| CTRI Number |
CTRI/2010/091/000282 [Registered on: 11/05/2010] |
| Last Modified On: |
25/02/2013 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
Type of Study
Modification(s)
|
Drug |
| Study Design |
Randomized, Parallel Group, Placebo Controlled Trial |
Public Title of Study
Modification(s)
|
Anemia in chronic Kidney disease (Oral Doses of GSK1278863A in anaemic pre-dialysis and hemodialysis-dependent patients) |
Scientific Title of Study
Modification(s)
|
GSK PHI112844: A Phase IIa, Randomized, Single-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of 28-day Repeat Oral Doses of GSK1278863A in anaemic pre-dialysis and hemodialysis-dependent patients |
| Trial Acronym |
|
Secondary IDs if Any
Modification(s)
|
| Secondary ID |
Identifier |
| NCT01047397 |
ClinicalTrials.gov |
| PHI112844 |
Other |
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Modification(s)
|
| Name |
Subhra Lahiri |
| Designation |
|
| Affiliation |
|
| Address |
Associate Vice President - Clinical Research
AXIS Clinicals Ltd, 1-121/1, Miyapur
Hyderabad
ANDHRA PRADESH
500050
India |
| Phone |
914040408035 |
| Fax |
914040408003 |
| Email |
Subhra.L@AxisClinicals.Com |
|
Details of Contact Person
Scientific Query
Modification(s)
|
| Name |
Subhra Lahiri |
| Designation |
|
| Affiliation |
|
| Address |
Associate Vice President - Clinical Research
AXIS Clinicals Ltd, 1121/1, Miyapur
Hyderabad
ANDHRA PRADESH
500050
India |
| Phone |
914040408035 |
| Fax |
914040408003 |
| Email |
Subhra.L@AxisClinicals.Com |
|
Details of Contact Person
Public Query
Modification(s)
|
| Name |
Subhra Lahiri |
| Designation |
|
| Affiliation |
|
| Address |
Associate Vice President - Clinical Research
AXIS Clinicals Ltd, 1-121/1, Miyapur
Hyderabad
ANDHRA PRADESH
500050
India |
| Phone |
914040408035 |
| Fax |
914040408003 |
| Email |
Subhra.L@AxisClinicals.Com |
|
Source of Monetary or Material Support
Modification(s)
|
| GlaxoSmithKline LLC,
Octagon Research Solutions, Incorporated
585 East Swedesford Road
Wayne, Pennsylvania 19087
USA |
|
Primary Sponsor
Modification(s)
|
| Name |
GlaxoSmithKline LLC |
| Address |
Octagon Research Solutions, Incorporated
585 East Swedesford Road
Wayne, Pennsylvania 19087
US |
| Type of Sponsor |
Pharmaceutical industry-Global |
|
Details of Secondary Sponsor
Modification(s)
|
| Name |
Address |
| AXIS Clinicals Ltd |
1-121/1, Miyapur,
Hyderabad-500049
INDIA |
|
Countries of Recruitment
Modification(s)
|
India
Australia
New Zealand
Russian Federation |
Sites of Study
Modification(s)
|
| No of Sites = 8 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr. Tarun Kumar Saha |
Apollo Hospitals |
St. John's Road,-500003
|
04027718888
04027712277
drtksaha@rediffmail.com |
| Dr Kalpana Mehta |
BYL Nair Hospitak |
Department of Nephrology
7th Floor, OPD Building
B. Y. L. Nair Hospital
A. L. Nair Road,
Mumbai Central,
Mumbai 400008
Mumbai
MAHARASHTRA |
04023027171
02223054531
kalpana.drs@gmail.com |
| Dr. G. Prasad |
King George Hospital |
Maharanipeta,-530002
|
0891 2717145
0891 2717145
drgullipalli123@yahoo.com |
| Dr. NP Singh |
MAMC - Lok Nayak Hospital |
122, BL Taneja Block,Jawaharlal Nehru Nagar-110002
New Delhi
DELHI |
011 23215510
011 23215510
nanu_singh@yahoo.com |
| Dr. Vishwanath S. |
Manipal Hospital |
98, Rustom Bagh,Old Airport Road-560017
Bangalore
KARNATAKA |
080 25023265
080 25207181
siddinivishwanath@hotmail.com |
| Dr. Manisha Sahay |
Osmania General Hospital |
Afzalgunj,-500012
Hyderabad
ANDHRA PRADESH |
04024617007
04024616687
drmanishasahay@gmail.com |
| Dr. Georgi Abraham |
Pondicherry Inst of Medical Sciences |
