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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02603172
• Date of registration: 09/11/2015
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: A Safety Study of GSK3039294 in Healthy Volunteers and Patients With Systemic Amyloidosis
• Scientific title: A Three-part Open-label, Non-randomised, Dose-escalation Study to Investigate the Safety and Tolerability of GSK3039294 Administered as a Single Dose to Healthy Volunteers, and as Repeat Dose to Healthy Volunteers and Patients With Systemic Amyloidosis
• Date of first enrolment: May 12, 2016
• Target sample size: 23
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT02603172
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

United Kingdom

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion criteria

Inclusion Criteria:

- 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.

- Additional Inclusion Criteria - Healthy Volunteers: Healthy as determined by a
responsible and experienced physician, based on a medical evaluation including medical
history, physical examination, laboratory tests and cardiac monitoring.

- Additional Inclusion Criteria - Healthy Volunteers: A subject with a clinical
abnormality or laboratory parameter(s) which is/are not specifically listed in the
inclusion or exclusion criteria, outside the reference range for the population being
studied may be included only if the investigator in consultation with the Medical
Monitor if required agree and document that the finding is unlikely to introduce
additional risk factors and will not interfere with the study procedures.

- Additional Inclusion Criteria - Healthy Volunteers: aspartate aminotransferase (AST),
alanine transaminase (ALT), alkaline phosphatase and bilirubin <=1.5 upper limit of
normal (ULN) (isolated bilirubin >1.5 ULN is acceptable if bilirubin is fractionated
and direct bilirubin <35%)

- Additional Inclusion Criteria - Patients: Subject medically diagnosed with systemic
amyloidosis

- Additional Inclusion Criteria - Patients: serum amyloid P component (SAP) scan
identifying amyloid at any anatomical site, including subset of patients with
moderate-large amyloid load in the liver

- Additional Inclusion Criteria - Patients: Up to and including New York Heart
Association (NYHA) class 2 with a stable clinical cardiac status 12 weeks prior to
screening

- Additional Inclusion Criteria - Patients: For Amyloid Light-chain (AL) amyloidosis
patients, >=12 months post-chemotherapy with a stable free light chain (FLC) ratio in
the preceding 4 months

- Additional Inclusion Criteria - Patients: estimated glomerular filtration rate (eGFR)
>50 mL/minute

- Additional Inclusion Criteria - Patients: Alanine amino transferase (ALT) <=3x upper
limit of normal (ULN) and bilirubin <=1.5x ULN (isolated bilirubin >1.5 xULN is
acceptable if bilirubin was fractionated and direct bilirubin <35%), irrespective of
alkaline phosphatase (ALP) level

- Additional Inclusion Criteria - Patients: Subject is ambulant and capable of attending
the clinical unit

Exclusion Criteria:

- 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

- Additional Exclusion Criteria - Healthy Volunteer: Current or chronic history of liver
disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's
syndrome or asymptomatic gallstones)

- Additional Exclusion Criteria - Healthy Volunteer: corrected QT interval using
Fridericia's formula (QTcF) >450 milliseconds (msec) fr


Age minimum: 18 Years
Age maximum: 70 Years
Gender: All

Health Condition(s) or Problem(s) studied

Amyloidosis

Intervention(s)

Drug: GSK3039294

Primary Outcome(s)

Part A: Number of Participants With Abnormal Urinalysis Data by Dipstick [Time Frame: Day 1]

Part A:Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time Frame: Up to Day 14]

Part C: Number of Participants With Abnormal Cardiac Telemetry Findings [Time Frame: Up to Day 35]

Part C: Number of Participants With Abnormal Vital Signs [Time Frame: Up to Day 35]

Part C: Number of Participants With Emergent Hematology Parameters by PCI Criteria [Time Frame: Up to Day 63]

Part A: Mean Change From Baseline in 12-lead Electrocardiogram (ECG) [Time Frame: 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 [Time Frame: 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) [Time Frame: 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 [Time Frame: Cohort 3: Up to Day 21; Cohort 4: Up to Day 35]

Part A: Number of Participants With Emergent Clinical Chemistry by Potentially Clinical Importance (PCI) Criteria [Time Frame: Day 1]

