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Submitted by: Nikki Francine Balde 2020-09-08 04:40:28 Last Updated by: Principe, Jeverly Ann S 2020-09-09 17:06:24


A randomized double-blind, placebo-controlled, multicenter trial assessing the impact of lipoprotein (a) lowering with TQJ230 on major cardiovascular events in patients with established cardiovascular disease

PHRR200909-002920

CTQJ230A12301

2020-CT0546

A randomized double-blind, placebo-controlled, multicenter trial assessing the impact of lipoprotein (a) lowering with TQJ230 on major cardiovascular events in patients with established cardiovascular disease

This is a pivotal phase 3 study designed to test the hypothesis that treatment with TQJ230 80 mg s.c QM will significantly reduce the risk of MACE, i.e. CV deaths, nonfatal myocardial infarction (MI), non-fatal stroke and urgent coronary re-vascularization in patients with established CVD and elevated levels of Lp(a) who are treated for CV risk factors other than Lp(a) according to local guidelines for the reduction of cardiovascular risk in patients with established CVD and elevated Lp(a). It has a randomized double-blind, parallel group, placebo-controlled, multicenter trial design.

Start Date Duration in Months Target Completion Date Actual Completion Date
2020-10-30 60 2025-10-30 0000-00-00

Pending

Not stated

Institution Classification Region LTO #
Novartis Healthcare Philippines, Inc. Private Business NCR LTO-3000006283930
Institution Region
Novartis Pharma Services AG Switzerland
Name E-Mail Institution and Institution Address
Anna Liza Calingasin anna_liza.calingasin@novartis.com Novartis Healthcare Philippines, Inc. 5th Floor, Ayala North Exchange Tower 1, Ayala Avenue corner Amorsolo Street, Legazpi Village, Makati City 1229
Name E-Mail Institution and Institution Address
Ivy Emily Peneyro-Vergara, MD ivy_emily.peneyrovergara@ novartis.com Novartis Healthcare Philippines, Inc. 5th Floor, Ayala North Exchange Tower 1, Ayala Avenue corner Amorsolo Street, Legazpi Village, Makati City 1229
Name Expertise Affiliation
Gregorio G. Rogelio, MD Internal Medicine, Cardiology, and Echocardiography St. Luke's Medical Center - Quezon City
Project Location Institutional Ethics Review Board
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Board

Cardiovascular Disease

  • Time to the first occurrence of CEC confirmed expanded MACE (cardiovascular death, nonfatal MI, non-fatal stroke and urgent coronary re-vascularization requiring hospitalization) in a population of patients with elevated Lp(a) ≥ 70 mg/dL.
  • Time to the first occurrence of CEC confirmed expanded MACE (cardiovascular death, non-fatal MI, non-fatal stroke and urgent coronary re-vascularization requiring hospitalization) in a subpopulation of patients
    with elevated Lp(a) ≥ 90 mg/dL

  • Time to the first occurrence of the CEC confirmed composite endpoint of MACE (CV death, non-fatal MI, and non-fatal stroke)
  • Time to the first occurrence of the CEC confirmed composite endpoint of CHD: CHD death, non-fatal MI, urgent coronary revascularization requiring hospitalization
  • CEC confirmed all-cause death from randomization to the end of study

Pending

  • Australia
  • China
  • Denmark
  • Germany
  • Hong Kong
  • India
  • Japan
  • Malaysia
  • Poland
  • Singapore
  • United States

Clinical Trial

CTQJ230A12301

CTA-2020-07-08-28

2020-08-07

0000-00-00

25

Unspecified

Unspecified

30 Oct 2020

Inclusion Criteria:

Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female 18 to ≤ 80 years of age
3. Lp(a) ≥ 70 mg/dL at the screening visit, measured at the Central laboratory
4. LDL-cholesterol lowering treatment at Randomization as follows:

  • subjects must be on an optimal LDL-C lowering treatment to meet the target LDL-C level according to local practice/guidelines, or
  • if subjects do not meet the target LDL-C level according to local practice/guidelines, they should be treated with the highest tolerated doses of statins and/or with other optimized LDL-lowering therapy (e.g. ezetimibe, cholesterol absorption inhibitor, fibrate, PCSK9 inhibitor), or
  • if subjects have a contraindication or do not tolerate statin treatment, they must be treated with other optimized LDL-lowering therapy (e.g. ezetimibe, cholesterol absorption inhibitor, fibrate, PCSK9 inhibitor) according to local practice/guidelines

