NCT05192941: V-DIFFERENCE

Study of Efficacy, Safety, Tolerability and Quality of Life of Inclisiran (KJX839) vs Placebo, on Top of Ongoing Individually Optimized Lipid-lowering Therapy, in Participants With Hypercholesterolemia

Completed Phase 4 Results posted Last updated 14 April 2026

What this trial tests

Phase 4 trial testing Inclisiran Sodium in Hypercholesterolemia in 1,770 participants. Completed in 19 March 2025.

Timeline

8 April 2022

Primary endpoint
11 June 2024

19 March 2025

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	1,770
Start date	8 April 2022
Primary completion	11 June 2024
Estimated completion	19 March 2025
Sites	136 locations across France, Estonia, Germany, Poland, Bulgaria, Latvia, Spain, Czechia

Drugs / interventions tested

• Inclisiran Sodium — full drug profile →
• Placebo

Conditions studied

• Hypercholesterolemia — all drugs for Hypercholesterolemia →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

Adults 18 to 99, any sex, with Hypercholesterolemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants Achieving Individual LDL-C Target (<55 mg/dL or <70 mg/dL) Primary · Day 90

Number of participants achieving individual Low-density Lipoprotein Cholesterol (LDL-C) target (\< 55 mg/dL or \< 70 mg/dL) at Day 90. The individual LDL-C target of the participants was determined according to their most recent individual cardiovascular risk category. A larger proportion of participants indicates a superior outcome.

Group	Value	95% CI
Inclisiran	752
Placebo	266

Relative Change From Baseline to Mean LDL-C Level Over the Double-blind Treatment Period Secondary · Baseline to Day 360

Relative (percentage) change from baseline in Low-density Lipoprotein Cholesterol (LDL-C) level averaged over the double-blind treatment period

Group	Value	95% CI
Inclisiran	-59.45	-60.79 – -58.11
Placebo	-24.31	-25.68 – -22.93

Number of Participants Experiencing at Least One Muscle-related Adverse Event From Day 1 to Day 360 Secondary · Day 1 to Day 360

The number of participants who experienced at least one muscle-related adverse event, defined as Standardized MedDRA Queries (SMQ) rhabdomyolysis / myopathy from Day 1 to Day 360. All muscle-related adverse events occurring between first dose of double-blind treatment and earliest date out of visit Day 360, death date and last contact date are considered.

Group	Value	95% CI
Inclisiran	107
Placebo	167

Number of Participants Experiencing Self-reported Pain Secondary · Day 1 to Day 360

Self-reported pain is reported at its worst in the last 24 h on a numeric rating scale from 0 (no pain) to 10 (pain as bad as you can imagine). Days with a score of 0 are considered as days without pain. The percentage of days with pain for each participant is calculated as number of days with pain divided by the total number of days where diary was completed, multiplied by 100. Diary data between the first dose of double-blind treatment up to the minimum of last contact date and Day 360 visit are considered.

Percentage of days with pain: 0%

Group	Value	95% CI
Inclisiran	143
Placebo	98

Percentage of days with pain: >0-20%

Group	Value	95% CI
Inclisiran	189
Placebo	177

Percentage of days with pain: >20-40%

Group	Value	95% CI
Inclisiran	45
Placebo	71

Percentage of days with pain: >40-60%

Group	Value	95% CI
Inclisiran	60
Placebo	44

Percentage of days with pain: >60-80%

Group	Value	95% CI
Inclisiran	48
Placebo	48

Percentage of days with pain: >80%

Group	Value	95% CI
Inclisiran	409
Placebo	432

Percentage of days with pain: Missing

Group	Value	95% CI
Inclisiran	4
Placebo	2

Annualized Number of Days With Pain Secondary · Day 1 to Day 360

Annualized rate refers to the estimated number of days with pain per year. Self-reported pain is reported at its worst in the last 24 h on a numeric rating scale from 0 (no pain) to 10 (pain as bad as you can imagine). Days with a score of 0 are considered as days without pain.

