E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HIV and hyperlipidemia or mixed dyslipidemia. |
|
E.1.1.1 | Medical condition in easily understood language |
HIV and high cholesterol ( elevated LDL cholesterol
in blood) and/or mixed dyslipidemia (abnormal amounts of
lipids in blood). |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
E.1.2 | System Organ Class | 100000004861 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020667 |
E.1.2 | Term | Hyperlipidemia |
E.1.2 | System Organ Class | 100000004861 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020180 |
E.1.2 | Term | HIV positive |
E.1.2 | System Organ Class | 100000004848 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058110 |
E.1.2 | Term | Dyslipidemia |
E.1.2 | System Organ Class | 100000004861 |
|
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 evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab administered every month (QM) compared with placebo QM on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in human immunodeficiency virus (HIV)-positive subjects with hyperlipidemia or mixed dyslipidemia. |
|
E.2.2 | Secondary objectives of the trial |
• To assess the effects of 24 weeks of SC evolocumab QM compared with placebo QM on change from baseline in LDL-C, and percent change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), lipoprotein(a) [Lp(a)], triglycerides, HDL-C, and very low-density lipoprotein cholesterol (VLDL-C), in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia
• To assess the effects of 24 weeks of SC evolocumab QM compared with placebo QM on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia
• To assess the effects of 24 weeks of SC evolocumab QM compared with placebo QM on percent of subjects attaining a 50% reduction in LDL-C from baseline in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
* Subject has provided written informed consent
* Male or female ≥ 18 years of age at signing of informed consent
* Known HIV infection with stable HIV therapy for ≥ 6 months prior to
randomization and not expected to change during the duration of study participation. Stable HIV therapy is defined as no new agents added and no dose change of any HIV drug within 6 months prior to randomization
* Cluster of differentiation 4 (CD4) ≥ 250 cells/mm3 for ≥ 6 months prior to randomization
* HIV viral load ≤ 50 copies/mL at screening and ≤ 200 copies/mL for ≥ 6 months prior to randomization
* Subject on stable lipid-lowering therapy for ≥ 4 weeks prior to randomization
and not expected to change during the duration of study participation. Subjects should be on maximally tolerated dose of statins.
* Subject without known clinical atherosclerotic CVD (ASCVD): fasting LDL-C of ≥ 100 mg/dL (2.6 mmol/L) or non-HDL-C of ≥ 130 mg/dL (3.4 mmol/L) as determined by the central laboratory at screening. Subject with known clinical ASCVD: fasting LDL-C of ≥ 70 mg/dL (1.8 mmol/L) or non-HDL-C of ≥ 100mg/dL (2.6 mmol/L) as determined by the central aboratory.
* Fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L) as determined by central laboratory during screening
* Subject tolerates screening placebo injection |
|
E.4 | Principal exclusion criteria |
* Subject taking a combination of background lipid-lowering therapy and HIV therapy known to have significant drug-drug interaction
* New York Heart Association III or IV heart failure, or last known left ventricular ejection fraction < 30%
* Known opportunistic infection/AIDS defining illness (including but not limited to candidiasis of bronchi, trachea, esophagus, or lungs, invasive cervical cancer, coccidioidomycosis, cryptococcosis, chronic intestinal (> 1-month duration) cryptosporidiosis, cytomegalovirus disease (particularly cytomegalovirus [CMV] retinitis), HIV-related encephalopathy, herpes simplex: chronic ulcer(s) (> 28 days duration); or bronchitis, pneumonitis, or esophagitis, histoplasmosis,
chronic intestinal (> 28 days duration) isosporiasis, Kaposi's sarcoma,
lymphoma, mycobacterium avium complex, tuberculosis, pneumocystis carinii pneumonia, recurrent pneumonia, progressive multifocal leukoencephalopathy, salmonella septicemia, toxoplasmosis of brain, or wasting syndrome due to HIV within 1 year prior to randomization
* Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft or stroke within 3 months prior to randomization
* Type 1 diabetes, new-onset (hemoglobin A1c [HbA1c] ≥ 6.5% or fasting plasma glucose ≥ 126 mg/dL at screening without known diagnosis) or poorly controlled (HbA1c ≥ 10%) type 2 diabetes by central laboratory during screening
* Uncontrolled hypertension defined as sitting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg during screening
* Subject has taken a cholesterylester transfer protein inhibitor in the last 12 months prior to randomization
* Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate < 30 mL/min/1.73 m2 during screening
* Persistent active liver disease or hepatic dysfunction defined as Child-Pugh score of C. Stable (in the opinion of the primary investigator and with aspartate aminotransferase [AST] and alanine aminotransferase [ALT] < 5 times upper limit of normal [ULN] and not expected to require new treatment[s] during study) chronic hepatitis C of at least 1 year duration prior to randomization is allowed
* Female subject of childbearing potential not willing to use acceptable method(s) of effective birth control during treatment with IP and for an additional 15 weeks after the end of treatment with IP. Female subjects of non-childbearing potential are not required to use contraception during the study and include those who have had a hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or who are postmenopausal.
* Female subject is pregnant or breast feeding, planning to become pregnant or planning to breastfeed during treatment with IP and/or within 15 weeks after the end of treatment with IP
* Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years prior to randomization
* Subject has previously received evolocumab or any other therapy to inhibit PCSK9
* Currently receiving treatment in another investigational device or drug study, or < 30 days before randomization since ending treatment on another investigational device or drug study(s) or planning to receive other investigational procedures while participating in this study
* Subject has known sensitivity to any of the active substances or their excipients to be administered during dosing, eg, carboxymethylcellulose
* Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject’s and investigator’s knowledge
* History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint:
*Percent change from baseline in LDL-C at week 24
Safety endpoints
*Subject incidence of treatment emergent adverse events
*Safety laboratory values and vital signs at each scheduled assessment
*Incidence of anti-evolocumab antibody (binding and neutralizing) formation |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1, week 12, week 20, week 24, week 36, week 52 |
|
E.5.2 | Secondary end point(s) |
For week 24 the following secondary endpoints will be characterized:
• Tier 1
− Change from baseline in LDL-C
− Percent change from baseline in non-HDL-C
− Percent change from baseline in ApoB
− Percent change from baseline in TC
− Achievement of target LDL-C < 70 mg/dL (1.8 mmol/L)
− LDL-C response (50% reduction of LDL-C from baseline)
• Tier 2
− Percent change from baseline in Lp(a)
− Percent change from baseline in triglycerides
− Percent change from baseline in HDL-C
− Percent change from baseline in VLDL-C |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 1, week 12, week 20, week 24, week 36, week 52 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Belgium |
Brazil |
Canada |
France |
Greece |
Italy |
Poland |
Portugal |
Romania |
South Africa |
Spain |
Switzerland |
United Kingdom |
United States |
|
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 | 1 |
E.8.9.1 | In the Member State concerned days | 14 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 14 |