Etanercept Plus Methotrexate Versus Methotrexate Alone in Children With Polyarticular Course Juvenile Rheumatoid Arthritis

• Sponsor: Amgen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03781375
• Collaborator: (none)
• Enrollment: 25
• Arms: 2
• Actual Duration (Months): 22

Study Details

Study Description

Brief Summary

The primary objective of this study was to determine the efficacy of etanercept plus methotrexate vs methotrexate alone in pediatric patients with active polyarticular course juvenile rheumatoid arthritis (JRA).

Condition or Disease	Intervention/Treatment	Phase
Juvenile Rheumatoid Arthritis	Drug: Etanercept; Drug: Placebo to Etanerceot; Drug: Methotrexate	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III Double Blind Randomized Study Comparing Etanercept (Enbrel) Combined With Methotrexate vs Methotrexate Alone in Children With Polyarticular Course Juvenile Rheumatoid Arthritis
• Actual Study Start Date: Aug 24, 2000
• Actual Primary Completion Date: Jun 20, 2002
• Actual Study Completion Date: Jun 24, 2002

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Methotrexate + Placebo Participants received placebo subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.	Drug: Etanercept; Administered by subcutaneous injection twice a week; Other Names: Enbrel ; Drug: Placebo to Etanerceot; Administered by subcutaneous injection twice a week; Drug: Methotrexate; Administered orally or subcutaneously once a week at the same dose as prior to study entry
Experimental: Methotrexate + Etanercept Participants received 0.4 mg/kg etanercept subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.	Drug: Etanercept; Administered by subcutaneous injection twice a week; Other Names: Enbrel ; Drug: Methotrexate; Administered orally or subcutaneously once a week at the same dose as prior to study entry

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a JRA Response at Month 6 [Baseline and month 6]

   Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 30% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR)

Secondary Outcome Measures

1. Percentage of Participants With a 50% Improvement in JRA DOI at Month 6 [Baseline and month 6]

   Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 50% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR)

2. Percentage of Participants With a 70% Improvement in JRA DOI at Month 6 [Baseline and month 6]

   Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 70% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR)

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have had a diagnosis of JRA by the American College of Rheumatology (ACR) criteria. Disease onset may have been systemic, polyarticular, or pauciarticular

• Disease course must have been polyarticular with at least 5 active joints

• Duration of disease was not limited, but must have been long enough for the patient to have been given a 3-month trial of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate at a dose between 0.3 and 1.0 mg/kg/week, orally (PO) or subcutaneously (SC)

• Receiving methotrexate at a dose between 0.3 mg/kg/wk and 1 mg/kg/wk at time of randomization. The dose of methotrexate must have been stable for one month prior to entry

• Patients may have failed prednisone, or been on a dosage of prednisone not to have exceeded 10 mg/day or 0.20 mg/kg/day (whichever was less)

• At the time of qualification (screening) for study and prior to wash-out of all disease modifying anti-rheumatic drugs (DMARDs), the patient must have had active disease, defined as ≥ 5 swollen joints accompanied by pain, and/or tenderness and/or warmth, and ≥ 3 joints with limitation of motion (LOM). (The joints with LOM may have been the same as those with swelling)

• Had good venous access and stable hematocrit ≥ 24 mL/dL

• Patients must have been pre-pubescent, or if post-pubertal at anytime during the study, and of child-bearing potential, must have been practicing adequate contraception

• Parent or legal guardian was able and willing to give informed consent

• Parent or legal guardian must have been willing to actively supervise storage and administration of study drug and ensure that the date and time of each dose was accurately recorded in the subject's diary

Exclusion Criteria:

• Was unable to meet the concurrent medication restrictions as described in the protocol

• Pregnant or nursing female

• Patients were excluded if they demonstrated clinically significant deviations from normal (as defined below) in any of the following laboratory parameters:

• thrombocytopenia; platelet count < 100,000/cmm

• leukopenia; total white cell count < 4000 cells/cmm

• neutropenia; neutrophils < 1000 cells/cmm

• hepatic transaminase levels > two times the upper limit of normal (ULN)

• serum bilirubin > two times the ULN

• estimated creatinine clearance of < 90 mL/min/1.73 M² body surface area (BSA)