Group	Value	95% CI
Inclisiran	198.63	180.46 – 218.62
Placebo	214.51	194.63 – 236.42

Average Absolute Change From Baseline in Short-Form Brief Pain Inventory (SF-BPI) Pain Severity Score Over the Double-blind Treatment Period Secondary · Baseline to Day 360

The Short-Form Brief Pain Inventory (SF-BPI) is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The query period covers the past 24 hours and takes 5 minutes for the participant to complete. The pain severity score was derived for each visit between screening and EOT/EOS (Day 360) as the average over the 4 items in the pain severity domain (questionnaire items number 3, 4, 5, 6). The derived pain severity score ranged between 0 (no pain) and 10 (pain as bad as you can imagine), with larger values indicatin

Group	Value	95% CI
Inclisiran	-0.21	-0.30 – -0.13
Placebo	-0.10	-0.19 – -0.02

Average Absolute Change From Baseline in Short-Form Brief Pain Inventory (SF-BPI) Pain Interference Score Over the Double-blind Treatment Period Secondary · Baseline to Day 360

The Short-Form Brief Pain Inventory (SF-BPI) is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The query period covers the past 24 hours and takes 5 minutes for the participant to complete. The pain interference score was derived for each visit between screening and EOT/EOS (Day 360) as the average over the 7 items in the pain interference domain (questionnaire items number 9A through 9G). The derived pain interference score ranged between 0 (does not interfere) and 10 (completely interferes), with larger

Group	Value	95% CI
Inclisiran	-0.06	-0.14 – 0.02
Placebo	0.05	-0.03 – 0.13

Number of Participants With Clinically Relevant Change in Short-Form Brief Pain Inventory (SF-BPI) Pain Severity Score From Baseline to Day 360. Secondary · Baseline to Day 360

The Short-Form Brief Pain Inventory (SF-BPI) is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The query period covers the past 24 hours and takes 5 minutes for the participant to complete. The pain severity score was derived for each visit between screening and EOT/EOS (Day 360) as the average over the 4 items in the pain severity domain (questionnaire items number 3, 4, 5, 6). The derived pain severity score ranged between 0 (no pain) and 10 (pain as bad as you can imagine), with larger values indicatin

Group	Value	95% CI
Inclisiran	123
Placebo	104

Number of Participants With Clinically Relevant Change in Short-Form Brief Pain Inventory (SF-BPI) Pain Interference Score From Baseline to Day 360 Secondary · Baseline to Day 360

The SF-BPI is a self-administered standardized fifteen items questionnaire that assesses how pain interferes with or influences a participant's life. The query period covers the past 24 hours and takes 5 minutes for the participant to complete. The pain interference score was derived for each visit between screening and EOT/EOS (Day 360) as the average over the 7 items in the pain interference domain (questionnaire items number 9A through 9G). The derived pain interference score ranged between 0 (does not interfere) and 10 (completely interferes), with larger values indicating a higher level

Group	Value	95% CI
Inclisiran	87
Placebo	70

Adverse events — posted to ClinicalTrials.gov

Time frame: Treatment-emergent adverse events were reported in the clinical database from first dose of study treatment until the study completion visit, up to a planned maximum duration of 360 days.. Reporting threshold: 1.999%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Inclisiran

Serious: 148/900 (16%)

Deaths: 6/900

Placebo

Serious: 148/870 (17%)

Deaths: 5/870

Total

Serious: 296/1770 (17%)

Deaths: 11/1770

Serious adverse events (229 terms)

