A Safety Study of GSK3039294 in Healthy Volunteers and Patients With Systemic Amyloidosis

NCT02603172 | Terminated Phase 1 Results

• 2 other identifiers: 2016642015-003088-13
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

GSK3039294 has been developed in order to offer an orally available alternative to parenteral CPHPC (GSK2315698 \[metabolite of GSK3039294\]) for plasma serum amyloid P component (SAP) depletion prior to use of anti SAP monoclonal antibody (mAb) in the treatment of systemic amyloidosis. This phase 1 study is intended to study safety, tolerability and pharmacokinetic (PK) profile of GSK3039294 in humans. This study consists of three parts. Part A will evaluate safety and tolerability of single doses of GSK3039294 in healthy subjects, Part B will evaluate safety and tolerability of repeat doses of GSK3039294 in healthy subjects, and Part C will evaluate safety and tolerability of repeat doses of GSK3039294 in subjects with systemic amyloidosis. Part A is a single dose, open label, dose escalation study. Two cohorts of subjects will be enrolled to provide data from 6 subjects per cohort and up to 4 different doses (2 dose levels per cohort) of GSK3039294 will be tested. For Cohorts 1 and 2, each subject may take part in two dosing periods. Part B is repeat dose, open label, dose escalation study. Sufficient number of subjects will be enrolled in Cohort 3a to ensure 6 completers (Cohort 3b will be conducted if required) and GSK3039294 will be administered repeatedly for a total of 21 days. Each subject will take part in a single study period. In Part C a single dose level of GSK3039294 will be tested for 21 days repeat dose, in 12 subjects with systemic amyloidosis. Each subject will take part in a single study period. The total duration for Part A is approximately 8 weeks, Part B is approximately 8-9 weeks, and Part C is approximately 13 weeks.

Conditions

Amyloidosis

Keywords

GSK3039294; GSK2315698; systemic amyloidosis; CPHPC; dose-escalation

Outcome Measures

Primary Outcomes (23)

• Part A:Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE is any untoward medical occurrence in a participants or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization clinical chemor prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention. Safety population consist of all participants who received at least one dose of the study medication.

  Up to Day 14

• Part A: Number of Participants With Emergent Clinical Chemistry by Potentially Clinical Importance (PCI) Criteria

  PCI ranges for the clinical chemistry parameters were as follows : albumin (low: \<0.86 gram \[g\] per liter \[L\]), calcium (low: \<0.91 millimole \[mmol\]/L and high: \>1.06 mmol/L), glucose (low: \<0.71 mmol/L and high: \>1.41 mmol/L), magnesium (low: \<0.63 mmol/L and high: \>1.03 mmol/L), phosphorous (low: \<0.80 mmol/L and high: \>1.14 mmol/L), potassium (low: \<0.86 mmol/L and high: \>1.10 mmol/L), sodium (low: \<0.96 mmol/L and high: \>1.03 mmol/L), and total carbon dioxide (CO2) (low: \<0.86 mmol/L and high: \>1.14 mmol/L).

  Day 1

• Part A: Number of Participants With Emergent Hematology by PCI Criteria

  PCI ranges for the hematology parameters were as follows: white blood cell (WBC) count (low: \<0.67 10\^9 cells/L and high: \>1.82 10\^9 cells/L), neutrophil count (low: \<0.83 10\^9 cells/L), hemoglobin (high: \>1.03 g/L in male, \>1.13 g/L in female), hemocrit (high: \>1.02 proportion of red blood cell \[RBC\] in blood for male, \>1.17 proportion of RBC in blood for female), platelet count (low: \<0.67 10\^9 cells/L and high: 1.57 10\^9 cells/L), and lymphocytes (low: \<0.81 10\^9 cells/L).

  Day 1

• Part A: Number of Participants With Abnormal Urinalysis Data by Dipstick

  Urine samples were collected and urinalysis included analysis of specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones by dipstick. The dipstick test gives results in a semi-quantitative manner.

  Day 1

• Part A: Mean Change From Baseline in 12-lead Electrocardiogram (ECG)

  Triplicate ECG was measured in semi-supine position after 5 minutes (min) rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and Fridericia's formula (QTcF) intervals. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

• Part A: Mean Change From Baseline in Heart Rate by 12-lead ECG

  Triplicate ECG was measured in semi-supine position after 5 min rest. A single 12-lead ECG was measured by using ECG machine that automatically measures the heart rate. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

• Part A: Mean Change From Baseline in Blood Pressure (BP)

  Systolic BP and diastolic BP were measured in semi-supine position after 5 min rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

• Part A: Mean Change From Baseline in Pulse Rate

  Pulse rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

• Part A: Mean Change From Baseline in Temperature

  Temperature was measured in semi-supine position after 5 min rest for the participants at indicated time points. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part A. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  Baseline (pre-dose) and 15, 30 minutes, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post-dose

• Part B:Number of Participants With AEs and SAEs

  An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention.

