Clinical Trials Register

Summary
EudraCT Number:	2014-001197-34
Sponsor's Protocol Code Number:	200942
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-11
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2014-001197-34

A.3

Full title of the trial

A repeat-dose, open-label, parallel-group study to assess the pharmacokinetics of GSK1278863 and metabolites in subjects
with End Stage Renal Disease undergoing peritoneal dialysis.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Characterize the pharmacokinetics of GSK1278863 and metabolites in subjects with End Stage Renal Disease undergoing peritoneal dialysis

A.3.2

Name or abbreviated title of the trial where available

GSK1278863

A.4.1

Sponsor's protocol code number

200942

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GlaxoSmithKline Research & Development Ltd
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	The GlaxoSmithKline Group of Companies
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	The GlaxoSmithKline Group of Companies
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline Research & Development Ltd
B.5.2	Functional name of contact point	Clinical Trials Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	1-3 Iron Bridge Road, Stockley Park West
B.5.3.2	Town/ city	Uxbridge, Middlesex
B.5.3.3	Post code	UB11 1BT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+4402089904466
B.5.5	Fax number	+4402089901234
B.5.6	E-mail	GSKClinicalSupportHD@gsk.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	GSK1278863
D.3.2	Product code	GSK1278863
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GSK1278863
D.3.9.3	Other descriptive name	GSK1278863
D.3.9.4	EV Substance Code	SUB72830
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Anemia associated with chronic kidney disease (CKD)

E.1.1.1

Medical condition in easily understood language

Anemia associated with chronic kidney disease (CKD)

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10064848
E.1.2	Term	Chronic kidney disease
E.1.2	System Organ Class	100000004857

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Characterize the steady-state PK of GSK1278863 and metabolites
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), GSK2531401 (M13) in ESRD subjects undergoing peritoneal dialysis.

E.2.2

Secondary objectives of the trial

Evaluate the safety and tolerability of GSK1278863 in ESRD subjects
undergoing peritoneal dialysis

Characterize the peritoneal dialysis clearance of GSK1278863 and metabolites in ESRD subjects undergoing peritoneal dialysis

Characterize the plasma profile of erythropoietin and hepcidin after repeat-dose administration of GSK1278863 in ESRD subjects undergoing peritoneal dialysis

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

Safety
1. Satisfactory medical evaluation based upon medical history, medication history, physical examination, and clinical laboratory data obtained at the Screening visit. The determination of clinical significance will be made by the Investigator and the GSK Medical Monitor and will require that the finding is unlikely to introduce
additional risk factors or interfere with the study procedures, or the integrity of the study.

2. QTc < 470 msec OR QTc < 480 msec in subjects with Bundle Branch Block. These should be based on average of triplicate values obtained over a brief recording period at Screening and on Day -1 and the single reading on Day 17. The same QT correction formula should be used to determine inclusion and discontinuation for any individual subject throughout the study.

3. Vitamin B12 and folate above the lower limit of normal at Screening.

4. AST, ALT, and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

Efficacy
5. A subject is eligible to enroll and participate in this study if he/she has ESRD and is on peritoneal dialysis for at least 2 months with estimated minimal residual kidney function (average urine output < 100 mL/daily) with stable Kt/V urea > 1.7 weekly.

6. No history of peritoneal dialysis-associated peritonitis, peritoneal catheter tunnel (exit site) infection or leakage for at least 3 months before study.

7. Meets the following erythropoiesis stimulating agent (ESA) criteria:
- Is ESA naive (i.e., no ESA use within the previous 12 weeks of screening)
OR
- Agrees to discontinue ESA (if currently using ESA) for at least 7 days prior to first dose of GSK1278863 until completion of Follow-up visit.
a. If the subject has a scheduled ESA interval which is ≤ 7 days, ESA
treatment must be discontinued for at least 7 days prior to first dose of
GSK1278863
b. If the subject has a scheduled ESA interval which is > 7 days, ESA
treatment must be discontinued for at least the scheduled interval
length (e.g., if ESA interval is 14 days, then ESA must be discontinued
for > 14 days) prior to the first dose of GSK1278863

8. Has a hemoglobin value:
- For ESA naïve subjects: <10.0 g/dL
- For subjects receiving ongoing ESA treatment: Smaller than or equal to 11.0 g/dL at Screening.

Other
9. Subjects who are ≥ 18 years of age at the time of Screening.

10. A female subject is eligible to participate if she is of:
- Childbearing potential, and agrees to use one of the contraception methods described in the protocol. This criterion must be followed from the time of Screening until completion of the Follow-up Visit.
- Non-childbearing potential, defined as pre-menopausal females with a
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (In questionable cases, a blood sample with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 IU/L and estradiol ≤10 pg/mL (or ≤37 pmol/L) is confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods described in the protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study
enrollment. For most forms of HRT, at least 2 months must elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

11. Body weight > 45 kg and < 140 kg at Screening.

12. The subject is mentally and legally able to comply with the requirements and restrictions of the protocol and has provided signed informed consent prior to participation in any protocol-specific procedures, including Screening procedures.