Kalathumettupathai,Kalapet-605014
Pondicherry
PONDICHERRY |
0413 2656702
0413 2656273
abraham_georgi@yahoo.com |
| Dr. Veerabhadra Gupta |
Rangdore Memorial Hospital |
1st Cross, Shankarpuram,Basavanagudi-560004
Bangalore
KARNATAKA |
080 26621642
080 26621645
drkvgupta@gmail.com |
|
Details of Ethics Committee
Modification(s)
|
| No of Ethics Committees= 8 |
| Name of Committee |
Approval Status |
| Ethics Committee-Apollo Hospitals |
Approved |
| Ethics Committee-BYL Nair Hospital & TN Medical College |
Approved |
| Ethics Committee-Manipal Hospital & Heart Foundation |
Approved |
| Ethics Committee-Osmania General Hospital |
Approved |
| Ethics Committee-Rangdore Memorial Hosiptal |
Approved |
| Institutional Ethics Committee, MAMC and Associated Lok Nayak, GB Pant Hospital, Guru Nanak Eye Center |
Approved |
| Institutional Ethics Committee-King George Hospital |
Approved |
| PIMS Institutional Ethical Committee |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
Health Condition / Problems Studied
Modification(s)
|
| Health Type |
Condition |
| Patients |
Anemia in Pre-dialysis and Hemodialysis-dependent Chronic Kidney Disease Patients, |
|
Intervention / Comparator Agent
Modification(s)
|
| Type |
Name |
Details |
| Intervention |
GSK1278863A |
25 Mg, once daily for 28 days orally. |
| Intervention |
GSK1278863A |
50 mg, once daily for 28 days orally. |
| Comparator Agent |
Placebo |
|
|
Inclusion Criteria
Modification(s)
|
| Age From |
18.00 Year(s) |
| Age To |
65.00 Year(s) |
| Gender |
Both |
| Details |
A patient will be eligible for inclusion in this study only if all of the following criteria apply:
1. Male or female between 18 and 85 years of age inclusive, at the time of signing the informed consent.
2. A male or female is eligible to enroll and participate in this study if he/she:
a. (Part 1) has Moderate to Severe Renal Impairment (equivalent to NKF KDOQI Stage 3 or 4, not receiving dialysis) as determined by estimated Glomerular Filtration Rate (eGFR) calculated by the abbreviated MDRD equation, and not expected to go on dialysis until ≥ 8 weeks after first administration of investigational product. Stage 5, non-dialysis patients with eGFR of 10 15 mL/min per 1.73 m2 will also be eligible for Part 1 on a case-by-case basis.
b. (Part 2) has Severe Renal Impairment and has been on stable hemodialysis treatment for 1 month prior to Screening (subjects with planned transition to hemodialysis) or 3 months prior to Screening (subjects emergently placed on hemodialysis). These subjects are equivalent to NKF KDOQI Stage 5.
c. otherwise healthy or considered clinically stable with respect to underlying renal impairment and with respect to underlying/chronic disease as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
d. has clinical laboratory test results that are considered clinically stable in the opinion of the principal investigator, especially if the clinical abnormality or laboratory parameter is deemed associated with the patient?s underlying renal impairment.
3. Meets the following erythropoiesis stimulating agent (ESA) criteria:
a. The patient is ESA naïve
OR
b. If the patient has a scheduled ESA interval which is ≤ 7 days, ESA treatment must be discontinued for at least 7 days
OR
c. If the patient has a scheduled ESA interval which is > 7 days, ESA treatment must be discontinued for at least that scheduled interval length (eg discontinued ≥ 14 days for a scheduled 14 day ESA interval)
AND
The patient will not resume ESA treatment until completion of the Follow-up Visit (Day 57).
