Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT02318784
• Collaborator: Amgen (Industry)
• Enrollment: 62
• Locations: 10
• Arm: 1
• Actual Duration (Months): 70
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if carfilzomib is safe and effective in the treatment of patients with advanced neuroendocrine tumors.

Condition or Disease	Intervention/Treatment	Phase
Neuroendocrine Cancer	Drug: Carfilzomib	Phase 2

Detailed Description

Neuroendocrine malignancies such as pancreatic neuroendocrine tumors (PNETs) and gastrointestinal (GI) carcinoids, are generally rare but their incidences are increasing. In vitro and in vivo studies have shown that proteasome inhibitors have activity against a variety of tumor types. Carfilzomib (Kyprolis®) is an irreversible proteasome inhibitor with a favorable safety profile that has been studied in a variety of hematologic and solid tumors. Carfilzomib received accelerated approval from the U.S. FDA in 2012, based on a favorable response rate, for the treatment of patients with multiple myeloma who received at least two prior therapies, and demonstrated disease progression within 60 days of completing the last therapy. In this multi-center study, the investigators propose to evaluate carfilzomib for the treatment of patients with advanced neuroendocrine cancers.

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers
• Actual Study Start Date: Jul 15, 2015
• Actual Primary Completion Date: May 15, 2021
• Actual Study Completion Date: May 15, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Carfilzomib Carfilzomib will be administered as intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle. Cycle 1: First two doses of Carfilzomib 20 mg/m2 IV; subsequent doses at 56 mg/m2 IV Cycle 2 onwards: Carfilzomib 56 mg/m2 IV	Drug: Carfilzomib; Other Names: Kyprolis

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [every 3 cycles (1 cycle= 28 days) until treatment discontinuation up to 4 years]

   Percentage of participants with confirmed complete response (CR) or partial response (PR) (i.e. 2 CRs or PRs at least 4 weeks apart) to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) CR=disappearance of all target lesions. PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

1. Disease Control Rate (DCR) [every 3 cycles (1 cycle= 28 days) until treatment discontinuation up to 4 years]

   Percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) (≥ 6 cycles) according to RECIST v1.1 criteria. Complete Response is defined per RECIST as the disappearance of all target/non-target lesions and normalization of tumor markers. Partial Response is defined per RECIST as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease is defined per RECIST as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest (nadir) sum LD since the treatment started.

2. Progression Free Survival (PFS) [up to 4 years]

   Measured from Day 1 of study drug administration to disease progression as defined by RECIST v1.1, or death on the study. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or unequivocal progression of non-target lesions or the appearance of one or more new lesions. Patients who did not have disease progression or death documented were censored on the date of the last visit with adequate assessment.

3. Number of Participants With Treatment-emergent Adverse Events as a Measure of Safety and Tolerability [From the day of the first dose to 30 days after the last dose of study medication, up to 4 years]

   The number of treatment-emergent adverse events will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adults with biopsy-proven advanced, unresectable or metastatic, well-to-moderately differentiated (or low grade) neuroendocrine carcinoma, including typical carcinoid, pancreatic islet cell and other well-to-moderately differentiated neuroendocrine carcinomas.

2. Measurable disease per Response Evaluation Criteria in Solid Tumors RECIST v 1.1 criteria.

3. Patients currently receiving or previously treated with single agent sandostatin LAR® are eligible. However, this is not a mandatory criterion to be included in the study.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.

5. Adequate hematologic, renal, and hepatic function.

6. Predicted life expectancy > 12 weeks.

Exclusion Criteria:

1. Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, globlet cell carcinoid, atypical carcinoid, anaplastic carcinoid, pulmonary neuroendocrine and small cell carcinoma are not eligible.

2. Patients who had radiation therapy, hormonal therapy, biologic therapy, investigational agents, or chemotherapy for cancer within 21 days or 5 half-lives of any chemotherapy or biologic/targeted agent, whichever is longer, prior to first treatment day of the study.

3. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would impair the ability of the patient to receive protocol treatment.

4. Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement.

5. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 2 weeks prior to study entry and there is no evidence of central nervous system disease progression, mild neurologic symptoms, and no requirement for chronic corticosteroid therapy.

6. Known diagnosis of human immunodeficiency virus, hepatitis B or hepatitis C.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rocky Mountain Cancer Center	Denver	Colorado	United States	80218
2	Florida Cancer Specialists	Fort Myers	Florida	United States	33916
3	Florida Hospital Cancer Institute	Orlando	Florida	United States	32804
4	Florida Cancer Specialists - North	Saint Petersburg	Florida	United States	33705
5	Ingalls Cancer Research Center	Harvey	Illinois	United States	60426
6	Research Medical Center	Kansas City	Missouri	United States	64132
7	Oncology Hematology Care, INC.	Cincinnati	Ohio	United States	45219
8	Spartanburg Regional Medical Center/Gibbs Cancer Center	Spartanburg	South Carolina	United States	29303
9	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203
10	Center for Cancer and Blood Disorders	Fort Worth	Texas	United States	76104

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Amgen

Investigators

• Study Chair: David Spigel, M.D., SCRI Development Innovations, LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 25, 2015

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT02318784
• Other Study ID Numbers: SCRI GI 195
• First Posted: Dec 17, 2014
• Last Update Posted: Jul 1, 2022
• Last Verified: Jun 1, 2022

• Keywords provided by SCRI Development Innovations, LLC: neuroendocrine malignancies; pancreatic neuroendocrine tumors (PNETs); gastrointestinal (GI) carcinoids; carfilzomib; Kyprolis; proteasome inhibitors
• Additional relevant MeSH terms: Carcinoma, Neuroendocrine

Study Results

Participant Flow

Arm/Group Title	Carfilzomib
Arm/Group Description	Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cycle 1: First two doses of Carfilzomib 20 mg/m^2 IV; subsequent doses at 56 mg/m2 IV Cycle 2 onwards: Carfilzomib 56 mg/m^2 IV
Period Title: Overall Study
STARTED	62
COMPLETED	0
NOT COMPLETED	62

Baseline Characteristics

Arm/Group Title	Carfilzomib
Arm/Group Description	Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cycle 1: First two doses of Carfilzomib 20 mg/m^2 IV; subsequent doses at 56 mg/m2 IV Cycle 2 onwards: Carfilzomib 56 mg/m^2 IV
Overall Participants	62
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63
Sex: Female, Male (Count of Participants)
Female	37 59.7%
Male	25 40.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	8 12.9%
White	54 87.1%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	62 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Percentage of participants with confirmed complete response (CR) or partial response (PR) (i.e. 2 CRs or PRs at least 4 weeks apart) to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) CR=disappearance of all target lesions. PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	every 3 cycles (1 cycle= 28 days) until treatment discontinuation up to 4 years

Outcome Measure Data

Analysis Population Description

All enrolled patients who received at least one full or partial dose of the study drug and who had measurable disease at baseline were included in the analysis.

Arm/Group Title	Carfilzomib
Arm/Group Description	Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cycle 1: First two doses of Carfilzomib 20 mg/m^2 IV; subsequent doses at 56 mg/m2 IV Cycle 2 onwards: Carfilzomib 56 mg/m^2 IV
Measure Participants	62
Number (95% Confidence Interval) [percentage of participants]	3.226 5.2%

2. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	Percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) (≥ 6 cycles) according to RECIST v1.1 criteria. Complete Response is defined per RECIST as the disappearance of all target/non-target lesions and normalization of tumor markers. Partial Response is defined per RECIST as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease is defined per RECIST as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest (nadir) sum LD since the treatment started.
Time Frame	every 3 cycles (1 cycle= 28 days) until treatment discontinuation up to 4 years

Outcome Measure Data

Analysis Population Description

All enrolled patients who received at least one full or partial dose of the study drug and who had measurable disease at baseline were included in the analysis.