5. At the randomization visit subjects must be optimally treated for other CV risk factors
according to local practice/guidelines
6. Established CV disease defined as ANY of the following three conditions:

1) History of spontaneous myocardial infarction (not resulting from PCI or CABG) having occurred in the period ≥ 3 months to ≤ 10 years prior to the screening visit and documented as follows (Thygesen et al 2018):

  • Acute MI (hospitalization records): requires documentation of a rise and/or fall of cardiac biomarkers (preferably cardiac troponin) with at least one value above the 99th percentile of the upper reference limit (URL) and at least one of the following :
    • Symptoms of ischemia
    • ECG changes indicative of acute myocardial ischemia (new ST-T changes or new LBBB; please see Appendix 2 for ST and T-wave changes)
    • Development of pathological Q waves (please see Appendix 2 for definitions of pathological Q waves)
    • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology
    • Identification of a coronary thrombus by angiography including intracoronary
      imaging
  • Prior MI (no complete hospital records for acute event available): requires documentation of any one of the following :
    • Pathological Q waves (please see Appendix 2 for definitions of pathological Q waves), with or without symptoms, in the absence of a non-ischemic cause
    • Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause

2) History of ischemic stroke (an acute episode of focal cerebral, spinal, or visual dysfunction caused by infarction of central nervous system tissue) having occurred in the period ≥ 3 months to ≤ 10 years prior to the screening visit documented by CT scan, MRI or other visualization method. Transient ischemic attack or embolic stroke (not of atherosclerotic origin) are not qualifying events.
3) Clinically significant symptomatic peripheral artery disease, evidenced by intermittent claudication with an ankle-brachial index ≤ 0.90 and/or limb amputation or revascularization due to lower limb ischemia. Thromboangiitis obliterans is not a qualifying event.

 

Exclusion Criteria:

Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) ≥ 160 mmHg and/ or diastolic blood pressure (DBP) ≥ 100 mmHg (mean of 3 measurements for each
SBP and DBP assessment) at the Screening visit.
2. Treatment with niacin in the 3 months before the screening visit; niacin in multi-vitamins is allowed
3. Treatment with stable dose of a PCSK9 inhibitor (evolocumab, alirocumab) for less than 12 weeks before Randomization
4. Treatment with lipoprotein apheresis, or already planned to start lipoprotein apheresis during the study

5. Within 3 months of screening and between Screening visit and Randomization visit (Day 1): myocardial infarction, stroke, coronary or lower limb re-vascularization, major cardiac or non-cardiac surgery. The subjects can be re-screened 3 months after the relevant event/procedure.
6. Planned or expected cardiac, cerebrovascular or peripheral artery surgery or coronary revascularization after Randomization visit (Day 1)
7. Heart failure New York Heart Association (NYHA) class IV at Screening visit or at Randomization visit (Day 1)
8. History of hemorrhagic stroke or other major bleeding, or if occurring between Screening visit and Randomization visit
9. Severe concomitant non-CV disease that is expected to reduce life expectancy to less than 5 years, at Screening visit or at Randomization visit (Day 1)
10. Known active severe infection or major hematologic, metabolic, gastrointestinal or endocrine dysfunction (e.g. uncontrolled thyroid dysfunction or uncontrolled diabetes mellitus) in the judgment of the investigator, at Screening visit or at Randomization visit (Day 1)
11. History of malignancy of any organ system (other than localized basal cell carcinoma or squamous cell carcinoma of the skin, or in situ cervical cancer), treated or untreated, within the past 5 years, or if diagnosed between Screening visit and Randomization visit (Day 1), regardless of whether there is evidence of local recurrence or metastases.
12. Platelet count <140,000 per μL from central laboratory test at Visit 1, confirmed by a second central laboratory test prior to the Randomization visit (Day 1)
13. eGFR ≤ 30 mL/min/1.73m2 from central laboratory test at Visit 1, confirmed by a second central laboratory test prior to the Randomization visit (Day 1); or patient on dialysis
14. Significant glomerular disease (including but not limited to IgA nephropathy, diabetic nephropathy, systemic lupus erythematosus, etc.) with urinary protein-creatinine ratio (PCR) > 500 mg/g (50 mg/mmol) at Visit 1, confirmed by a second central laboratory test prior to the Randomization visit (Day 1)
15. Active liver disease or hepatic dysfunction, defined as AST or ALT ≥ 2 times the ULN from central laboratory test at Screening visit, confirmed by a second central laboratory test prior to the Randomization visit (Day 1)
16. Total bilirubin ≥ 1.5 times the ULN from central laboratory test at Screening visit, confirmed by a second central laboratory test prior to the Randomization visit (Day 1)
17. Positive HIV, Hepatitis C screening or Hepatitis B Surface Antigen tests from central laboratory test at Screening visit
18. Any other conditions, at Screening visit or between Screening visit and Randomization visit (Day 1), which in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study
19. Treatment with an oligonucleotide or SiRNA within 9 months of screening visit. Exceptions are GalNac oligonucleotide or GalNac siRNA which can be used if approved by health authorities and if allowed for use in the study by the Sponsor.
20. History of hypersensitivity to the study drug or their excipients or to drugs of similar chemical classes