  Cohort 3: Up to Day 21; Cohort 4: Up to Day 35

• Part B: Number of Participants With Emergent Clinical Chemistry by PCI Criteria

  PCI ranges for the clinical chemistry parameters were as follows: albumin (low: \<0.86 g/L), calcium (low: \<0.91 mmol/L and high: \>1.06 mmol/L), glucose (low: \<0.71 mmol/L and high: \>1.41 mmol/L), magnesium (low: \<0.63 mmol/L and high: \>1.03 mmol/L), phosphorous (low: \<0.80 mmol/L and high: \>1.14 mmol/L), potassium (low: \<0.86 mmol/L and high: \>1.10 mmol/L), sodium (low: \<0.96 mmol/L and high: \>1.03 mmol/L), and total CO2 (low: \<0.86 mmol/L and high: \>1.14 mmol/L).

  Cohort 3 and 4: Up to Day 3

• Part B: Number of Participants With Emergent Hematology by PCI Criteria

  PCI ranges for the hematology parameters were as follows: WBC count (low: \<0.67 10\^9 cells/L and high: \>1.82 10\^9 cells/L), neutrophil count (low: \<0.83 10\^9 cells/L), hemoglobin (high: \>1.03 g/L in male, \>1.13 g/L in female), hemocrit (high: \>1.02 proportion of RBC in blood for male, \>1.17 proportion of RBC in blood for female), platelet count (low: \<0.67 10\^9 cells/L and high: 1.57 10\^9 cells/L), and lymphocytes (low: \<0.81 10\^9 cells/L).

  Cohort 3 and 4: Up to Day 3

• Part B: Number of Participants With Abnormal Urinalysis Data by Dipstick

  Urine samples were collected and urinalysis included analysis of specific gravity, pH, glucose, protein, blood, ketones by dipstick. The dipstick test gives results in a semi-quantitative manner.

  Cohort 3 and 4: Up to Day 3

• Part B: Mean Change From Baseline in 12-lead ECG

  Triplicate ECG was measured in semi-supine position after 5 minutes rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and QTcF intervals. Baseline is defined as the latest available assessment pre the first dose of study drug in Part B. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  Cohort 3: Baseline (pre-dose), Day 1 (1 hour), Days 2, 3, 4, 5, 6, 7 (pre-dose and 1 hour), 8 and 21; Cohort 4: Up to Day 35

• Part B: Mean Change From Baseline in Heart Rate by 12-lead ECG

  Triplicate ECG was measured in semi-supine position after 5 min rest. A single 12-lead ECG was measured by using ECG machine that automatically measures heart rate. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part B. Change from Baseline was calculated as any visit post Baseline value minus Baseline value.

  Cohort 3: Baseline (pre-dose), Day 1 (1 hour), Days 2, 3, 4, 5, 6, 7 (pre-dose and 1 hour), 8 and 21; Cohort 4: Up to Day 35

• Part B: Number of Participants With Abnormal Cardiac Telemetry Findings

  The cardiac monitoring was measured by using an appropriate nonimplantable recording device which is acceptable to the participants. This was evaluated the arrhythmic background of eligible cardiac amyloidosis participants such that false positive attribution of arrhythmias to GSK3039294 during repeat dosing was minimized.

  Cohort 3: Up to Day 8

• Part C: Number of Participants With AEs and SAEs

  An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  Up to Day 63

• Part C: Number of Participants With Emergent Clinical Chemistry by PCI Criteria

  PCI parameters for the clinical chemistry that were planned for analysis are as follows: albumin, calcium, glucose, magnesium, phosphorous , potassium , sodium , and total CO2. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  Up to Day 63

• Part C: Number of Participants With Emergent Hematology Parameters by PCI Criteria

  Hematology parameters that were planned for analysis were as follows: WBC count , neutrophil count , hemoglobin , hemocrit , platelet count , and lymphocytes. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  Up to Day 63

• Part C: Number of Participants With Emergent Urinalysis Parameters by PCI Criteria

  Urine samples were planned to be collected and urinalysis included analysis of specific gravity, pH, glucose, protein, blood, ketones by dipstick. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  Up to Day 63

• Part C: Number of Participants With Abnormal 12-lead ECG Findings

  Triplicate ECG was planned to be measured in semi-supine position after 5 minutes rest. A single 12-lead ECG was measured by using ECG machine that automatically measured PR, QRS, QT, and QTcF intervals. Baseline is defined as the latest available assessment pre the first dose of study drug within each period in Part C. Change from Baseline was calculated as any visit post Baseline value minus Baseline value. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  Up to Day 35

• Part C: Number of Participants With Abnormal Vital Signs

  Vital signs included systolic and diastolic BP, pulse rate, heart rate and temperature. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  Up to Day 35

• Part C: Number of Participants With Abnormal Cardiac Telemetry Findings

  The cardiac monitoring was planned to be measured by using an appropriate nonimplantable recording device which is acceptable to the participants. This was evaluated the arrhythmic background of eligible cardiac amyloidosis participants such that false positive attribution of arrhythmias to GSK3039294 during repeat dosing was minimized. This analysis was planned but not performed for Part C as the study was terminated early during Part B.