Arm/Group Title	Carfilzomib
Arm/Group Description	Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cycle 1: First two doses of Carfilzomib 20 mg/m^2 IV; subsequent doses at 56 mg/m2 IV Cycle 2 onwards: Carfilzomib 56 mg/m^2 IV
Measure Participants	62
Number (95% Confidence Interval) [percentage of participants]	58 93.5%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Measured from Day 1 of study drug administration to disease progression as defined by RECIST v1.1, or death on the study. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or unequivocal progression of non-target lesions or the appearance of one or more new lesions. Patients who did not have disease progression or death documented were censored on the date of the last visit with adequate assessment.
Time Frame	up to 4 years

Outcome Measure Data

Analysis Population Description

All enrolled patients who received at least one full or partial dose of the study drug and who had measurable disease at baseline were included in the analysis.

Arm/Group Title	Carfilzomib
Arm/Group Description	Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cycle 1: First two doses of Carfilzomib 20 mg/m^2 IV; subsequent doses at 56 mg/m2 IV Cycle 2 onwards: Carfilzomib 56 mg/m^2 IV
Measure Participants	62
Median (95% Confidence Interval) [months]	8

4. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events as a Measure of Safety and Tolerability
Description	The number of treatment-emergent adverse events will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03
Time Frame	From the day of the first dose to 30 days after the last dose of study medication, up to 4 years

Outcome Measure Data

Analysis Population Description

All enrolled patients who received at least one full or partial dose of the study drug.

Arm/Group Title	Carfilzomib
Arm/Group Description	Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cycle 1: First two doses of Carfilzomib 20 mg/m^2 IV; subsequent doses at 56 mg/m2 IV Cycle 2 onwards: Carfilzomib 56 mg/m^2 IV
Measure Participants	62
Count of Participants [Participants]	56 90.3%

