Pegfilgrastim and Rituximab in Treating Patients With Untreated, Relapsed, or Refractory Follicular Lymphoma, Small Lymphocytic Lymphoma, or Marginal Zone Lymphoma

• Sponsor: Roswell Park Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01682044
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 20
• Location: 1
• Arm: 1
• Duration (Months): 116.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects and how well giving pegfilgrastim together with rituximab works in treating patients with untreated, relapsed, or refractory follicular lymphoma, small lymphocytic lymphoma (SLL), or marginal zone lymphoma (MZL). Colony-stimulating factors, such as pegfilgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of therapy. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or tumor cancer-killing substances to them. Giving pegfilgrastim together with rituximab may kill more cancer cells

Condition or Disease	Intervention/Treatment	Phase
Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma	Biological: pegfilgrastim; Biological: rituximab; Other: flow cytometry; Procedure: biopsy; Other: immunohistochemistry staining method; Genetic: western blotting	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the safety of Pegfilgrastim in combination with rituximab in patients with untreated or relapsed/refractory follicular, SLL or MZL.

SECONDARY OBJECTIVES:

1. To evaluate the efficacy (including overall response rate and durability of objective responses) of Pegfilgrastim in combination with rituximab in patients with untreated or relapsed/refractory follicular, SLL or MZL.

2. To evaluate functional and phenotypic characteristics of host neutrophils undergoing treatment with Pegfilgrastim and rituximab.

3. To evaluate changes in cluster of differentiation (CD)20 antigen expression and density of expression in patients receiving Pegfilgrastim and rituximab.

4. To evaluate changes in serum levels of tumor necrosis factor (TNF), interferon alpha (INFalpha) and free radical levels in patients undergoing treatment with Pegfilgrastim and rituximab.

OUTLINE:

Patients receive pegfilgrastim subcutaneously (SC) followed by rituximab intravenously (IV) 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 2 years, and then yearly for 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Clinical Trial of Rituximab in Combination With Pegfilgrastim in Patients With Indolent B-Cell (CD-20-Positive) Lymphoma
• Study Start Date: Apr 17, 2007
• Actual Primary Completion Date: Nov 22, 2013
• Actual Study Completion Date: Dec 22, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (colony-stimulating factor and monoclonal antibody) Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity.

Biological: pegfilgrastim; Given SC; Other Names: Filgrastim SD-01 GCSF-SD01 Neulasta SD-01 sustained duration G-CSF ; Biological: rituximab; Given IV; Other Names: IDEC-C2B8 IDEC-C2B8 monoclonal antibody Mabthera MOAB IDEC-C2B8 Rituxan ; Other: flow cytometry; Correlative studies; Procedure: biopsy; Correlative studies; Other Names: biopsies ; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry ; Genetic: western blotting; Correlative studies; Other Names: Blotting, Western Western Blot

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [Up to 90 days after the last dose of study drugs]

   Frequency of Adverse Events, Graded According to NCI CTCAE v3.0. Grade 1: Mild AE; Grade 2: Moderate AE; Grade 3: Severe AE; Grade 4: Life-threatening or disabling AE; Grade 5: Death related to AE

Secondary Outcome Measures

1. Overall Response Rate [Up to 43 weeks]

   Overall Response is defined as Complete Response: During observation, no disease is apparent, including measurable and non-measurable disease, and no evidence of disease is observed for at least 28 days, as confirmed by a second assessment following the original observation of no disease; and Partial Response: A 50% or greater decrease from baseline in the sum of the products of the longest perpendicular diameters of all the measured lesions is noted for at least 28 days as confirmed by a second assessment following the observation of the 50% or greater decrease, and no appearance of new lesions is noted.

2. Percent Change in Functional and Phenotypic Characteristics of Host Neutrophils From Baseline [Baseline and weeks 1, 3, 5, 7, 15, 23, 31, and 39]

   Mean percent change in CD11b level from baseline at each visit

3. Percent Change in CD20 Antigen Expression and Density of Expression [At 4 years]

   Percent change in CD20 antigen expression and density of expression

4. Percent Change in Serum Levels of Tumor Necrosis Factor (TNF) From Baseline [Baseline and weeks 1, 3, 5, 7, 15, 23, 31, and 39]

   Mean percent change in TNF level from baseline at each visit.

5. Percent Change in Serum Levels of Interferon Alpha (INF) From Baseline [Baseline and weeks 1, 3, 5, 7, 15, 23, 31, and 39]

   Mean percent change in INF level from baseline.

