| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Thromboembolism in subjects who have undergone an elective primary unilateral total knee replacement |
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| E.1.1.1 | Medical condition in easily understood language |
| Prevention of forming blood clot following surgery for replacement of the knee |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066899 |
| E.1.2 | Term | Venous thromboembolism |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the efficacy of JNJ-70033093 in preventing total VTE events (proximal and/or distal DVT [asymptomatic confirmed by venography assessment or objectively confirmed symptomatic], nonfatal PE), or any death during the treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the dose response of JNJ-70033093 for the occurrence of the endpoint of any bleeding events during the treatment period.
To determine the efficacy of JNJ-70033093 in preventing total VTE events during the full study period.
To assess the dose response of JNJ-70033093 for the rate of any bleeding throughout the full study period.
To assess the dose response of JNJ-70033093 for the prevention of major VTE (death, asymptomatic or symptomatic proximal DVT or PE) during the treatment period and throughout the full study period.
To assess the effect of individual doses of JNJ 70033093 compared with enoxaparin for both efficacy and safety endpoints.
To compare the effect of JNJ-70033093 with enoxaparin for the individual components of the total VTE endpoint.
To assess the PK of JNJ-70033093 in men and women undergoing primary unilateral TKR surgery and the relation of these measures to efficacy and safety endpoints (eg, exposure-response analyses).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male or female.
50 years of age, or older.
Medically stable and appropriate for anticoagulant prophylaxis as determined by the investigator on the basis of physical examination, medical history, and vital signs performed as part of screening for elective TKR surgery.
Medically stable and appropriate for anticoagulant prophylaxis on the basis of clinical laboratory tests performed as part of local standard-of-care as part of screening for elective TKR surgery. If the results of laboratory tests are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the subject’s source documents and initialed by the investigator.
Has plans to undergo an elective primary unilateral TKR surgery.
Must sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
A woman of childbearing potential (WOCBP) must have a negative urine or highly sensitive serum (Beta human chorionic gonadotropin) up to 2 days before the administration of the study drug.
A woman must be (as defined in the protocol Section 10.5, Appendix 5, Contraceptive and Barrier Guidance and Collection of Pregnancy Information).
a. Not of childbearing potential
b. Of childbearing potential and
o Practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to
remain on a highly effective method for the duration of study drug with JNJ-70033093 plus 5 half-lives of study drug plus 30 days (duration of
ovulatory cycle) for a total of 34 days after the completion of treatment.
Examples of highly effective methods of contraception are located in
Section 10.5, Appendix 5, Contraceptive and Barrier Guidance and
Collection of Pregnancy Information.
o Pregnancy testing (serum or urine) prior to the first dose of study drug.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 34 days
after the last dose.
A male subject must wear a condom when engaging in any activity with a WOCBP during the study and for the duration of treatment with JNJ-
70033093 plus 5 half-lives of the study drug plus 90 day (duration of sperm turnover) for a total of 94 days after the completion of treatment.
Male subjects should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break
or leak. This criterion does not apply to male subjects randomly assigned to enoxaparin.
A male subject must agree not to donate sperm for the purpose of reproduction during the study and for the duration of treatment with
JNJ-70033093 plus 5 half-lives of the study drug plus 90 days (duration of sperm turnover) for a total of 94 days after the completion of
treatment. This criterion does not apply to male subjects randomly assigned to enoxaparin.
Willing and able to adhere to the lifestyle restrictions (Section 5.3, Lifestyle Considerations) specified in this protocol.
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|
| E.4 | Principal exclusion criteria |
History of any condition for which the use of LMWH is not recommended in the opinion of the investigator (eg, previous allergic reaction, creatinine clearance <30 mL/minute).
History of severe hepatic impairment.
Planned bilateral revision or unicompartmental procedure.
Planned postoperative epidural analgesia with an epidural catheter.
•If an epidural catheter was used, it must be removed at least 5 hours prior to postoperative study drug administration.
NOTE: if a subject had an epidural or spinal anesthesia procedure with bleeding or significant trauma at the time of surgery, they should not be
randomized.
Unable to undergo venography (eg, due to contrast agent allergy, poor venous access, or impaired renal function that would increase the risk of
contrast-induced nephropathy).
Known previous PE or DVT in either lower extremity.
Known allergies, hypersensitivity, or intolerance to JNJ-70033093 or its excipients (refer to IB).
Contraindications to the use of or known allergies, hypersensitivities, or intolerance to enoxaparin per local prescribing information (eg, heparin
and pork products).
Any condition requiring chronic antithrombotic therapy (eg, atrial fibrillation, mechanical heart valve, recent coronary intervention), except for aspirin less than or equal to 100 mg per day.
Use of strong CYP3A4/P-gp inhibitors or strong CYP3A4/P-gp inducers in the 7 days prior to randomization or the need for ongoing treatment with concomitant oral or IV therapy with strong CYP3A4/P-gp inhibitors or strong CYP3A4/P-gp inducers during the treatment period.
Taken any disallowed therapies as noted in the protocol Section 6.5, Concomitant Therapy before the planned first dose of study drug.
Planned use of intermittent pneumatic compression after the first postoperative dose of the study drug.
Received an investigational study drug (including investigational vaccines) or used an invasive investigational medical device within 60 days before the planned first dose of study drug or is currently enrolled in an investigational study.
Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
Has surgery planned (except the TKR study) during the time the subject is expected to participate in the study for which anticoagulant therapy would be interrupted.
Previously randomized subject in this study or participated in previous studies with JNJ 70033093.
Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.
At the time of informed consent, the subject does not agree to following up with scheduled study visits or allowing a telephone contact to the subject’s alternative means of contact (eg subject’s children, spouse, significant other, caretaker, legal representative, healthcare professional), as necessary, until the end of the study, should he or she discontinue prematurely.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Total VTE during the treatment period up to the time of venography as assessed by the CEC. Proof-of-efficacy is reached by either showing a positive dose response or having less than a 30% total VTE event rate in the combined dose group. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The composite endpoint of any bleeding event on treatment. Any bleeding will be defined as the composite of major bleeding according to
the ISTH criteria modified for the surgical setting, clinically relevant nonmajor bleeding events, or minimal bleeding events as assessed by
the CEC.
Total VTE as assessed by the CEC through Week 6.
Occurrence of the composite endpoint of any bleeding events, the composite endpoint of major or clinically relevant nonmajor bleeding events, and the individual components of the composite endpoint of any bleeding as assessed by the CEC through Week 6.
Major VTE as assessed by the CEC during the treatment period and through Week 6.
Total VTE and any bleeding as assessed by the CEC during the treatment period and during the full study period (6 weeks).
All individual components of the primary efficacy endpoint as assessed by the CEC during the treatment period and during the full study period (6 weeks).
Estimation of PK parameters and the effects of demographics and laboratory values (eg, body weight, age, gender, renal function) on the PK of JNJ 70033093.
Estimation of the relationship between JNJ-70033093 exposure with probability of total VTE during the treatment period up to the time of
venography and the probability of the composite endpoint of major or clinically relevant nonmajor bleeding events, and the individual
components of the composite endpoint of any bleeding event on treatment.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Chile |
| Israel |
| Japan |
| Malaysia |
| Mexico |
| Russian Federation |
| South Africa |
| Thailand |
| Turkey |
| Ukraine |
| United States |
| Belgium |
| Bulgaria |
| Greece |
| Hungary |
| Italy |
| Latvia |
| Lithuania |
| Poland |
| Portugal |
| Spain |
| Czechia |
| Argentina |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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