  Up to Day 35

Secondary Outcomes (28)

• Part A: Area Under the Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) of GSK3039294 and GSK2315698

  Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

• Part A: AUC(0-inf) Corrected for Dose of Prodrug (AUC[0-inf]/D) of GSK3039294 and GSK2315698

  Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

• Part A: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of GSK3039294 and GSK2315698

  Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

• Part A: AUC(0-t) Corrected for Dose of Prodrug (AUC[0-t]/D) of GSK3039294 and GSK2315698

  Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

• Part A: Maximum Observed Plasma Concentration (Cmax) of GSK3039294 and GSK2315698

  Pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 and 48 hours post-dose

Study Arms (5)

Part A: Cohort 1

EXPERIMENTAL

Subjects will receive a single dose of GSK3039294 (Dose level 1) on Day 1 and will remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14. Subjects will receive Dose level 2 on Day 15 (Period 2).

Drug: GSK3039294

Part A: Cohort 2

EXPERIMENTAL

Subjects will receive a single dose of GSK3039294 (Dose level 3) on Day 1 and will remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14. Subjects will receive Dose level 4 on Day 15 (Period 2).

Drug: GSK3039294

Part B: Cohort 3a

EXPERIMENTAL

Subjects will receive repeat dosing of GSK3039294 for a total of 21 days. The dose will be escalated every week throughout the study duration. Subjects will first receive a low dose given once daily. After 7 days, if well tolerated, the total daily dose will be increased and, GSK3039294 will be given, for example, as twice daily dosing for 7 days. At the end of this 7 day period and if previous dosing was well tolerated, the dose will be increased to a maximum daily dose that will not exceed pre-clinical safety exposure limits. On Day 4 and 5 GSK3039294 will be administered under fasted and fed conditions, respectively, to investigate the food effect on the PK.

Drug: GSK3039294

Part B: Cohort 3b

EXPERIMENTAL

Subjects will be enrolled in Cohort 3b only if required for further investigation. Subjects will receive GSK3039294 for 21 consecutive days and more than one dose level or regimen may be investigated, for example on the first 10 days the dose may be administered thrice daily, and on the last 11 days may be administered twice daily.

Drug: GSK3039294

Part C: Cohort 4

EXPERIMENTAL

Subjects will receive repeat dosing of GSK3039294 at the predicted optimal clinical dose determined from Part B for a total of 21 days.

Drug: GSK3039294

Interventions

GSK3039294 DRUG

GSK3039294 will be provided as white, opaque capsules. A single capsule or multiple capsules (20 mg to 200 mg), depending on the dosage required, will be taken orally with water.

Part A: Cohort 1; Part A: Cohort 2; Part B: Cohort 3a; Part B: Cohort 3b; Part C: Cohort 4

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age: 18 to 70 years of age inclusive at the time of signing the informed consent.
• Non-smokers and Smokers. Smokers (\<5 /day) are permitted but must be willing to abstain for the duration of residential study sessions and / or dosing period (whichever is longer).
• Body weight \>50 kilograms (kg) and body mass index (BMI) within the range 18.5-32 kg/square meter (m\^2) (inclusive) and excluding the effects of peripheral oedema.
• Male or female
• Female subjects are eligible to participate if they are of non-childbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy or bilateral oophorectomy; or postmenopausal defined as 12 month of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \>40 milli-international units (MIU)/milliliter (mL) and estradiol \< 40 picograms (pg)/mL (147 picomoles \[pmol\]/liter \[L\]) is confirmatory
• Male subjects with female partners of child bearing potential must comply with one of the following contraception requirements from the time of first dose of study medication until completion of the follow-up visit: (a.) Vasectomy with documentation of azoospermia; (b.) Male condom plus partner use of one of the following contraceptive options: Contraceptive subdermal implant that meets the effectiveness criteria of a \<1% rate of failure per year, as stated in the product label, Intrauterine device or intrauterine system that meets the standard operating procedure (SOP) effectiveness criteria including a \<1% rate of failure per year, as stated in the product label, Oral Contraceptive either combined or progestogen alone, Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches, Occlusive cap (female diaphragm or cervical/vault cap) with a vaginal spermicide (foam, gel, cream or suppository). These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

You may not qualify if:

• Prohibited medication
• History of regular alcohol consumption within 6 months of the study defined as: For United Kingdom (UK )sites - healthy volunteers: an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• History of sensitivity to any of the study medications, or metabolite thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation
• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
• A positive pre-study drug/alcohol screen
• A positive test for human immunodeficiency virus (HIV) antibody
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 84 days
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Prior to Part A for subjects participating in Parts A and B
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day Lactating females
• Poor or unsuitable venous access

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

MeSH Terms

Conditions

Amyloidosis; Immunoglobulin Light-chain Amyloidosis

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2015
• First Posted: November 11, 2015
• Study Start: May 12, 2016
• Primary Completion: May 10, 2017
• Study Completion: May 10, 2017
• Last Updated: September 23, 2019
• Results First Posted: September 23, 2019

Record last verified: 2019-08

Locations

GB (1)