levels tested for safety. Study drug will be discontinued if CK levels are markedly elevated (\>10 x ULN)
Symptomatic recurrent major VTE	180 days (+/- 21 days)	Symptomatic recurrent major VTE (proximal DVT or segmental or larger PE) in patients taking generic rosuvastatin (full trial primary outcome). Coordinators will submit a report to the independent adjudication committee for participants that undergo investigation for suspected recurrent VTE during the study.
Components of major VTE	180 days (+/- 21 days)	1. Proximal DVT; 2. Segmental or greater PE
Arterial Vascular Events	180 days (+/- 21 days)	At the 3-month call and 6-month visit the research coordinator will follow an interview script to screen for inter-current suspected arterial events. Any reported potential arterial events will trigger a more in-depth evaluation.; 1. Fatal myocardial infarction; 2. Non-fatal myocardial infarction; 3. Hospitalization for unstable angina; 4. Coronary artery revascularization; 5. Sudden cardiac death; 6. Ischemic stroke
All-cause mortality	180 days (+/- 21 days)	All-cause mortality
Bleeding	180 days (+/- 21 days)	At each follow-up visit the research coordinator will follow an interview script to screen for suspected major and clinically relevant non-major bleeding events. Suspected bleeding that lasts more than 10 minutes, required intervention to control or for which the patient sought medical attention will be adjudicated by an independent committee using ISTH bleeding criteria.

Trial Locations

Locations (6)

Østfold Hospital Trust; 🇳🇴 Grålum, Norway

Hamilton Health Sciences Corporation; 🇨🇦 Hamilton, Ontario, Canada

Nova Scotia Health Authority; 🇨🇦 Halifax, Nova Scotia, Canada

Ottawa Hospital; 🇨🇦 Ottawa, Ontario, Canada

Lawson Health Research Institute, London Health Sciences Centre; 🇨🇦 London, Ontario, Canada

Sir Mortimer B. Davis Jewish General Hospital; 🇨🇦 Montreal, Quebec, Canada