Clinical trial NCT02679664: StAtins for Venous Event Reduction in Patients With Venous Thromboembolism Pilot Study
Official title: StAtins for Venous Event Reduction in Patients With Venous Thromboembolism: A Pilot Study Assessing Feasibility of an RCT to Evaluate if Generic Rosuvastatin Reduces the Risk of Recurrent VTE in Patients With Symptomatic Major VTE.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Venous Thromboembolism
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
First posted: 2016-02-10
Enrollment: 312
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of participants recruited per center per month - [Study Feasibility]
timeFrame: 3 years
measure: Incidence of PTS
timeFrame: 180 days (+/- 21 days)
Secondary outcomes:
measure: Symptomatic recurrent major VTE
timeFrame: 180 days (+/- 21 days)
measure: Components of major VTE
timeFrame: 180 days (+/- 21 days)
measure: Non-major VTE
timeFrame: 180 days (+/- 21 days)
measure: Arterial Vascular Events
timeFrame: 180 days (+/- 21 days)
measure: All-cause mortality
timeFrame: 180 days (+/- 21 days)
measure: Bleeding
timeFrame: 180 days (+/- 21 days)
measure: Muscle Toxicity
timeFrame: 180 days (+/- 21 days)
Other outcomes:
Locations:
city: Halifax
country: Canada
facility: Nova Scotia Health Authority
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Corporation
state: Ontario
city: London
country: Canada
facility: Lawson Health Research Institute, London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Montreal
country: Canada
facility: Sir Mortimer B. Davis Jewish General Hospital
state: Quebec
city: Grålum
country: Norway
facility: Østfold Hospital Trust
Study officials:
affiliation: Ottawa Hospital Research Institute
name: Marc Rodger, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Delluc A, Ghanima W, Kovacs MJ, Shivakumar S, Kahn SR, Sandset PM, Kearon C, Mallick R, Rodger MA. Prevention of post-thrombotic syndrome with rosuvastatin: A multicenter randomized controlled pilot trial (SAVER). Thromb Res. 2022 May;213:119-124. doi: 10.1016/j.thromres.2022.03.014. Epub 2022 Mar 19.