Swiss Multi-centre, Randomized, Placebo Controlled Trial of Pregabalin for Prevention of Persistent Pain in High Risk Patients Undergoing Breast Cancer Surgery (PREVENT)

• ClinicalTrials.gov Identifier: NCT03216187
• Recruitment Status: Recruiting
• First Posted: July 13, 2017
• Last Update Posted: January 21, 2022
• Sponsor: Benno Rehberg-Klug
• Collaborators: University Hospital, Geneva; Centre Hospitalier Universitaire Vaudois; University Hospital Inselspital, Berne
• Information provided by (Responsible Party): Benno Rehberg-Klug, University Hospital, Geneva

Tracking Information

• First Submitted Date: July 10, 2017
• First Posted Date: July 13, 2017
• Last Update Posted Date: January 21, 2022
• Actual Study Start Date: January 9, 2018
• Estimated Primary Completion Date: January 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 10, 2017)

incidence of "clinically important pain" at 3 months after surgery [ Time Frame: 3 months ]

"Clinically important pain" is defined by: taking analgesics for pain at the surgical site OR average resting pain at the surgical site >3/10 OR average movement-induced pain at the surgical site >5/10.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 13, 2017)

• Pregabalin-related side effects [ Time Frame: 10 days ]
  blurred vision or diplopia, somnolence or sleepiness, abnormal thinking, confusional state, disturbed attention, and falls, as well as the effects noted in the "generic assessment of side effects" GASE questionnaire
• retention rates of pregabalin treatment [ Time Frame: 30 days ]
• acute pain intensity and patient-reported pain outcome at 24h [ Time Frame: 24 hours ]
  PAIN-OUT questionnaire
• pain intensity at rest and movement, pain interference [ Time Frame: 3, 6, and 12 months ]
  Brief Pain Inventory, BPI
• neuropathic pain [ Time Frame: 3, 6, and 12 months ]
  incidence of neuropathic pain defined as a DN4-self-evaluation score ≥4
• patient-reported relevance of pain [ Time Frame: 3, 6, and 12 months ]
  response to the question: "do you consider your pain as significant?"
• Patient-reported acceptance of the preventive treatment [ Time Frame: 3 months ]
  response to the question "In retrospect, do you consider the preventive treatment worthwhile, given your pain outcome and your experience of taking the medication?")
• Expectations about treatment benefits before treatment and after [ Time Frame: 10 days ]
  responses to the questions: "How much pain do you expect 3 months from now?"" "How efficient do you think the study treatment is against the long-term pain (i.e. what is the success rate in %)?" "How well do you think it will work for you? (i.e. reduction in pain score 0-10)". Beliefs about treatment attribution after 10 days of treatment (question: "Do you think that you received the real drug or the placebo?")

Original Secondary Outcome Measures (submitted: July 10, 2017)

• Pregabalin-related side effects [ Time Frame: 10 days ]
  blurred vision or diplopia, somnolence or sleepiness, abnormal thinking, confusional state, disturbed attention, and falls, as well as the effects noted in the "generic assessment of side effects" GASE questionnaire
• retention rates of pregabalin treatment in the subgroups receiving neutral or positive side effect information [ Time Frame: 30 days ]
• acute pain intensity and patient-reported pain outcome at 24h [ Time Frame: 24 hours ]
  PAIN-OUT questionnaire
• pain intensity at rest and movement, pain interference [ Time Frame: 3, 6, and 12 months ]
  Brief Pain Inventory, BPI
• neuropathic pain [ Time Frame: 3, 6, and 12 months ]
  incidence of neuropathic pain defined as a DN4-self-evaluation score ≥4
• patient-reported relevance of pain [ Time Frame: 3, 6, and 12 months ]
  response to the question: "do you consider your pain as significant?"
• Patient-reported acceptance of the preventive treatment [ Time Frame: 3 months ]
  response to the question "In retrospect, do you consider the preventive treatment worthwhile, given your pain outcome and your experience of taking the medication?")
• Expectations about treatment benefits before treatment and after [ Time Frame: 10 days ]
  responses to the questions: "How much pain do you expect 3 months from now?"" "How efficient do you think the study treatment is against the long-term pain (i.e. what is the success rate in %)?" "How well do you think it will work for you? (i.e. reduction in pain score 0-10)". Beliefs about treatment attribution after 10 days of treatment (question: "Do you think that you received the real drug or the placebo?")

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Swiss Multi-centre, Randomized, Placebo Controlled Trial of Pregabalin for Prevention of Persistent Pain in High Risk Patients Undergoing Breast Cancer Surgery
• Official Title: Swiss Multi-centre, Randomized, Placebo Controlled Trial of Pregabalin for Prevention of Persistent Pain in High Risk Patients Undergoing Breast Cancer Surgery
• Brief Summary: This study will test the benefits and risks of using pregabalin perioperatively to prevent persistent postoperative pain in patients at high risk (>30%) of developing such pain after breast cancer surgery.

