Adult Subjects With Elevated Low-Density Lipoprotein-Cholesterol to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects
Study Details
Study Description
Brief Summary
Objectives: The primary and secondary objectives of the study are presented below. Exploratory objectives are presented in the body of the protocol.
Primary:
• To determine the safety and tolerability of RN0191 administered as escalating single subcutaneously (SC) doses in adult subjects with elevated low-density lipoprotein-cholesterol
Secondary:
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To evaluate the single-dose pharmacokinetics (PK) of RN0191 in adult subjects with elevated low-density lipoprotein-cholesterol
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To evaluate the pharmacodynamic (PD) effect of RN0191 on serum levels of low-density lipoprotein-cholesterol (LDL-C)
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To evaluate the PD effect of RN0191 on plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9)
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a randomized, placebo-controlled, single ascending-dose (SAD) study of RN0191 administered SC to adult subjects with elevated low-density lipoprotein-cholesterol. Subjects who have signed an Ethics Committee (EC)-approved informed consent form (ICF) and have met all the protocol eligibility criteria during screening may be enrolled into the study. In this SAD study, adult subjects with elevated LDL-C will be enrolled in up to 4 cohorts. Each cohort will comprise 8 subjects randomized in a 3:1 ratio (1:1 ratio for sentinel subjects; 5:1 ratio for non-sentinel subjects) to receive a single dose of RN0191 (n=6) or placebo (n=2), respectively.
Subjects will be screened from Day -45 to Day -2 before study drug administration. Eligible subjects will be admitted to the clinical study site on Day -1 to determine continued eligibility and for baseline assessment. Subjects will be randomized on Day 1 of the residential period and will receive a single dose of RN0191 or placebo. Subjects will be discharged from the clinical study site on Day 2 after completing the 24-hour post dose follow-up assessments.
Subjects will return to the clinical study site on an outpatient basis for PK monitoring through Day 8, safety, tolerability assessments through Day 57, and for PD monitoring at specified time points through Day 85. If, at Day 85. LDL-C levels have not returned to ≥70% of baseline (average of all pre-dose values before dosing on Day 1), subjects will return to the clinical study site for PD monitoring visits on Day 99 and Day 113 and, thereafter, every 4 weeks until LDL-C levels return to ≥70% of baseline as described above.
Sentinel Dosing Dosing in all cohorts will begin with administration of RN0191 or placebo to two sentinel participants (one RN0191, one placebo). If deemed safe and tolerated by the Investigator, the same dose of RN0191 or placebo will be administered to subjects 3 to 8 at least 48 hours after dosing of Subject 2. Dose escalation will require approval by the Safety Review Committee (SRC) based on all cumulative safety, tolerability, available PK and PD data for prior cohorts, and through at least Day 8. the SRC will vote to approve the opening for enrollment of the next planned cohort/dose level. SRC decisions will be based on all cumulative safety, tolerability, available PK and PD data at least through Day 8 of the current cohort. Escalation to the next highest dose level will proceed until the dose level of 500mg is completed, or the trial is halted prematurely by the principal investigator (PI), SRC, or Sponsor due to safety or other reasons. All subjects who withdraw from the study prior to their End-of-Study (EOS) visit, for reasons other than an adverse event (AE), may be replaced.