• known human immunodeficiency virus (HIV), hepatitis B surface antigen positivity not related to vaccination, or hepatitis C antibody positivity

• Had received etanercept, antibody to tumor necrosis factor (TNF) (i.e. infliximab or D2E7), antibody to cluster of differentiation (CD)4 (anti-CD4), diphtheria interleukin (IL)-2 fusion protein (DAB-IL-2) or leflunomide

• Had received DMARDs including D-penicillamine, hydroxychloroquine, sulfasalazine, oral or injectable gold, cyclosporin, azathioprine; intravenous immunoglobulin (IV Ig); or broadly immunosuppressant chemotherapeutic agents (e.g. cyclophosphamide, FK506, mycophenolate mofetil [CellCept]), for at least 28 days prior to enrollment and dosing of study drug. All DMARDs, other than methotrexate, must have been washed-out for a minimum of 28 days

• Had received intraarticular glucocorticoid injection within 28 days prior to enrollment on study

• Had previously received live virus vaccine within 3 months prior to study entry

• Had participated in a study of an investigational drug or biologic requiring informed-consent within three months prior to study entry

• Any concurrent medical condition which would have, in the investigator's opinion, compromised the patient's ability to tolerate the study drug or would have made the patient unable to cooperate with the protocol

• History of/or current psychiatric illness that would have interfered with ability to comply with protocol requirements or give informed consent

• Chronic or recurrent infections, or currently active infection at screening

• History of alcohol or drug abuse that would have interfered with ability to comply with protocol requirements

• Inability to have complied with the study requirements

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03781375
• Other Study ID Numbers: 20021628; 016.0028
• First Posted: Dec 19, 2018
• Last Update Posted: Aug 2, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Arthritis, Juvenile; Etanercept; Methotrexate

Study Results

Participant Flow

Recruitment Details	This study was conducted at 7 centers in the United States. The study consisted of a 6-month double-blind treatment period followed by a 6-month open-label period where all participants received etanercept + methotrexate. Early transition to open-label treatment was allowed after 2 months of blinded treatment, for disease flare or lack of response.
Pre-assignment Detail	Participants were randomized equally into 1 of 2 treatments for the double-blind portion of the study. Randomization was stratified by route of methotrexate administration (oral [PO] vs subcutaneous [SC]) prior to randomization.

Arm/Group Title	Methotrexate + Placebo	Methotrexate + Etanercept
Arm/Group Description	Participants received placebo subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.	Participants received 0.4 mg/kg etanercept subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.
Period Title: Double-blind Phase
STARTED	12	13
Received Study Drug	12	13
COMPLETED	5	7
NOT COMPLETED	7	6
Period Title: Double-blind Phase
STARTED	11	9
Received Study Drug	10	9
COMPLETED	8	6
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Methotrexate + Placebo	Methotrexate + Etanercept	Total
Arm/Group Description	Participants received placebo subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.	Participants received 0.4 mg/kg etanercept subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.	Total of all reporting groups
Overall Participants	12	13	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.75 (5.71)	11.38 (3.40)	10.12 (4.75)
Sex: Female, Male (Count of Participants)
Female	7 58.3%	6 46.2%	13 52%
Male	5 41.7%	7 53.8%	12 48%
Race/Ethnicity, Customized (Count of Participants)
White	10 83.3%	10 76.9%	20 80%
Black	2 16.7%	0 0%	2 8%
Hispanic	0 0%	2 15.4%	2 8%
Oher	0 0%	1 7.7%	1 4%
Methotrexate Dosage Route (Count of Participants)
Orally	5 41.7%	6 46.2%	11 44%
Subcutaneously	7 58.3%	7 53.8%	14 56%
Type of Arthritis at Onset (Count of Participants)
Pauciarticular	1 8.3%	4 30.8%	5 20%
Polyarticular	7 58.3%	9 69.2%	16 64%
Systemic	4 33.3%	0 0%	4 16%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a JRA Response at Month 6
Description	Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 30% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR)
Time Frame	Baseline and month 6

Outcome Measure Data

Analysis Population Description

All randomized participants; participants with missing data are counted as non-responders.