Detailed Description

BACKGROUND Persistent postsurgical pain occurs in more than 30% of patients undergoing breast cancer surgery. Evidence that gabapentinoids such as pregabalin may reduce the incidence of persistent postsurgical pain is ambiguous, potentially because in previous trials prophylactic treatment was administered to every patient undergoing surgery. The patients at low risk of long term pain, were exposed to side effects without much benefit to expect.

AIM Validating or refuting the utility of pregabalin to prevent long term post-operative pain in patients at high risk of persistent pain after breast cancer surgery.

METHODS Randomized, double-blind, placebo-controlled trial of pregabalin (2*150mg from the day before breast cancer surgery until 2 weeks after surgery) in patients at high risk of persistent pain (>30%). High-risk patients are identified by a risk score derived from a previous observational study. The main outcome is the incidence of clinically important pain (necessitating analgesic treatment, or having an intensity of >3 at rest or >5 on movement) at 3 months after surgery. Secondary outcomes are: incidence of neuropathic pain, pain interference, and incidences at 6 and 12 months of follow-up. In addition, side effects of pregabalin and the retention rate during the treatment period will be monitored, as well as patient expectancies.

RELEVANCE This is the first study for prevention of persistent postoperative pain which targets only high-risk patients, thus lowering a false negative outcome and averting the risk of side effects for patients at low risk.

The study is powered to show a reduction of the incidence of clinically important pain at 3 months of 20%. In the case the study shows that this can be achieved and pregabalin is well tolerated, the preventive use of pregabalin for breast cancer surgery would be justified at least in high-risk patients. On the other hand, a negative result would indicate the futility of pregabalin prevention, which is already in routine use in many hospitals.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

double-blinded, randomized, placebo-controlled trial

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

study drugs (including identical placebos) and randomisation lists are prepared by the hospital pharmacy and are kept secret from the investigators until the end of the study and the "freezing" of the electronic data base (an interim analysis will be performed when data for the primary outcome are available for 60 patients per arm. Stopping rules are a difference in the incidence of the primary outcome of less than 8.2% (futility) or more than 19.9% (superiority)).

Primary Purpose: Prevention

• Condition: Persistent Postoperative Pain

Intervention

• Drug: Pregabalin
  pregabalin 150 mg capsules
  Other Name: Pregabalin 150mg capsules
• Drug: Placebos
  capsules identical to pregabalin but without active drug
  Other Name: placebo capsules

Study Arms

• Experimental: Pregabalin
  Pregabalin 150 mg twice daily, starting from the evening before surgery, continuing with two times 150mg per day for 12 days, and ending with one 150mg capsule every evening for the final 3 days.
  Intervention: Drug: Pregabalin
• Placebo Comparator: Placebo
  Identical placebo capsules twice daily, starting from the evening before surgery, continuing with two capsules per day for 12 days, and ending with one capsule every evening for the final 3 days.
  Intervention: Drug: Placebos

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 10, 2017): 300
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 1, 2024
• Estimated Primary Completion Date: January 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• patients scheduled for breast surgery for cancer, either breast-conserving (tumorectomy/ quadrantectomy) or mastectomy, with or without immediate reconstruction, and with or without axillary dissection.
• patients of 18 years or more scheduled for above mentioned type of surgery
• ability to speak and read French, English or German
• high (>30%) risk of clinically important persistent pain: identified with 2 or more points of a risk score including the items: pre-existing pain at surgical site (2 points), history of depression (1 point), age < 50 years (1 point), and high expected acute pain (>6/10, 1 point).
• Informed Consent as documented by signature.

Exclusion Criteria:

• Inability to understand the consent form and to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant
• Participation in another study with investigational drug within the 30 days preceding and during the present study,
• Previous enrolment into the current study,
• Enrolment of the investigator, his/her family members, employees and other dependent persons
• Pregnancy or lactation - Renal insufficiency (creatinine clearance < 60 ml/min)
• Allergy to pregabalin or the ingredients of the capsules
• Long-term preoperative therapy with gabapentinoids or high-dose opioids (more than 60 mg of morphine equivalents)
• Symptomatic cardiac insufficiency (peripheral oedema, NYHA class III - marked limitation of physical activity)
• Suicidal ideation, identified by the question: "have you been bothered by thoughts that you would be better off dead, or of killing yourself?"
• Planned fertility preservation immediately after surgery before a planned chemotherapy
• Known or suspected non-compliance, or substance-use disorder with impact on medication adherence

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Benno Rehberg-Klug, MD; +4179 55 32132; benno.rehberg-klug@hcuge.ch

Contact: Stanislas Mathivon, MS; +41795533678; stanislas.mathivon@hcuge.ch

• Listed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT03216187
• Other Study ID Numbers: PREVENT
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Benno Rehberg-Klug, University Hospital, Geneva
• Study Sponsor: Benno Rehberg-Klug

Collaborators

• University Hospital, Geneva
• Centre Hospitalier Universitaire Vaudois
• University Hospital Inselspital, Berne

Investigators

• Study Director: Benno Rehberg-Klug, MD; HUG
• Study Director: Marc Suter, MD; CHUV
• Study Director: Ulrike Stamer, MD; Inselspital

• PRS Account: University Hospital, Geneva
• Verification Date: January 2022