The starting dose for subjects in Cohort 1 will be 25 mg RN0191 (or placebo). The following are the planned dose levels for subsequent cohorts in the SAD phase; however, the actual dose administered will be determined by the SRC:
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Cohort 2: 100 mg RN0191 or placebo
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Cohort 3: 300 mg RN0191 or placebo
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Cohort 4: 500 mg RN0191 or placebo The Sponsor may request an interim descriptive analysis of the change from baseline in PCSK9 and other lipid parameters any time after all subjects planned for enrollment in each cohort have received RN0191 or placebo. This interim analysis may be performed for administrative purposes and will not impact the conduct of this study. Descriptive statistics for change from baseline in PD measures will be evaluated based on multiple time points' change compare with baseline; the frequency of AEs for a specific preferred term will be calculated for pooled active and pooled placebo groups; the frequency of AEs for a specific preferred term will be calculated for pooled active and pooled placebo groups.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Cohort 1 will be 25 mg RN0191 (or placebo)
|
Drug: RN0191 INJECTION
a sterile solution in each bottle for subcutaneous (SC) injection
|
| Active Comparator: Cohort 1 will be 100 mg RN0191 (or placebo)
|
Drug: RN0191 INJECTION
a sterile solution in each bottle for subcutaneous (SC) injection
|
| Active Comparator: Cohort 1 will be 300 mg RN0191 (or placebo)
|
Drug: RN0191 INJECTION
a sterile solution in each bottle for subcutaneous (SC) injection
|
| Active Comparator: Cohort 1 will be 500 mg RN0191 (or placebo)
|
Drug: RN0191 INJECTION
a sterile solution in each bottle for subcutaneous (SC) injection
|
Outcome Measures
Primary Outcome Measures
- Exploratory objectives are presented in the body of the protocol. [For each subject in the study, the duration of the study clinic visits is approximately 21 weeks from screening to Day 85/EOS examination.]
• To determine the safety and tolerability of RN0191 administered as escalating single subcutaneously (SC) doses in adult subjects with elevated low-density lipoprotein-cholesterol
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male and female subjects, aged 18 to 60 years, inclusive.
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Body mass index between 18 and 32 kg/m2, inclusive, with body weight > 45 kg for females and >50 kg for males.
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Serum LDL-C ≥100mg/dL (2.6 mmol/L) at screening and Day -1.
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Fasting triglycerides < 400 mg/dL (<4.52 mmol/L) at screening and Day -1.
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Adequate complete blood counts (complete blood counts [CBCs]; if outside the reference range, CBC values that are not clinically relevant and are acceptable to the Investigator)
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Female subjects are eligible to participate if they are confirmed either not women of child-bearing potential (WOCBP), or have a negative urine pregnancy test at Day 1, are not breastfeeding, and willing and able to abide by the contraception guidelines.
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Male subjects who can produce viable sperm are eligible to participate if they agree to use an adequate method of contraception as per the contraceptive guidance from Screening (signing the ICF) until at least 3 months post dose. Subjects with a partner(s) who is (are) not of childbearing potential are exempt from these requirements.
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Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration. In addition, male subjects must refrain from donating sperm from Screening (signing the ICF) until at least 3 months post dose.
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Willing to comply with protocol required visit schedule and visit requirements and provide written informed consent
Exclusion Criteria:
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Male and female subjects, aged 18 to 60 years, inclusive.
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Body mass index between 18 and 32 kg/m2, inclusive, with body weight > 45 kg for females and >50 kg for males .
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Serum LDL-C ≥100mg/dL (2.6 mmol/L) at screening and Day -1.
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Fasting triglycerides < 400 mg/dL (<4.52 mmol/L) at screening and Day -1.
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Adequate complete blood counts (complete blood counts [CBCs]; if outside the reference range, CBC values that are not clinically relevant and are acceptable to the Investigator).
-
Female subjects are eligible to participate if they are confirmed either not women of child-bearing potential (WOCBP), or have a negative urine pregnancy test at Day 1, are not breastfeeding, and willing and able to abide by the contraception guidelines (signing the ICF).
-
Male subjects who can produce viable sperm are eligible to participate if they agree to use an adequate method of contraception as per the contraceptive guidance in Appendix 3 from Screening (signing the ICF) until at least 3 months post dose. Subjects with a partner(s) who is (are) not of childbearing potential are exempt from these requirements.
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Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration. In addition, male subjects must refrain from donating sperm from Screening (signing the ICF) until at least 3 months post dose.
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Willing to comply with protocol required visit schedule and visit requirements and provide written informed consent.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Ikaria Bioscience Pty Ltd
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- RN0191-101