4. Has a hemoglobin value:
a. For ESA naïve patients: ≤11.0 g/dL
b. For patients receiving ongoing ESA treatment: ≤11.5 g/dL at Screening with a re check value of ≤11.0 g/dL after appropriate ESA discontinuation according to Inclusion 3 and prior to commencing study drug dosing.
5. Has serum ferritin at Screening:
a. ≥40 μg/L with the absence of microcytic or hypochromic RBCs (regardless of transferrin saturation %)
OR
b. 25-39 μg/L with transferrin saturation % ≥20% (fraction saturation ≥0.20) and the absence of microcytic or hypochromic RBCs
6. Has Vitamin B12 and folate above the lower limit of normal at Screening
7. A female patient is eligible to participate if she is:
a. of childbearing potential, and must agree to use one of the contraception methods in Section 8.1.1. This criterion must be followed from the time of Screening until completion of the Follow-up Visit (Day 57).
OR
b. of 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) > 40 MlU/ml and estradiol < 40 pg/ml (<140 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 in Section 8.1.1 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 2-4 weeks will 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.
8. Male patients must agree to use one of the contraception methods listed in Section 8.1.2. This criterion must be followed from the time of the first dose of study drug until completion of the Follow-up Visit (Day 57).
9. Body weight ≥ 45 kg
10. QTcB or QTcF < 450 msec; or QTc < 480 msec in patients with bundle branch block. These should be based on an average of triplicate values obtained at Screening.
11. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form |
|
| ExclusionCriteria |
| Details |
A patient will not be eligible for inclusion in this study if any of the following criteria apply:
1. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months prior to Screening and one of the following:
? evidence of autoimmune anemia
? prior anti-viral therapy
? evidence of liver damage
2. A positive test for HIV antibody.
3. A pre-study drug screen that is positive due to drug use not associated with a current medication prescription. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
4. A value at Screening is greater than 1.5 times the upper limit of reference range for AST, ALT, or direct bilirubin.
5. Hemolysis/hemolytic anemia or active bleeding/blood loss
6. Androgen therapy within 8 weeks prior to first dose of study drug (Day 1).
7. Red blood cell transfusion within 90 days prior to first dose of study drug (Day 1).
8. Iron replacement therapy:
a. Intravenous iron replacement therapy within 30 days prior to the first dose of study drug on Day 1 until completion of the Follow-up Visit (Day 57).
b. Oral iron replacement therapy started or discontinued within 30 days prior to Screening. (Patients currently receiving oral iron replacement therapy which was initiated at least 30 days prior to Screening, will be allowed to continue their oral iron replacement therapy during the study and should not discontinue the therapy until after completion of all study drug doses and Day 29 assessments.)
9. History of thrombosis defined as deep vein thrombosis, stroke, pulmonary embolism or other thrombosis related condition within 1 year prior to Screening.
10. Known active decompensated hyperparathyroidism or history of bone marrow fibrosis.
11. Systemic hematologic disease, including, but not limited to sickle cell disease, hemosiderosis, hemochromatosis, myelodysplastic syndrome, hematologic malignancy, myeloma
12. Post-renal transplantation patients with functioning transplant. (Failed transplant subjects back on hemodialysis are eligible).
13. Acute peptic ulcer disease or history of chronic rectal bleeding.
14. History of malignancy tumor within 5 years prior to Screening or are receiving medication for cancer. Non-melanoma skin cancer within the past 5 years that has been definitively removed is allowed.
15. Patients 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 the study drugs. 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 Gilberts syndrome.
16. Active infection or acute inflammatory disease as determined by clinical assessment.
17. Class III heart failure with evidence of recent progression (worsening dyspnea, hospitalization within 2-3 months for symptoms, etc), or Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
18. Uncontrolled hypertension (diastolic BP >100 mmHg or systolic BP >160 mmHg at Screening)
19. Myocardial infarction or acute coronary syndrome within 1 year prior to Screening.
20. History of seizure disorder.
21. Proliferative choroidal or retinal disease, such as neovascular age-related macular degeneration or proliferative diabetic retinopathy that is likely to require treatment (intraocular injections or laser photocoagulation) during the study.