Adverse Events

Time Frame	From the day of the first dose to 30 days after the last dose of study medication, up to 4 years
Adverse Event Reporting Description	All patients who received at least one dose of protocol treatment were followed for safety. Adverse events and serious adverse events were collected from the day of the first dose to 30 days after the last dose of the study medication and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Arm/Group Title	Carfilzomib
Arm/Group Description	Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cycle 1: First two doses of Carfilzomib 20 mg/m^2 IV; subsequent doses at 56 mg/m2 IV Cycle 2 onwards: Carfilzomib 56 mg/m^2 IV
All Cause Mortality
	Carfilzomib
	Affected / at Risk (%)	# Events
Total	10/62 (16.1%)
Serious Adverse Events
	Carfilzomib
	Affected / at Risk (%)	# Events
Total	31/62 (50%)
Blood and lymphatic system disorders
Anaemia	1/62 (1.6%)	1
Thrombocytopenia	1/62 (1.6%)	1
Thrombotic thrombocytopenic purpura	1/62 (1.6%)	1
Cardiac disorders
Acute left ventricular failure	1/62 (1.6%)	1
Cardiac arrest	2/62 (3.2%)	2
Cardiac failure acute	1/62 (1.6%)	1
Cardiac failure congestive	1/62 (1.6%)	1
Endocrine disorders
Ectopic ACTH syndrome	1/62 (1.6%)	1
Gastrointestinal disorders
Abdominal pain	1/62 (1.6%)	1
Colitis	1/62 (1.6%)	1
Diarrhoea	1/62 (1.6%)	1
Nausea	1/62 (1.6%)	1
Small intestinal obstruction	2/62 (3.2%)	3
Vomiting	2/62 (3.2%)	2
General disorders
Asthenia	1/62 (1.6%)	1
Chest pain	1/62 (1.6%)	1
Pyrexia	1/62 (1.6%)	1
Ticuspid valve replacement	1/62 (1.6%)	1
Hepatobiliary disorders
Cholangitis	1/62 (1.6%)	1
Infections and infestations
Bacteraemia	1/62 (1.6%)	1
Cellulitis	1/62 (1.6%)	1
Enteritis infectious	1/62 (1.6%)	1
Kidney infection	1/62 (1.6%)	1
Pyelonephritis	1/62 (1.6%)	1
Sepsis	2/62 (3.2%)	2
Staphylococcal bacteraemia	1/62 (1.6%)	1
Urinary tract infection	1/62 (1.6%)	1
Wound infection	1/62 (1.6%)	1
Injury, poisoning and procedural complications
Subdural haematoma	1/62 (1.6%)	2
Metabolism and nutrition disorders
Dehydration	3/62 (4.8%)	8
Failure to thrive	1/62 (1.6%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/62 (1.6%)	1
Muscular weakness	1/62 (1.6%)	1
Nervous system disorders
Cerebrovascular accident	1/62 (1.6%)	1
Cognitive disorder	1/62 (1.6%)	1
Haemorrhagic transformation stroke	1/62 (1.6%)	1
Metabolic encephalopathy	1/62 (1.6%)	1
Syncope	1/62 (1.6%)	1
Psychiatric disorders
Confusional state	1/62 (1.6%)	1
Mental status changes	1/62 (1.6%)	1
Renal and urinary disorders
Nephrolithiasis	1/62 (1.6%)	1
Renal failure	2/62 (3.2%)	2
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/62 (1.6%)	1
Acute respiratory failure	1/62 (1.6%)	1
Chronic obstructive pulmonary disease	1/62 (1.6%)	1
Dyspnoea	1/62 (1.6%)	1
Pneumonitis	2/62 (3.2%)	2
Pulmonary embolism	1/62 (1.6%)	1
Vascular disorders
Deep vein thrombosis	1/62 (1.6%)	1
Hypertension	1/62 (1.6%)	1