E.4

Principal exclusion criteria

Safety
1. A positive test for HIV antibody.
2. Uncontrolled hypertension (diastolic BP >100 mmHg or
systolic BP >170 mmHg) at Screening.
3. History of drug abuse or dependence within 6 months of the study.
4. History of sensitivity to GSK1278863, or its components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.
5. History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency).
6. History of thrombosis defined as deep vein thrombosis, stroke, pulmonary embolism or other thrombosis related condition within 3 months prior to Screening.
7. History of myocardial infarction or acute coronary syndrome within 3 months prior to Screening.
8. History of stroke or transient ischaemic attack within 3 months prior to Screening.
9. Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, and/or hepatic function that could interfere with the absorption, metabolism, and/or excretion of GSK1278863. Examples of conditions that could interfere with normal gastrointestinal anatomy or motility include gastrointestinal
bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn’s disease, ulcerative colitis, or celiac sprue. Examples of conditions that could interfere with hepatic function include Gilbert’s syndrome.
10. Evidence of active peptic, duodenal or esophageal ulcer disease at Screening OR history of clinically significant GI bleeding within 3 months prior to Screening.
11. Subjects with chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease).
12. Subjects with a history of symptomatic right heart failure.
13. Subjects with Class III or Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
14. Active malignancy or diagnosis of malignancy within 5 years prior to Screening (excluding successfully treated basal or squamous cell carcinoma).
15. History of proliferative vascular eye disease (e.g., choroidal or retinal disease, such as neovascular age-related macular degeneration, proliferative diabetic retinopathy or macular edema) based upon having had an ophthalmologic exam within 12 months prior to Screening.
16. Pregnant females as determined by positive serum -hCG test at Screening or Day -1.
17. Lactating females.
18. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period prior to first dose.
19. Consumption of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, kale, broccoli, green beans, or apples from 7 days prior to the first dose of investigational product until the Follow-up visit, unless in the opinion of the Investigator and GSK Medical Monitor this will not interfere with the study procedures and compromise subject safety.
20. Use or planned use of any prescription or non-prescription drugs that are prohibited (see Section 5.10.2) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of GSK1278863 until completion of the follow-up visit, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or
compromise subject safety.
21. The following medications are specifically prohibited for the duration of the study (from Screening to the follow-up visit at the end of the study):
- Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) with the exception of low dose (≤325 mg/day) aspirin/acetylsalicylic acid. Occasional NSAID use is permitted (refer to Section 5.10.2.2).
- Immunosuppressant drugs and drugs used to treat malignancies (including corticosteroids at doses >10 mg prednisolone per day or equivalent) within 2 weeks of first dose of GSK1278863.
Note: Failed transplant subjects back on peritoneal dialysis are eligible for participating in this study but should not be on immunosuppressive medications within 3 months prior to Screening.
22. The subject has participated in a clinical trial and has received an experimental 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).
Efficacy
23. The values of ferritin and transferrin within 3 months prior to Screening are:
a. transferrin saturation < 20%
b. serum ferritin < 100 μg/L

Please refer to the protocol P22 for further details.

E.5 End points

E.5.1

Primary end point(s)

AUC(0-τ), AUC(0-∞) (Day 1 only), and Cmax of GSK1278863 and metabolites

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 1 and Day 14

E.5.2

Secondary end point(s)

• Subject incidence of treatment-emergent adverse events, including clinically-significant changes in physical exams, laboratory safety tests, ECG and vital signs

• Peritoneal dialysis clearance, tmax and t½ of GSK1278863 and metabolites

• Accumulation ratio and time invariance ratio (as data permit) of GSK1278863 and metabolites

•Erythropoietin and hepcidin plasma concentrations

E.5.2.1

Timepoint(s) of evaluation of this end point

• Adverse events: Day 1 to 17

• Laboratory safety tests, ECG, Vital signs: Day 1 & 17

• Peritoneal dialysis clearance, tmax and t½ of GSK1278863 and metabolites: Day 1 & 14

• Accumulation ratio and time invariance ratio (as data permit) of GSK1278863 and metabolites: Day 14

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pharmacokinetic

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

GSK1278863

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

United States

E.8.7

Trial has a data monitoring committee

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

LVLS

A completed subject is one who has completed all phases of the study including the follow-up visit.

The end of the study is defined as the last subject’s last visit.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects will not receive any additional treatment from GSK after completion of the study.

The Investigator is responsible for ensuring that consideration has been given to the poststudy care of the patient’s medical condition, whether or not GSK is providing specific post-study treatment.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-08-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-11-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-05-10

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