Part B: Mean Change From Baseline in Heart Rate by 12-lead ECG [Time Frame: 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 A: Mean Change From Baseline in Pulse Rate [Time Frame: 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 [Time Frame: 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 Emergent Hematology by PCI Criteria [Time Frame: Cohort 3 and 4: Up to Day 3]

Part B: Number of Participants With Abnormal Urinalysis Data by Dipstick [Time Frame: Cohort 3 and 4: Up to Day 3]

Part C: Number of Participants With Emergent Urinalysis Parameters by PCI Criteria [Time Frame: Up to Day 63]

Part B: Number of Participants With Emergent Clinical Chemistry by PCI Criteria [Time Frame: Cohort 3 and 4: Up to Day 3]

Part C: Number of Participants With Abnormal 12-lead ECG Findings [Time Frame: Up to Day 35]

Part C: Number of Participants With AEs and SAEs [Time Frame: Up to Day 63]

Part C: Number of Participants With Emergent Clinical Chemistry by PCI Criteria [Time Frame: Up to Day 63]

Part A: Number of Participants With Emergent Hematology by PCI Criteria [Time Frame: Day 1]

Part B: Mean Change From Baseline in 12-lead ECG [Time Frame: 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 [Time Frame: Cohort 3: Up to Day 8]

Secondary Outcome(s)

Part A: Time to Reach Cmax (Tmax) of GSK3039294 and GSK2315698 [Time Frame: 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 B: Area Under the Concentration-time Curve From Time Zero to 6 Hours Post Dose (AUC[0-6]) of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part A: AUC(0-inf) Corrected for Dose of Prodrug (AUC[0-inf]/D) of GSK3039294 and GSK2315698 [Time Frame: 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 B: AUC(0-t) of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part C: AUC(0-t) of GSK3039294 and GSK2315698 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Part A: Maximum Observed Plasma Concentration (Cmax) of GSK3039294 and GSK2315698 [Time Frame: 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 B: AUC([0-inf]/D) of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part B: AUC(0-inf) of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part B: t1/2 of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part C: Cmax/D of GSK3039294 and GSK2315698 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Part A: Area Under the Concentration-time Curve Extrapolated to Infinity (AUC[0-inf]) of GSK3039294 and GSK2315698 [Time Frame: 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 B: Plasma Serum Amyloid P Component (SAP) Level of GSK3039294 [Time Frame: Cohort 3:Days1(pre-dose, 2hour post-dose),2(pre-dose),4(pre-dose),5(pre-dose, 30min,1,2,3,4,6 hours post-dose),7(pre-dose)and 21post-dose;Cohort4:Days1(pre-dose, 2 hour post-dose),2(pre-dose),4(pre-dose), 5(pre-dose, and 2 hours post-dose) and 35post-dose]

Part A: Terminal Half-life (t1/2) of GSK3039294 and GSK2315698 [Time Frame: 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 C: AUC(0-inf)/D of GSK3039294 and GSK2315698 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Part C: Tmax of GSK3039294 and GSK2315698 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Part C: Time to Repletion of SAP [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Part C: Cmax of GSK3039294 and GSK2315698 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

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 [Time Frame: 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 [Time Frame: 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 B: Cmax of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part B: Tmax of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part C: t1/2 of GSK3039294 and GSK2315698 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Part C: AUC(0-inf) of GSK3039294 and GSK2315698 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Part C: AUC(0-t)/D of GSK3039294 and GSK2315698 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Part B: AUC(0-t)/D of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part A: Cmax Corrected for Dose of Prodrug (Cmax/D) of GSK3039294 and GSK2315698 [Time Frame: 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 B: Cmax/D of GSK3039294 and GSK2315698 [Time Frame: Cohort 3- Day 4 and 5: pre-dose, and 0.5, 1, 2, 3, 4, and 6 hours post-dose; Cohort 4: Day 4 (pre-dose), Day 5 (pre-dose and 0.5, 1, 2, 3, 4, and 6 hours post-dose)]

Part C: Plasma SAP Levels of GSK3039294 [Time Frame: Day 1 (pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 hours post-dose); Day 2 to 20 (pre-dose); Day 21 (pre-dose, and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose; Week 4 and 5]

Secondary ID(s)

2015-003088-13

201664

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 23/09/2019
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02603172