Malignant hypertension	1/62 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Carfilzomib
	Affected / at Risk (%)	# Events
Total	61/62 (98.4%)
Blood and lymphatic system disorders
Anaemia	12/62 (19.4%)	41
Increased tendency to bruise	1/62 (1.6%)	1
Leukocytosis	1/62 (1.6%)	1
Lymphadenopathy	1/62 (1.6%)	1
Neutropenia	1/62 (1.6%)	1
Thrombocytopenia	11/62 (17.7%)	89
Cardiac disorders
Acute left ventricular failure	2/62 (3.2%)	2
Atrial fibrillation	2/62 (3.2%)	2
Palpitations	2/62 (3.2%)	2
Ear and labyrinth disorders
Ear pruritus	1/62 (1.6%)	1
Endocrine disorders
Ectopic ACTH syndrome	1/62 (1.6%)	1
Hyperthyroidism	1/62 (1.6%)	1
Eye disorders
Blepharitis	1/62 (1.6%)	1
Cataract	1/62 (1.6%)	1
Conjunctival haemorrhage	2/62 (3.2%)	3
Diplopia	1/62 (1.6%)	1
Eye haematoma	1/62 (1.6%)	1
Eye swelling	1/62 (1.6%)	2
Lacrimation increased	1/62 (1.6%)	1
Periorbital oedema	2/62 (3.2%)	4
Vision blurred	4/62 (6.5%)	4
Gastrointestinal disorders
Abdominal discomfort	1/62 (1.6%)	1
Abdominal distension	10/62 (16.1%)	15
Abdominal pain	11/62 (17.7%)	19
Abdominal pain upper	6/62 (9.7%)	6
Abdominal rigidity	1/62 (1.6%)	1
Barrett's oesophagus	1/62 (1.6%)	1
Constipation	11/62 (17.7%)	15
Defaecation urgency	1/62 (1.6%)	1
Diarrhoea	26/62 (41.9%)	70
Discoloured vomit	1/62 (1.6%)	1
Dry mouth	6/62 (9.7%)	6
Dyspepsia	4/62 (6.5%)	4
Dysphagia	2/62 (3.2%)	3
Enteritis	1/62 (1.6%)	1
Eructation	2/62 (3.2%)	2
Flatulence	8/62 (12.9%)	10
Gastritis	2/62 (3.2%)	2
Gastrointestinal haemorrhage	1/62 (1.6%)	1
Gastrooesophageal reflux disease	4/62 (6.5%)	4
Gingival bleeding	1/62 (1.6%)	1
Haematochezia	2/62 (3.2%)	2
Haemorrhoids	2/62 (3.2%)	2
Nausea	37/62 (59.7%)	74
Pancreatic cyst	1/62 (1.6%)	1
Pancreatic failure	1/62 (1.6%)	1
Proctalgia	1/62 (1.6%)	1
Rectal haemorrhage	2/62 (3.2%)	2
Retching	3/62 (4.8%)	4
Stomatitis	2/62 (3.2%)	3
Toothache	2/62 (3.2%)	2
Vomiting	32/62 (51.6%)	66
General disorders
Asthenia	10/62 (16.1%)	14
Catheter site bruise	1/62 (1.6%)	1
Catheter site inflammation	1/62 (1.6%)	1
Catheter site pain	3/62 (4.8%)	3
Catheter site related reaction	2/62 (3.2%)	2
Chest pain	4/62 (6.5%)	4
Chills	12/62 (19.4%)	29
Early satiety	1/62 (1.6%)	1
Fatigue	33/62 (53.2%)	65
Feeling hot	1/62 (1.6%)	1
Gait disturbance	1/62 (1.6%)	2
Generalised oedema	1/62 (1.6%)	1
Influenza like illness	1/62 (1.6%)	1
Infusion site pain	1/62 (1.6%)	1
Localised oedema	2/62 (3.2%)	2
Malaise	1/62 (1.6%)	1
Non-cardiac chest pain	2/62 (3.2%)	2
Oedema	1/62 (1.6%)	1
Oedema peripheral	20/62 (32.3%)	33
Pain	7/62 (11.3%)	8
Peripheral swelling	4/62 (6.5%)	4
Pyrexia	18/62 (29%)	35
Thirst	1/62 (1.6%)	1
Immune system disorders
Hypersensitivity	1/62 (1.6%)	1
Infections and infestations
Bronchitis	1/62 (1.6%)	1
Cellulitis	5/62 (8.1%)	7
Chronic sinusitis	1/62 (1.6%)	1
Clostridium difficile infection	1/62 (1.6%)	1
Conjunctivitis	1/62 (1.6%)	1
Conjunctivitis viral	1/62 (1.6%)	1
Device related infection	1/62 (1.6%)	2
Ear infection	1/62 (1.6%)	1
Eye infection	1/62 (1.6%)	2
Eye infection viral	1/62 (1.6%)	1