Arm/Group Title	Methotrexate + Placebo	Methotrexate + Etanercept
Arm/Group Description	Participants received placebo subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.	Participants received 0.4 mg/kg etanercept subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.
Measure Participants	12	13
Number [percentage of participants]	33 275%	38 292.3%

2. Secondary Outcome

Title	Percentage of Participants With a 50% Improvement in JRA DOI at Month 6
Description	Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 50% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR)
Time Frame	Baseline and month 6

Outcome Measure Data

Analysis Population Description

All randomized participants; participants with missing data were counted as non-responders.

Arm/Group Title	Methotrexate + Placebo	Methotrexate + Etanercept
Arm/Group Description	Participants received placebo subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.	Participants received 0.4 mg/kg etanercept subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.
Measure Participants	12	13
Number [percentage of participants]	25 208.3%	38 292.3%

3. Secondary Outcome

Title	Percentage of Participants With a 70% Improvement in JRA DOI at Month 6
Description	Response was defined using the JRA definition of improvement (JRA DOI) as a ≥ 70% improvement from baseline in at least three of the six JRA Core Set Criteria and ≥ 30% worsening in not more than one of the six assessments. The JRA Core Set Criteria consist of: Physician's global assessment of disease severity assessed on a visual analog scale (VAS) from 1 to 10 Patient's/Parent's global assessment of overall well being assessed on a VAS from 1 to 10 Number of active joints (swelling, not due to deformity, or if no swelling is present, limitation of motion accompanied by pain on passive motion and/or tenderness and/or warmth) Number of joints with limitation of motion Childhood Health Assessment Questionnaire (CHAQ) Erythrocyte sedimentation rate (ESR)
Time Frame	Baseline and month 6

Outcome Measure Data

Analysis Population Description

All randomized participants; participants with missing data were counted as non-responders.

Arm/Group Title	Methotrexate + Placebo	Methotrexate + Etanercept
Arm/Group Description	Participants received placebo subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.	Participants received 0.4 mg/kg etanercept subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months. After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.
Measure Participants	12	13
Number [percentage of participants]	8 66.7%	38 292.3%