6. Percent Change in Serum Levels of Free Radical Levels (MFI) From Baseline [Baseline and weeks 1, 3, 5, 7, 15, 23, 31, and 39]

   Mean percent change in MFI level from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Untreated or relapsed/refractory follicular, SLL or MZL (i.e. no limit to number of prior treatments as long as patients meet other study criteria)

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Measurable tumor size (at least one node measuring 4 cm^2 in bidimensional measurement)

• Expected survival of > 6 months

• Prior rituximab or other monoclonal immunotherapy permitted and eligible for rituximab monotherapy

• Full recovery from any significant toxicity associated with prior surgery, radiation therapy, chemotherapy, or immunotherapy

• Absolute neutrophil count > 1.0 x 10^9/L

• Platelets > 50 x 10^9/L

• Patients may receive erythropoietin growth factors to maintain adequate hemoglobin levels (>= 8.0 mg/dl)

• Creatinine < 1.5 x upper normal levels (UNL)

• Total bilirubin < 1.5 mg/dL (> 25.65 umol/L)

• Aspartate aminotransferase < 5 x UNL

• Alkaline phosphatase < 5 x UNL

• Informed consent approved in institutional review board (lRB)

• CD20+ B-cell lymphoma

Exclusion Criteria:

• Prior history of human immunodeficiency virus (HIV)-positivity (routine HIV testing is required pretreatment)

• Serious non-malignant disease (e.g. active uncontrolled bacterial, viral, or fungal infections) or other conditions which, in the opinion of the principal investigator would compromise other protocol objectives

• Presence of central nervous system (CNS) lymphoma

• Chemotherapy within 4 weeks of the first scheduled study treatment

• Another primary malignancy (other than squamous or basal cell carcinoma of the skin or in-situ carcinoma of the cervix) for which the patient has not been disease-free for at least five years

• Major surgery, other than diagnostic surgery, within four weeks

• Patients with non-Hodgkin lymphoma (NHL) other than relapsed/refractory follicular, MZL or SLL

• Patients must not have a history of cardiac disease, defined as New York Heart Association Class II or greater or clinical evidence of congestive heart failure

• Concurrent use of other investigational agents

• Pregnant or breast feeding

• Subjects of reproductive potential who are not using adequate contraceptive precautions, in the judgment of the investigator

• Known hypersensitivity to any recombinant E coli-derived product, murine proteins, or any components of the study medications

• Concerns for the subject's compliance with the protocol

• Any premalignant myeloid condition or any malignancy with myeloid characteristics (e.g. myelodysplastic syndromes, acute or chronic myelogenous leukemia)

• Patient is currently enrolled in, or has not yet completed at least 30 days since ending another investigational device or drug trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Roswell Park Cancer Institute	Buffalo	New York	United States	14263

Sponsors and Collaborators

• Roswell Park Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Francisco Hernandez-ILizaliturri, Roswell Park Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 4, 2013

More Information

Publications

None provided.

• Responsible Party: Roswell Park Cancer Institute
• ClinicalTrials.gov Identifier: NCT01682044
• Other Study ID Numbers: I 83106; NCI-2011-00134; NCT00524628
• First Posted: Sep 10, 2012
• Last Update Posted: Oct 9, 2017
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Rituximab

Study Results

Participant Flow

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Period Title: Overall Study
STARTED	20
COMPLETED	16
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Overall Participants	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.9 (13.1)
Sex: Female, Male (Count of Participants)
Female	6 30%
Male	14 70%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Frequency of Adverse Events, Graded According to NCI CTCAE v3.0. Grade 1: Mild AE; Grade 2: Moderate AE; Grade 3: Severe AE; Grade 4: Life-threatening or disabling AE; Grade 5: Death related to AE
Time Frame	Up to 90 days after the last dose of study drugs

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Measure Participants	20
Grade 1	3 15%
Grade 2	9 45%
Grade 3	6 30%
Grade 4	1 5%
Grade 5	1 5%

2. Secondary Outcome

Title	Overall Response Rate
Description	Overall Response is defined as Complete Response: During observation, no disease is apparent, including measurable and non-measurable disease, and no evidence of disease is observed for at least 28 days, as confirmed by a second assessment following the original observation of no disease; and Partial Response: A 50% or greater decrease from baseline in the sum of the products of the longest perpendicular diameters of all the measured lesions is noted for at least 28 days as confirmed by a second assessment following the observation of the 50% or greater decrease, and no appearance of new lesions is noted.
Time Frame	Up to 43 weeks