Fungal infection	1/62 (1.6%)	1
Herpes zoster	2/62 (3.2%)	2
Influenza	2/62 (3.2%)	2
Oral candidiasis	3/62 (4.8%)	3
Oral herpes	3/62 (4.8%)	3
Perirectal abscess	1/62 (1.6%)	1
Pharyngitis streptococcal	1/62 (1.6%)	1
Pneumonia	2/62 (3.2%)	4
Sepsis	1/62 (1.6%)	1
Sinusitis	4/62 (6.5%)	4
Upper respiratory tract infection	8/62 (12.9%)	15
Urinary tract infection	4/62 (6.5%)	12
Wound infection	1/62 (1.6%)	1
Injury, poisoning and procedural complications
Burns second degree	1/62 (1.6%)	1
Contusion	2/62 (3.2%)	4
Facial bones fracture	1/62 (1.6%)	1
Fall	1/62 (1.6%)	2
Infusion related reaction	3/62 (4.8%)	3
Muscle strain	1/62 (1.6%)	1
Tooth fracture	1/62 (1.6%)	1
Wound	1/62 (1.6%)	1
Investigations
Alanine aminotransferase	1/62 (1.6%)	2
Alanine aminotransferase increased	6/62 (9.7%)	11
Ammonia increased	1/62 (1.6%)	1
Aspartate aminotransferase increased	6/62 (9.7%)	15
Blood alkaline phosphatase increased	6/62 (9.7%)	19
Blood bilirubin increased	6/62 (9.7%)	19
Blood calcium increased	1/62 (1.6%)	1
Blood creatine increased	2/62 (3.2%)	2
Blood creatinine increased	8/62 (12.9%)	22
Blood glucose increased	2/62 (3.2%)	3
Blood potassium decreased	1/62 (1.6%)	1
Blood pressure increased	2/62 (3.2%)	6
Body temperature increased	1/62 (1.6%)	2
Brain natriuretic peptide increased	1/62 (1.6%)	1
Cardiac murmur	1/62 (1.6%)	1
Creatinine renal clearance decreased	2/62 (3.2%)	3
Creatinine renal clearance increased	1/62 (1.6%)	1
Ejection fraction decreased	1/62 (1.6%)	1
Glomerular filtration rate decreased	1/62 (1.6%)	1
Haemoglobin decreased	2/62 (3.2%)	5
Neutrophil count decreased	1/62 (1.6%)	1
Platelet count	1/62 (1.6%)	1
Platelet count decreased	9/62 (14.5%)	72
Protein total decreased	1/62 (1.6%)	1
Respiratory rate increased	1/62 (1.6%)	2
Staphylococcus test positive	1/62 (1.6%)	1
Transferrin saturation decreased	1/62 (1.6%)	1
Urine bilirubin increased	1/62 (1.6%)	1
Weight decreased	9/62 (14.5%)	15
Weight increased	2/62 (3.2%)	2
White blood cell count increased	1/62 (1.6%)	1
Metabolism and nutrition disorders
Decreased appetite	12/62 (19.4%)	17
Dehydration	10/62 (16.1%)	21
Fluid retention	2/62 (3.2%)	2
Hypercholesterolaemia	1/62 (1.6%)	1
Hyperglycaemia	5/62 (8.1%)	8
Hyperkalaemia	2/62 (3.2%)	5
Hypernatraemia	1/62 (1.6%)	1
Hypoalbuminaemia	2/62 (3.2%)	5
Hypocalcaemia	3/62 (4.8%)	6
Hypoglycaemia	1/62 (1.6%)	1
Hypokalaemia	6/62 (9.7%)	10
Hypomagnesaemia	3/62 (4.8%)	3
Hypovolaemia	1/62 (1.6%)	1
Iron deficiency	3/62 (4.8%)	3
Vitamin B12 deficiency	1/62 (1.6%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	7/62 (11.3%)	10
Back pain	11/62 (17.7%)	21
Flank pain	1/62 (1.6%)	1
Intervertebral disc degeneration	1/62 (1.6%)	1
Joint swelling	1/62 (1.6%)	1
Muscle spasms	4/62 (6.5%)	9
Muscle tightness	1/62 (1.6%)	1
Muscular weakness	4/62 (6.5%)	5
Musculoskeletal discomfort	2/62 (3.2%)	4
Musculoskeletal pain	2/62 (3.2%)	2
Musculoskeletal stiffness	1/62 (1.6%)	1
Myalgia	4/62 (6.5%)	4
