Optimizing therapy with n=1-studies: negating the 'nocebo' effect in statin-intolerance

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

10 Dec 2024 → ongoing

Decision date (initial)

2024-06-28

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

ZonMw Rational Pharmacotherapy 12th open call

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The key objective of the study is to assess whether an ‘n=1 study’ (randomized, double blind, cross-over trial with counseling on patients’ individual treatment results) will increase statin use and reduce the prescription of PCSK9i compared to usual care at 12 months (t12m) after randomization.

Secondary objectives 13

1. 1. To assess statin use at 6 (t6m), 24 (t24m), 36 (t36m) and 48 months (t48m) after randomization.
2. 2. To assess PCSK9i use at 6 (t6m), 12 (t12m), 24 (t24m), 36 (t36m) and 48 months (t48m)
3. 3. To assess LDLc levels at 6 (t6m), 12 (t12m), 24 (t24m), 36 (t36m) and 48 months (t48m)
4. 4. To assess quality of life at 6 (t6m), 12 (t12m), 24 (t24m), 36 (t36m) and 48 months (t48m)
5. 5. To assess reported side effects at 6 (t6m), 12 (t12m), 24 (t24m), 36 (t36m) and 48 months (t48m)
6. 6. To assess cost effectiveness (HTA) at 6 (t6m), 12 (t12m) and 24 (t24m) months
7. 7. To assess patients’ acceptability to participate in n=1 trials
8. 8. To assess applicability in clinical care (health care professionals work load)
9. 9. To assess patients’ perceived treatment concordance during n=1 trials
10. 10. To assess physical and mental complaints during placebo and statin therapy
11. 11. To assess differences in patients’ views on medication and decisional conflict regarding choice for LLT before and after the implementation of the n=1-intervention
12. 12. To assess differences in the level of physician trust among patients before and after the implementation of the n=1-intervention.
13. 13. To assess biopsychosocial differences between statin-intolerant and nocebo-intolerant patients and their differences with regard to views on medication and decisional conflict.

Conditions and MedDRA coding

Statin-intolerance

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. 1. Aged 18 years or older.
2. 2. Previously taken two or more statins and withdrawn from statins because of (perceived) side effects.
3. 3. Clinical indication for lipid lowering therapy related to secondary prevention of cardiovascular disease (previous CVD) or prevention of cardiovascular disease (both primary and secondary) in familial hypercholesterolemia.
4. 4. Provided full informed consent.

Exclusion criteria 9

1. 1. A contra-indication for rosuvastatin therapy related to: a. Previous statin use causing anaphylaxis or other moderate/severe allergic reaction. b. Previous statin use causing myopathy (serum rise of creatine kinase more than 3 times the upper limit of normal) or rhabdomyolysis. c. Previous statin use with liver function abnormalities, defined as aspartate aminotransferase (AST) or alanine aminotransferase >3 times the upper limit of normal. d. Previous statins use causing severe health issues. e. Planned pregnancy within 12 months, pregnancy or breastfeeding. f. Currently taking other drugs with known relevant interactions to rosuvastatin as listed in the Investigational Medicinal Product Dossier (IMPD). g. Any other contraindication for rosuvastatin as listed in the Investigational Medicinal Product Dossier (IMPD).
2. 2. History of myopathy or any other condition that causes severe chronic pain.
3. 3. History of severe mental illness (as their experience of symptoms may already be altered).
4. 4. History of cirrhosis or severe renal insufficiency (eGFR < 20 ml/min/1,73m2)
5. 5. Insufficient ability to fill in questionnaires in the digital platform; a. No access to a smartphone, tablet or personal computer. b. Insufficient understanding of the Dutch or English language.
6. 6. Clinical judgement of the health care professional that LDLc-lowering therapy is not relevant for the prognosis (e.g. severe frailty, dementia, end-stage heart failure, end-stage malignancy).
7. 7. A recent cardiovascular event in the past 3 months.
8. 8. Clinical judgement of the health care professional who considers participation unethical or otherwise unwanted.
9. 9. Clinical judgement of the health care professional that LDL-c lowering therapy cannot be withheld in a patient with a recent cardiovascular event in the past 12 months.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. (self-reported) statin use 12 months after inclusion.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Sponsor organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

Ruben Mijnster

Public contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

Ruben Mijnster

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications