Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AMG 986 Administered Orally to Healthy Volunteers and Participants With Severely Impaired Renal Function

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03318809
• Collaborator: (none)
• Enrollment: 12
• Locations: 4
• Arms: 2
• Actual Duration (Months): 3.7
• Patients Per Site: 3
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

A study to assess the safety, tolerability, and pharmacokinetics of AMG 986 given orally as a single dose to healthy participants and participants with severely impaired kidney function.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: AMG 986	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is a multisite (approximately 3 sites), open-label, non-randomized, single-dose study in participants with severely impaired kidney function and healthy participants. About 12 participants will be assigned to two groups: Group 1: 6 with severely impaired kidney function , and Group 2: 6 with normal kidney function.This is a multisite (approximately 3 sites), open-label, non-randomized, single-dose study in participants with severely impaired kidney function and healthy participants. About 12 participants will be assigned to two groups: Group 1: 6 with severely impaired kidney function , and Group 2: 6 with normal kidney function.
• Masking: None (Open Label)
• Masking Description: The patient, investigator, investigative staff, medical monitor and care provider will not be masked for the study.
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Single-dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AMG 986 Administered Orally to Healthy Volunteers and Subjects With Severely Impaired Renal Function
• Actual Study Start Date: Dec 12, 2017
• Actual Primary Completion Date: Mar 12, 2018
• Actual Study Completion Date: Apr 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1: Severely Renal Impaired Participants Participants with severely impaired renal function (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m^2) receive a single oral dose of 200 mg AMG 986.	Drug: AMG 986; tablets for oral administration
Active Comparator: Group 2: Healthy Participants Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) receive a single oral dose of 200 mg AMG 986.	Drug: AMG 986; tablets for oral administration

Outcome Measures

Primary Outcome Measures

1. AMG 986 Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Sample (AUClast) [Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose]

2. AMG 986 PK Parameter: Maximum Observed Plasma Concentration After Dosing (Cmax) [1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose]

3. AMG 986 PK Parameter: Terminal Phase Half-Life (t1/2,z) [Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose]

4. AMG 986 PK Parameter: Time of Maximum Plasma Concentration (Tmax) [Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose]

5. AMG 986 PK Parameter: Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUCinf) [Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose]

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [From first dose of study drug up to Day 30]

   An adverse event is defined as any untoward medical occurrence in a clinical trial subject. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: fatal life threatening (places the subject at immediate risk of death) requires in patient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male or female subjects, who are > or = 18 and < or = 65 years of age at the time of screening

• Subject has provided informed consent prior to initiation of any study-specific activities/procedures

• Women must be of non-reproductive potential (ie, postmenopausal, history of hysterectomy, or history of bilateral oophorectomy)

• Men must agree to practice an acceptable method of effective birth control while on study through 11 weeks after receiving the dose of study drug.

• Men must be willing to abstain from sperm donation while on study through 11 weeks after receiving the dose of study drug

• Body Mass Index > or = 18 and < or = 38 kg/m^2 at screening

• Physical examination and 12-lead electrocardiograms (ECGs) are clinically acceptable to the investigator

• Non-hypertensive subjects or subjects with treated, stable hypertension as defined by blood pressure not exceeding 170/100 mm Hg as an average during screening and day -1; for subjects with renal impairment, no change in dosage and medication for > or = 4 weeks prior to screening, and expected to remain on this dose and medication for the entire duration of the study

• Willing to maintain current general diet and physical activity regimen

• Renal function in 1 of the following 2 categories at the time of screening: Group 1 - Severe Renal Impairment (eGFR 15 to 29 mg/min/1.73 m^{2) and not anticipated to require hemodialysis or renal transplantation, and anticipated to have renal function appropriate to severe renal impairment for the duration of the study OR Group 2 - Normal renal function (eGFR > or = 90 mg/min/1.73 m}2)

Exclusion Criteria:

• Subjects whose second modification of diet in renal disease (MDRD) eGFR result on day -1 is not within 15% of the first eGFR result performed during the screening period. Healthy volunteers who have normal renal function, but show a difference greater than 15% in eGFR based on MDRD during the screening period, will be included in the trial at the discretion of the investigator and the sponsor after a 24-hour creatinine clearance has been performed that meets eligibility criteria.

• Subjects who are the recipient of a renal transplant and/or are on immunosupressants.

• Subjects with a history of hospitalization for heart disease or angina within 4 months of screening.

• Current or prior malignancy within 5 years of enrollment with the exception of non-melanoma skin cancers, cervical or breast ductal carcinoma in situ, and adenocarcinoma of the prostate Stage I or IIa (defined as T1, T2a or T2b, N0-, M0 with documented serum prostate-specific antigen (PSA) < 20 ng/mL and Gleason score ≤ 7) per the American Joint Committee on Cancer (AJCC) primary tumor, regional lymph nodes, and distant metastasis system.

• Positive for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C virus antibodies (HepCAb) at screening

• 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.

• Subject previously has entered this study or has been previously exposed to AMG 986.

• Heart rate ≥ 100 beats per minute after 5 minutes of rest or an untreated symptomatic bradyarrhythmia within 1 month prior to enrollment.

• Known history of drug or alcohol abuse within last 12 months.

• Currently receiving treatment in another investigational device or drug study or less than 30 days or 5 half-lives (whichever is longer) since ending treatment on another investigational device or drug study(s) prior to receiving the dose of investigational product (AMG 986).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Tustin	California	United States	92780
2	Research Site	Orlando	Florida	United States	32809
3	Research Site	Minneapolis	Minnesota	United States	55404
4	Research Site	San Antonio	Texas	United States	78215

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Sep 28, 2017
• Statistical Analysis Plan - Jan 12, 2018

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Trivedi A, Mather O, Vega S, Simiens MA, Hellawell J, Lee E. Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986. Drugs R D. 2022 Mar;22(1):89-94. doi: 10.1007/s40268-021-00380-1. Epub 2022 Jan 29.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03318809
• Other Study ID Numbers: 20150186
• First Posted: Oct 24, 2017
• Last Update Posted: Jun 23, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Amgen: Cardiovascular Diseases; Renal Impairment; Heart Diseases
• Additional relevant MeSH terms: Renal Insufficiency

Study Results

Participant Flow

Recruitment Details	This study was conducted in 4 centers in the United States.

Arm/Group Title	Group 1: Severely Renal Impaired Participants	Group 2: Healthy Participants
Arm/Group Description	Participants with severely impaired renal function (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.	Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.
Period Title: Overall Study
STARTED	6	6
COMPLETED	6	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Group 1: Severely Renal Impaired Participants	Group 2: Healthy Participants	Total
Arm/Group Description	Participants with severely impaired renal function (eGFR 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.	Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.	Total of all reporting groups
Overall Participants	6	6	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.7 (8.1)	57.8 (3.3)	57.3 (5.9)
Sex: Female, Male (Count of Participants)
Female	3 50%	3 50%	6 50%
Male	3 50%	3 50%	6 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 16.7%	1 8.3%
Not Hispanic or Latino	6 100%	5 83.3%	11 91.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 16.7%	1 16.7%	2 16.7%
Black (or African American)	3 50%	3 50%	6 50%
White	2 33.3%	2 33.3%	4 33.3%

Outcome Measures

1. Primary Outcome

Title	AMG 986 Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Sample (AUClast)
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants for whom at least 1 PK parameter or endpoint could be reliably estimated.

Arm/Group Title	Group 1: Severely Renal Impaired Participants	Group 2: Healthy Participants
Arm/Group Description	Participants with severely impaired renal function (eGFR 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.	Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.
Measure Participants	6	6
Geometric Mean (Geometric Coefficient of Variation) [hr*ng/mL]	80,000 (33.6)	64,500 (70.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Severely Renal Impaired Participants, Group 2: Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments	Analysis of Variance
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Group 1/Group 2)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 90%; 0.73 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	The ratio and confidence interval (CI) are based on natural log scale data converted back to the original scale.

2. Primary Outcome

Title	AMG 986 PK Parameter: Maximum Observed Plasma Concentration After Dosing (Cmax)
Time Frame	1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants for whom at least 1 PK parameter or endpoint could be reliably estimated.

Arm/Group Title	Group 1: Severely Renal Impaired Participants	Group 2: Healthy Participants
Arm/Group Description	Participants with severely impaired renal function (eGFR 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.	Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.
Measure Participants	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	10,600 (45.3)	7520 (50.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Severely Renal Impaired Participants, Group 2: Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments	Analysis of Variance
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Group 1/Group 2)
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 90%; 0.88 to 2.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	The ratio and CI are based on natural log scale data converted back to the original scale.

3. Primary Outcome

Title	AMG 986 PK Parameter: Terminal Phase Half-Life (t1/2,z)
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants for whom at least 1 PK parameter or endpoint could be reliably estimated.

Arm/Group Title	Group 1: Severely Renal Impaired Participants	Group 2: Healthy Participants
Arm/Group Description	Participants with severely impaired renal function (eGFR 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.	Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.
Measure Participants	6	6
Geometric Mean (Geometric Coefficient of Variation) [hours]	18.4 (21.1)	21.1 (44.6)

4. Primary Outcome

Title	AMG 986 PK Parameter: Time of Maximum Plasma Concentration (Tmax)
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants for whom at least 1 PK parameter or endpoint could be reliably estimated.

Arm/Group Title	Group 1: Severely Renal Impaired Participants	Group 2: Healthy Participants
Arm/Group Description	Participants with severely impaired renal function (eGFR 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.	Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.
Measure Participants	6	6
Median (Full Range) [hours]	1.1	1.5

5. Primary Outcome

Title	AMG 986 PK Parameter: Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUCinf)
Time Frame	Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants for whom at least 1 PK parameter or endpoint could be reliably estimated.

Arm/Group Title	Group 1: Severely Renal Impaired Participants	Group 2: Healthy Participants
Arm/Group Description	Participants with severely impaired renal function (eGFR 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.	Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.
Measure Participants	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	80,800 (33.6)	65,800 (68.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: Severely Renal Impaired Participants, Group 2: Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments	Analysis of Variance
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Group 1/Group 2)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 90%; 0.73 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	The ratio and CI are based on natural log scale data converted back to the original scale.

6. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	An adverse event is defined as any untoward medical occurrence in a clinical trial subject. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: fatal life threatening (places the subject at immediate risk of death) requires in patient hospitalization or prolongation of existing hospitalization results in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event
Time Frame	From first dose of study drug up to Day 30

Outcome Measure Data

Analysis Population Description

The safety analysis set included all study participants who received at least 1 dose of AMG 986.

Arm/Group Title	Group 1: Severely Renal Impaired Participants	Group 2: Healthy Participants
Arm/Group Description	Participants with severely impaired renal function (eGFR 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.	Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.
Measure Participants	6	6
TEAEs	2 33.3%	1 16.7%
Serious TEAEs	0 0%	0 0%

Adverse Events

Time Frame	From first dose of study drug up to Day 30
Arm/Group Title	Group 1: Severely Renal Impaired Participants		Group 2: Healthy Participants
Arm/Group Description	Participants with severely impaired renal function (eGFR 15 to 29 mL/min/1.73 m^2) received a single oral dose of 200 mg AMG 986.		Participants with normal renal function (eGFR >= 90 mL/min/1.73 m^2 or above) received a single oral dose of 200 mg AMG 986.
All Cause Mortality
	Group 1: Severely Renal Impaired Participants		Group 2: Healthy Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)
Serious Adverse Events
	Group 1: Severely Renal Impaired Participants		Group 2: Healthy Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Group 1: Severely Renal Impaired Participants		Group 2: Healthy Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		1/6 (16.7%)
Gastrointestinal disorders
Nausea	0/6 (0%)		1/6 (16.7%)
Nervous system disorders
Dizziness	0/6 (0%)		1/6 (16.7%)
Headache	1/6 (16.7%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/6 (16.7%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.