21. Use of other investigational drugs within 5 half-lives of Screening visit, or within 30 days, whichever is longer
22. Unwillingness or inability (e.g. physical or cognitive) to comply with study procedures and medication administration (injections) and schedule
23. Pregnant or nursing (lactating) women
24. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug. Such methods include:

  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  • Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
  • Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception

Interventional

TQJ230

Investigational/ Control Drug Pharmaceutical Dosage Form Route of Administration Supply Type
TQJ230 80mg Solution for injection Subcutaneous injection Solution for injection in pre-filled syringe
Placebo Solution for injection Subcutaneous injection Solution for injection in pre-filled syringe

None

Randomized

Double Blind

Subjects, investigator staff, persons performing the assessments, and the clinical trial team (CTT) will remain blind to the identity of the treatment from the time of randomization until database lock, using the following methods: (1) Randomization data are kept strictly confidential until the time of unblinding, and will not be accessible by anyone else involved in the study with the following exceptions: of the independent statistician and programmer who need to have access to prepare safety and efficacy interim analysis reports for the DMC and the bioanalyst (to avoid the unnecessary analysis of placebo samples). These personnel will not be involved in any other trial activities. (2) The identity of the treatments will be concealed by the use of study treatment that are all identical in packaging, labeling, schedule of administration and appearance. (3) Pharmacokinetics (PK), biomarkers, anti-drug antibodies, and results from Lp(a) and lipid measurements after the randomization visit should be blinded for subjects, investigator staff, persons performing the assessments, and the CTT. Lp(a) and lipids local lab assessments are prohibited during the duration of the trial. Investigators will be notified by the Central laboratory in case a LDL-C value has increased above the pre-defined algorithmic threshold of the value at randomization or, if the latter missing, the last LDL-C value assessed by the Central laboratory prior to randomization. In addition, investigators and site staff involved in the conduct of this trial and all medical personnel involved in the subject's care and management should refrain from obtaining lipid panels between the time from Randomization (Day 1) to study completion. If a lipid panel is obtained all reasonable actions must be taken toensure the study subject is not informed of the results. The randomization codes associated with subjects from whom PK samples are taken will be disclosed to PK analysts who will keep PK results confidential until data base lock. Unblinding will occur in the case of subject emergencies and at the conclusion of the study.

Parallel

Study TQJ230A12301 is a pivotal phase 3 study designed to test the hypothesis that treatment with TQJ230 80 mg s.c QM will significantly reduce the risk of MACE, i.e. CV deaths, nonfatal myocardial infarction (MI), non-fatal stroke and urgent coronary re-vascularization in patients with established CVD and elevated levels of Lp(a) who are treated for CV risk factors other than Lp(a) according to local guidelines for the reduction of cardiovascular risk in patients with established CVD and elevated Lp(a).

Phase III

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