Adverse Events

Time Frame	Up to 12 months on-study evaluations plus 1 month follow-up
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Methotrexate + Placebo (Blinded Phase)		Methotrexate + Etanercept (Blinded Phase)		Methotrexate + Etanercept (Open Label Phase)
Arm/Group Description	Participants received placebo subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months.		Participants received 0.4 mg/kg etanercept subcutaneous injections twice weekly and methotrexate once a week at the same dose as prior to study entry for 6 months.		After month 6 participants received open-label 0.4 mg/kg etanercept twice weekly plus methotrexate for an additional 6 months.
All Cause Mortality
	Methotrexate + Placebo (Blinded Phase)		Methotrexate + Etanercept (Blinded Phase)		Methotrexate + Etanercept (Open Label Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Methotrexate + Placebo (Blinded Phase)		Methotrexate + Etanercept (Blinded Phase)		Methotrexate + Etanercept (Open Label Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		1/13 (7.7%)		0/19 (0%)
Infections and infestations
Appendicitis	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Metabolism and nutrition disorders
Dehydration	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Methotrexate + Placebo (Blinded Phase)		Methotrexate + Etanercept (Blinded Phase)		Methotrexate + Etanercept (Open Label Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)		12/13 (92.3%)		15/19 (78.9%)
Blood and lymphatic system disorders
Anaemia	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Leukopenia	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Lymphadenopathy	0/12 (0%)		2/13 (15.4%)		1/19 (5.3%)
Ear and labyrinth disorders
Cerumen impaction	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Ear pain	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Tinnitus	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Eye disorders
Blepharospasm	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Uveitis	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Vision blurred	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Gastrointestinal disorders
Abdominal pain	2/12 (16.7%)		3/13 (23.1%)		2/19 (10.5%)
Abdominal pain upper	2/12 (16.7%)		1/13 (7.7%)		2/19 (10.5%)
Abdominal tenderness	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Constipation	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Diarrhoea	3/12 (25%)		0/13 (0%)		3/19 (15.8%)
Flatulence	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Gastritis	0/12 (0%)		1/13 (7.7%)		1/19 (5.3%)
Mouth ulceration	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Nausea	1/12 (8.3%)		1/13 (7.7%)		0/19 (0%)
Rectal haemorrhage	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Stomatitis	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Vomiting	3/12 (25%)		3/13 (23.1%)		3/19 (15.8%)
General disorders
Chest pain	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Fatigue	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Injection site erythema	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Injection site pain	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Injection site pruritus	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Injection site rash	0/12 (0%)		1/13 (7.7%)		1/19 (5.3%)
Injection site reaction	0/12 (0%)		0/13 (0%)		3/19 (15.8%)
Oedema peripheral	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Pain	0/12 (0%)		1/13 (7.7%)		1/19 (5.3%)
Peripheral swelling	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Pyrexia	2/12 (16.7%)		0/13 (0%)		0/19 (0%)
Immune system disorders
Seasonal allergy	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Infections and infestations
Beta haemolytic streptococcal infection	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Cellulitis	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Chronic sinusitis	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Fungal skin infection	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Gastroenteritis	0/12 (0%)		0/13 (0%)		2/19 (10.5%)
Gastroenteritis viral	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Influenza	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Otitis media	2/12 (16.7%)		0/13 (0%)		3/19 (15.8%)
Pharyngitis	0/12 (0%)		1/13 (7.7%)		1/19 (5.3%)
Rhinitis	0/12 (0%)		0/13 (0%)		2/19 (10.5%)
Sinusitis	2/12 (16.7%)		1/13 (7.7%)		2/19 (10.5%)
Upper respiratory tract infection	2/12 (16.7%)		4/13 (30.8%)		2/19 (10.5%)
Urinary tract infection	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Injury, poisoning and procedural complications
Fall	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Meniscus injury	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Mouth injury	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Thermal burn	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Investigations
Blood pressure diastolic increased	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Body temperature increased	1/12 (8.3%)		0/13 (0%)		1/19 (5.3%)
Liver function test increased	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Lymph node palpable	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Dehydration	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/12 (0%)		1/13 (7.7%)		1/19 (5.3%)
Arthritis	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Back pain	0/12 (0%)		1/13 (7.7%)		1/19 (5.3%)
Flank pain	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Muscle spasms	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Muscular weakness	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Musculoskeletal pain	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Pain in extremity	0/12 (0%)		1/13 (7.7%)		1/19 (5.3%)
Rheumatoid arthritis	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Nervous system disorders
Dizziness	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Headache	3/12 (25%)		6/13 (46.2%)		3/19 (15.8%)
Hypoaesthesia	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Lethargy	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Migraine	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Tongue biting	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Psychiatric disorders
Aggression	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Depression	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Tic	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Renal and urinary disorders
Haematuria	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Nephrolithiasis	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Proteinuria	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/12 (8.3%)		2/13 (15.4%)		0/19 (0%)
Epistaxis	1/12 (8.3%)		1/13 (7.7%)		0/19 (0%)
Nasal congestion	0/12 (0%)		1/13 (7.7%)		1/19 (5.3%)
Oropharyngeal pain	0/12 (0%)		3/13 (23.1%)		3/19 (15.8%)
Respiratory disorder	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Rhinitis allergic	1/12 (8.3%)		2/13 (15.4%)		0/19 (0%)
Rhinorrhoea	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Sinus congestion	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Upper respiratory tract congestion	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Upper-airway cough syndrome	0/12 (0%)		2/13 (15.4%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders
Alopecia	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Ecchymosis	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Eczema	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Pruritus	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Pseudoporphyria	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Rash	0/12 (0%)		3/13 (23.1%)		4/19 (21.1%)
Rash erythematous	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Rash pruritic	0/12 (0%)		1/13 (7.7%)		0/19 (0%)
Skin atrophy	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Skin burning sensation	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Skin discolouration	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Skin exfoliation	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Skin fissures	0/12 (0%)		0/13 (0%)		1/19 (5.3%)
Skin hypopigmentation	1/12 (8.3%)		0/13 (0%)		0/19 (0%)
Vascular disorders
Hot flush	0/12 (0%)		1/13 (7.7%)		0/19 (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.