Reaction	System	Inclisiran	Placebo	Total
Atrial fibrillation	Cardiac disorders	—	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—	—
Angina pectoris	Cardiac disorders	—	—	—
Peripheral arterial occlusive disease	Vascular disorders	—	—	—
Coronary artery disease	Cardiac disorders	—	—	—
Pneumonia	Infections and infestations	—	—	—
Angina unstable	Cardiac disorders	—	—	—
COVID-19	Infections and infestations	—	—	—
Cardiac failure	Cardiac disorders	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—
Chest pain	General disorders and administration site conditions	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—
Acute coronary syndrome	Cardiac disorders	—	—	—
Ventricular tachycardia	Cardiac disorders	—	—	—
Ischaemic stroke	Nervous system disorders	—	—	—
Syncope	Nervous system disorders	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—
Cholecystitis	Hepatobiliary disorders	—	—	—
Cerebrovascular accident	Nervous system disorders	—	—	—
Aortic aneurysm	Vascular disorders	—	—	—
Atrioventricular block	Cardiac disorders	—	—	—
Cardiac failure congestive	Cardiac disorders	—	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—
Spinal stenosis	Musculoskeletal and connective tissue disorders	—	—	—

Other adverse events (23 terms — click to expand)

Reaction	System	Inclisiran	Placebo	Total
Nasopharyngitis	Infections and infestations	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—
COVID-19	Infections and infestations	—	—	—
Diabetes mellitus inadequate control	Metabolism and nutrition disorders	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Hypertension	Vascular disorders	—	—	—
Urinary tract infection	Infections and infestations	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Bronchitis	Infections and infestations	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Influenza	Infections and infestations	—	—	—
Blood creatine phosphokinase increased	Investigations	—	—	—
Headache	Nervous system disorders	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—
Gamma-glutamyltransferase increased	Investigations	—	—	—

Most-reported serious reactions: Atrial fibrillation, Osteoarthritis, Angina pectoris, Peripheral arterial occlusive disease, Coronary artery disease, Pneumonia, Angina unstable, COVID-19.

Data from ClinicalTrials.gov NCT05192941 adverse events section.

Sponsor's own description

Study of efficacy, safety, tolerability and quality of life of inclisiran (KJX839) vs placebo, on top of ongoing individually optimized lipid-lowering therapy, in participants with hypercholesterolemia

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.
   Bao X, Liang Y, Chang H, Cai T, et al · · 2024 · cited 101× · PMID 38185721 · DOI 10.1038/s41392-023-01690-3
2. Inclisiran, Low-Density Lipoprotein Cholesterol and Lipoprotein (a).
   Katsiki N, Vrablik M, Banach M, Gouni-Berthold I. · · 2023 · cited 50× · PMID 37111334 · DOI 10.3390/ph16040577
3. Clinical potential of inclisiran for patients with a high risk of atherosclerotic cardiovascular disease.
   Nishikido T. · · 2023 · cited 28× · PMID 36717882 · DOI 10.1186/s12933-023-01752-4
4. Development of Novel siRNA Therapeutics: A Review with a Focus on Inclisiran for the Treatment of Hypercholesterolemia.
   Ebenezer O, Comoglio P, Wong GK, Tuszynski JA. · · 2023 · cited 21× · PMID 36835426 · DOI 10.3390/ijms24044019
5. Current RNA strategies in treating cardiovascular diseases.
   Chia SPS, Pang JKS, Soh BS. · · 2024 · cited 13× · PMID 38291757 · DOI 10.1016/j.ymthe.2024.01.028
6. RNA interference therapy in cardiology: will new targets improve therapeutic goals?
   Fazoli RT, Drager LF, Kalil-Filho R, Generoso G. · · 2024 · cited 4× · PMID 39188988 · DOI 10.7573/dic.2024-3-1
7. Inclisiran-based treatment strategy in hypercholesterolaemia: the VICTORION-Difference trial.
   Landmesser U, Laufs U, Schatz U, Winzer EB, et al · · 2025 · cited 2× · PMID 40884558 · DOI 10.1093/eurheartj/ehaf685
8. Design and rationale of the VICTORION-Difference study: A phase 4 randomized, double-blind, placebo-controlled clinical trial to assess inclisiran's early efficacy, safety, tolerability, as well as its impact on quality of life in individuals with hypercholesterolemia.
   Landmesser U, Laufs U, Schatz U, Winzer EB, et al · · 2025 · cited 1× · PMID 40436308 · DOI 10.1016/j.ahj.2025.05.014