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Measure Participants	20
Number (95% Confidence Interval) [percentage of participants]	60 300%

3. Secondary Outcome

Title	Percent Change in Functional and Phenotypic Characteristics of Host Neutrophils From Baseline
Description	Mean percent change in CD11b level from baseline at each visit
Time Frame	Baseline and weeks 1, 3, 5, 7, 15, 23, 31, and 39

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Measure Participants	20
week 1	-20.2 (34.0)
week 3	-35.5 (28.3)
week 5	-24.7 (117.7)
week 7	-56.8 (27.4)
week 15	-23.8 (40.1)
week 23	-19.7 (35.7)
week 31	-18.7 (47.0)
week 39	-10.1 (42.7)

4. Secondary Outcome

Title	Percent Change in CD20 Antigen Expression and Density of Expression
Description	Percent change in CD20 antigen expression and density of expression
Time Frame	At 4 years

Outcome Measure Data

Analysis Population Description

Samples tissues were not large enough to perform analysis. No participants were analyze.

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Measure Participants	0

5. Secondary Outcome

Title	Percent Change in Serum Levels of Tumor Necrosis Factor (TNF) From Baseline
Description	Mean percent change in TNF level from baseline at each visit.
Time Frame	Baseline and weeks 1, 3, 5, 7, 15, 23, 31, and 39

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Measure Participants	20
week 1	51.5 (65.1)
week 3	14.5 (47.7)
week 5	11.2 (50.1)
week 7	8.3 (34.2)
week 15	42.7 (76.4)
week 23	27.2 (80.6)
week 31	45.6 (100.5)
week 39	50.2 (110.6)

6. Secondary Outcome

Title	Percent Change in Serum Levels of Interferon Alpha (INF) From Baseline
Description	Mean percent change in INF level from baseline.
Time Frame	Baseline and weeks 1, 3, 5, 7, 15, 23, 31, and 39

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Measure Participants	20
week 1	-18.8 (33.2)
week 3	-27.8 (42.9)
week 5	48.1 (124.6)
week 7	8.0 (71.4)
week 15	1.5 (78.6)
week 23	-14.1 (43.9)
week 31	-33.0 (49.5)
week 39	-7.5 (45.1)

7. Secondary Outcome

Title	Percent Change in Serum Levels of Free Radical Levels (MFI) From Baseline
Description	Mean percent change in MFI level from baseline.
Time Frame	Baseline and weeks 1, 3, 5, 7, 15, 23, 31, and 39

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
Measure Participants	20
week 1	-32.0 (66.8)
week 3	-22.4 (71.0)
week 5	-45.4 (66.5)
week 7	-20.4 (89.9)
week 15	-5.8 (137.6)
week 23	0.4 (219.1)
week 31	295.8 (996.1)
week 39	16.0 (285.6)