Neck pain	1/62 (1.6%)	1
Osteoarthritis	1/62 (1.6%)	2
Pain in extremity	6/62 (9.7%)	9
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Seborrhoeic keratosis	1/62 (1.6%)	1
Nervous system disorders
Amnesia	1/62 (1.6%)	1
Cognitive disorder	1/62 (1.6%)	1
Dizziness	14/62 (22.6%)	14
Dysgeusia	1/62 (1.6%)	2
Headache	26/62 (41.9%)	41
Hypersomnia	1/62 (1.6%)	1
Hypoaesthesia	3/62 (4.8%)	3
Lethargy	2/62 (3.2%)	3
Memory impairment	1/62 (1.6%)	1
Migraine	1/62 (1.6%)	1
Neuropathy peripheral	2/62 (3.2%)	2
Paraesthesia	1/62 (1.6%)	1
Peripheral sensory neuropathy	2/62 (3.2%)	2
Presyncope	1/62 (1.6%)	1
Seizure	2/62 (3.2%)	2
Somnolence	1/62 (1.6%)	1
Taste disorder	1/62 (1.6%)	1
Psychiatric disorders
Abnormal dreams	1/62 (1.6%)	1
Anxiety	1/62 (1.6%)	1
Confusional state	2/62 (3.2%)	2
Delirium	1/62 (1.6%)	1
Depression	4/62 (6.5%)	4
Insomnia	14/62 (22.6%)	21
Irritability	1/62 (1.6%)	1
Mental status changes	2/62 (3.2%)	4
Renal and urinary disorders
Acute kidney injury	3/62 (4.8%)	3
Chromaturia	1/62 (1.6%)	1
Chronic kidney disease	1/62 (1.6%)	7
Dysuria	3/62 (4.8%)	3
Nephrolithiasis	1/62 (1.6%)	1
Proteinuria	1/62 (1.6%)	1
Renal impairment	2/62 (3.2%)	3
Urinary incontinence	1/62 (1.6%)	1
Urinary retention	1/62 (1.6%)	1
Urinary tract pain	1/62 (1.6%)	1
Reproductive system and breast disorders
Oedema genital	1/62 (1.6%)	1
Vaginal haemorrhage	1/62 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/62 (1.6%)	2
Cough	12/62 (19.4%)	21
Dysphonia	2/62 (3.2%)	2
Dyspnoea	16/62 (25.8%)	26
Dyspnoea exertional	2/62 (3.2%)	2
Dyspnoea paroxysmal nocturnal	1/62 (1.6%)	1
Hypoxia	3/62 (4.8%)	3
Lower respiratory tract congestion	1/62 (1.6%)	1
Nasal congestion	4/62 (6.5%)	4
Oropharyngeal pain	3/62 (4.8%)	3
Paranasal sinus hypersecretion	1/62 (1.6%)	1
Pneumonitis	2/62 (3.2%)	2
Productive cough	1/62 (1.6%)	1
Pulmonary oedema	1/62 (1.6%)	1
Rhinitis allergic	3/62 (4.8%)	4
Rhinorrhoea	2/62 (3.2%)	3
Sleep apnoea syndrome	1/62 (1.6%)	1
Throat irritation	1/62 (1.6%)	1
Upper respiratory tract congestion	1/62 (1.6%)	1
Upper-airway cough syndrome	1/62 (1.6%)	4
Wheezing	1/62 (1.6%)	1
Skin and subcutaneous tissue disorders
Alopecia	3/62 (4.8%)	3
Ecchymosis	1/62 (1.6%)	1
Erythema	2/62 (3.2%)	4
Hair colour changes	1/62 (1.6%)	1
Hyperhidrosis	4/62 (6.5%)	4
Night sweats	6/62 (9.7%)	7
Petechiae	1/62 (1.6%)	1
Precancerous skin lesion	1/62 (1.6%)	1
Pruritus	2/62 (3.2%)	5
Rash	5/62 (8.1%)	6
Rash macular	1/62 (1.6%)	1
Rash maculo-papular	4/62 (6.5%)	5
Rash pruritic	1/62 (1.6%)	1
Skin hyperpigmentation	1/62 (1.6%)	3
Skin irritation	1/62 (1.6%)	1
Skin lesion	1/62 (1.6%)	1
Skin ulcer	2/62 (3.2%)	2
Urticaria	1/62 (1.6%)	1
Surgical and medical procedures
Skin neoplasm excision	1/62 (1.6%)	1
Vascular disorders
Embolism	1/62 (1.6%)	1
Flushing	4/62 (6.5%)	4
Hot flush	4/62 (6.5%)	5
Hypertension	16/62 (25.8%)	21
Hypotension	7/62 (11.3%)	7
Pallor	1/62 (1.6%)	1
Phlebitis	1/62 (1.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.