22. Pregnant females as determined by positive serum or urine hCG test at Screening or prior to the first dose of study drug (Day 1).
23. Lactating females.
24. History of drug abuse or dependence within 6 months prior to Screening.
25. Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.
26. Use of prescription drugs within 7 days prior to first dose of study drug (Day 1) until after completion of all study drug doses and Day 29 assessments:
? which are known to be inhibitors of CYP 2C8
OR
? which are known to be both CYP 2C8 and OATP1B1 substrates
OR
? which rely mainly on OATP1B1/1B3 for hepatic clearance as described in Section 9 of the protocol.
27. Use of prescription drugs within 14 days prior to first dose of study drug (Day 1) until completion of all study drug doses and Day 29 assessments, which are known to be inducers of CYP 2C8, as described in Section 9 of the protocol.
28. Use of non-prescription drugs, including vitamins, herbal and dietary supplements (including St John?s Wort) 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 study drug (Day 1) through the Follow-up Visit (Day 57), unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise patient safety and GSK Medical Monitor concurs.
29. History of sensitivity to any of the study drugs, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
30. History of sensitivity to heparin or heparin-induced thrombocytopenia. (if the clinical site uses heparin to maintain intravenous cannula patency)
31. The patient 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).
32. Exposure to more than four experimental investigational products within 12 months prior to the first dose of study drug (Day 1).
33. Patient is mentally or legally incapacitated |
|
Method of Generating Random Sequence
Modification(s)
|
Computer generated randomization |
Method of Concealment
Modification(s)
|
Centralized |
Blinding/Masking
Modification(s)
|
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded |
Primary Outcome
Modification(s)
|
| Outcome |
TimePoints |
1.Rate of response for patients achieving the target increases from baseline of hemoglobin levels, hemoglobin actual values, rate of rise, maximum change from baseline, and rate of decline following stopping of dosing
2. adverse events reporting, clinical safety laboratory tests (hematology, chemistry, and, when obtainable, urinalysis), vital signs (blood pressure and heart rate), ECG, and clinical monitoring/observation |
Screening, Day 1, 4, 8, 15, 22, 29, 36, 57 |
|
Secondary Outcome
Modification(s)
|
| Outcome |
TimePoints |
1.AUC(0-∞), AUC(0-τ), Cmax, tmax and t1/2, on Days 1, 15, and 22 through sparse sampling/population pharmacokinetics in subset of patients.
2. Actual values and change from baseline for erythropoietin, absolute and percent reticulocytes, hematocrit, and total RBCs.
3. Actual values and change from baseline for VEGF, hepcidin, TIBC, transferrin saturation (%), serum iron, serum ferritin, and fetal hemoglobin, as appropriate (also fetal hemoglobin as a percent of total hemoglobin) |
Day 1, 4, 8,15, 22, 29 and 57 |
|
Target Sample Size
Modification(s)
|
Total Sample Size="140"
Sample Size from India="40"
Final Enrollment numbers achieved (Total)= ""
Final Enrollment numbers achieved (India)="" |
Phase of Trial
Modification(s)
|
Phase 2 |
Date of First Enrollment (India)
Modification(s)
|
07/06/2010 |
| Date of Study Completion (India) |
Date Missing |
| Date of First Enrollment (Global) |
12/03/2010 |
| Date of Study Completion (Global) |
Date Missing |
Estimated Duration of Trial
Modification(s)
|
Years="1"
Months="0"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Completed |
| Recruitment Status of Trial (India) |
Completed |
Publication Details
Modification(s)
|
None Yet |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
|
Brief Summary
Modification(s)
|
Compound 1278863A is a novel small molecule agent, which stimulates erythropoiesis through inhibition of hypoxia-inducible factor (HIF)-prolyl hydroxylases (EGLNs). This compound is being developed for the treatment of anemia. This study, PHI112844, will be the first administration of compound 1278863A to investigate the pharmacodynamics/efficacy, safety, tolerability, and pharmacokinetics of repeat oral doses in anemic pre-dialysis patients with moderate or severe renal impairment and in hemodialysis-dependent CKD patients. India will recruit 45 patients starting 1 June 2010. |