Adverse Events

Arm/Group Title	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
Arm/Group Description	Patients receive pegfilgrastim SC followed by rituximab IV 3 days later in weeks 1, 3, 5, 7, 15, 23, 31, and 39. Treatment continues in the absence of disease progression or unacceptable toxicity. pegfilgrastim: Given SC rituximab: Given IV flow cytometry: Correlative studies biopsy: Correlative studies immunohistochemistry staining method: Correlative studies western blotting: Correlative studies
All Cause Mortality
	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
	Affected / at Risk (%)	# Events
Total	2/20 (10%)
Cardiac disorders
Coronary artery occlusion	1/20 (5%)	1
Sinus tachycardia	1/20 (5%)	1
Ventricular arrhythmia	1/20 (5%)	1
Ear and labyrinth disorders
Vertigo	1/20 (5%)	1
General disorders
Death	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Colony-stimulating Factor and Monoclonal Antibody)
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Anaemia	11/20 (55%)	15
Leukopenia	4/20 (20%)	11
Lymphopenia	8/20 (40%)	25
Neutropenia	2/20 (10%)	5
Thrombocytopenia	7/20 (35%)	14
Cardiac disorders
Supraventricular extrasystoles	1/20 (5%)	1
Tachycardia	1/20 (5%)	1
Ear and labyrinth disorders
Ear discomfort	1/20 (5%)	1
Eye disorders
Diplopia	1/20 (5%)	1
Lacrimation increased	1/20 (5%)	1
Vitreous floaters	1/20 (5%)	1
Gastrointestinal disorders
Abdominal discomfort	1/20 (5%)	1
Abdominal pain	2/20 (10%)	2
Constipation	2/20 (10%)	2
Diarrhoea	2/20 (10%)	3
Gastrooesophageal reflux disease	1/20 (5%)	1
Hiatus hernia	1/20 (5%)	1
Intestinal mass	1/20 (5%)	1
Nausea	7/20 (35%)	10
Vomiting	4/20 (20%)	5
General disorders
Asthenia	2/20 (10%)	2
Chills	6/20 (30%)	8
Discomfort	1/20 (5%)	1
Fatigue	4/20 (20%)	6
Infusion site pain	1/20 (5%)	1
Malaise	1/20 (5%)	1
Oedema peripheral	1/20 (5%)	1
Pain	4/20 (20%)	4
Pyrexia	2/20 (10%)	2
Sensation of foreign body	1/20 (5%)	1
Hepatobiliary disorders
Hyperbilirubinaemia	1/20 (5%)	1
Immune system disorders
Cytokine release syndrome	6/20 (30%)	6
Infections and infestations
Cellulitis	1/20 (5%)	1
Influenza	1/20 (5%)	1
Nasopharyngitis	1/20 (5%)	1
Respiratory tract infection	3/20 (15%)	3
Sinusitis	1/20 (5%)	1
Upper respiratory tract infection	1/20 (5%)	1
Injury, poisoning and procedural complications
Procedural pain	1/20 (5%)	1
Investigations
Alanine aminotransferase increased	1/20 (5%)	1
Aspartate aminotransferase increased	3/20 (15%)	4
Blood albumin	1/20 (5%)	1
Blood alkaline phosphatase	15/20 (75%)	52
Blood alkaline phosphatase increased	3/20 (15%)	5
Blood creatine	1/20 (5%)	1
Blood creatinine	2/20 (10%)	2
Blood creatinine increased	1/20 (5%)	3
Blood glucose	1/20 (5%)	1
Blood glucose decreased	1/20 (5%)	2
Blood potassium decreased	1/20 (5%)	2
Blood sodium	2/20 (10%)	2
Blood sodium decreased	1/20 (5%)	1
Blood sodium increased	1/20 (5%)	1
Blood uric acid increased	4/20 (20%)	10
Body temperature increased	2/20 (10%)	2
Haemoglobin decreased	1/20 (5%)	1
Heart rate increased	2/20 (10%)	2
Weight decreased	3/20 (15%)	3
Weight increased	1/20 (5%)	1
Metabolism and nutrition disorders
Hyperalbuminaemia	1/20 (5%)	2
Hypercalcaemia	1/20 (5%)	3
Hyperglycaemia	5/20 (25%)	7
Hyperkalaemia	3/20 (15%)	4
Hypernatraemia	4/20 (20%)	4
Hyperphosphataemia	3/20 (15%)	4
Hyperuricaemia	6/20 (30%)	11
Hypoalbuminaemia	1/20 (5%)	1
Hypoglycaemia	1/20 (5%)	1
Hypokalaemia	1/20 (5%)	2
Hyponatraemia	3/20 (15%)	3
Hypophosphataemia	3/20 (15%)	8
Musculoskeletal and connective tissue disorders
Back pain	2/20 (10%)	5
Bone pain	11/20 (55%)	17
Flank pain	1/20 (5%)	1
Muscular weakness	1/20 (5%)	1
Musculoskeletal discomfort	1/20 (5%)	1
Pain in extremity	1/20 (5%)	1
Nervous system disorders
Burning sensation mucosal	1/20 (5%)	3
Dizziness	2/20 (10%)	3
Headache	4/20 (20%)	5
Psychiatric disorders
Anorexia nervosa	1/20 (5%)	1
Anxiety	1/20 (5%)	1
Nervousness	1/20 (5%)	1
Renal and urinary disorders
Bladder discomfort	1/20 (5%)	1
Dysuria	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	5/20 (25%)	5
Dyspnoea	1/20 (5%)	1
Dyspnoea exertional	3/20 (15%)	3
Oropharyngeal pain	1/20 (5%)	1
Rhinorrhoea	1/20 (5%)	1
Sinus congestion	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Acne	1/20 (5%)	1
Cold sweat	1/20 (5%)	1
Dry skin	1/20 (5%)	1
Hyperhidrosis	2/20 (10%)	2
Night sweats	2/20 (10%)	3
Pruritus	1/20 (5%)	4
Vascular disorders
Flushing	1/20 (5%)	1
Hypertension	2/20 (10%)	2
Pallor	1/20 (5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.