ENFORCE: GRASPA Treatment for Patients With Acute Myeloblastic Leukemia

• Sponsor: ERYtech Pharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01810705
• Collaborator: (none)
• Enrollment: 123
• Locations: 21
• Arms: 2
• Actual Duration (Months): 57.3
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The protocol aims at adding GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) to standard chemotherapy (low-dose cytarabine) to treat patients older than 65 years diagnosed with AML and unfit for intensive chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: GRASPA	Phase 2

Detailed Description

L-asparaginase (ASNase) holds a key role in chemotherapy for Acute Lymphoblastic Leukemia (ALL) in children and young adults. In elderly patients, its efficacy is counterbalanced by its toxicity, which impairs its use. However, a study conducted with GRASPA (L-asparaginase encapsulated in red blood cells, eryaspase) in elderly ALL (study reference "GRASPALL-GRAAL SA2 2008") showed that efficacy/safety profile was positive, paving the way for introducing ASNase benefit into chemotherapy for elderly patients.

In adults, Capizzi (1988) reported a significant benefit of ASNase associated with high-dose cytarabine treatment (HiDAC) in Acute Myeloid Leukemia (AML). Indeed, there was an overall statistically superior complete remission rate for HiDAC/ASNase (40%) vs HiDAC (24%) and an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks vs 15.9 weeks).

Another study in elderly patients also displayed positive results for ASNase treatment (Petti, 1989), as well as recent single case reports that point out the potential benefit of ASNase in different AML or mixed lineage leukemia (Horikoshi, 2009; Rubnitz, 2009).

Our preclinical results also showed that an AML cell line and blast cells from the bone marrow of AML patients were sensitive to ASNase in vitro.

However, up to now, the toxicity of ASNase for elderly had prevented its use in this population that represents the majority of AML patients.

Considering the promising results of ASNase for AML treatment and the better safety profile offered by GRASPA (L-aspariginase encapsulated in red blood cells, erysapase), a multicenter, randomized, controlled IIb trial is open for recruitment. Efficacy and tolerability of GRASPA plus low-dose cytarabine will be evaluated versus low-dose cytarabine alone in treatment of AML patients over 65 year-old, unfit for intensive chemotherapy.

One hundred and twenty-three patients (65-85 year-old) newly diagnosed for AML are planned for inclusion in the study.

A 2:1 randomization will be respected (82 patients treated with GRASPA® plus low-dose cytarabine and 41 patients treated with low-dose cytarabine alone). Each patient will be followed for 24 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 123 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open, Randomized, Controlled Phase IIb Trial Evaluating Efficacy and Tolerability of GRASPA (L-asparaginase Encapsulated in Red Blood Cells, Eryaspase) Plus Low-dose Cytarabine vs Low-dose Cytarabine Alone, in Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) Elderly Patients, Unfit for Intensive Chemotherapy
• Actual Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Nov 10, 2017
• Actual Study Completion Date: Nov 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GRASPA patients will receive one injection of GRASPA (100 IU/kg) after each course of low-dose cytarabine (see Arm "Control")	Drug: GRASPA; Patients receiving Intervention (experimental group) will be treated with one injection of graspa per cycle of treatment, each cycle during 28 days, for a duration up to 24 cycles maximum; Other Names: L-asparaginase encapsulated in red blood cells
No Intervention: Control patients will receive successive courses of low intensive chemotherapy, as subcutaneous low-dose cytarabine 20mg twice daily for 10 days per course (from day 1 to day 10), each course occurring every 28 days, for a duration up to 24 months

Outcome Measures

Primary Outcome Measures

1. Overall Survival [Each patient will be followed for a duration of 24 months.]

   OS is defined as the time elapsed between randomization and death from any cause.

Secondary Outcome Measures

1. Response to Treatment [Each patient will be followed for a duration of 24 months.]

   Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophil or platelet regeneration, CRi), Partial remission (PR)

2. Progression Free Survival (PFS) [Each patient will be followed for a duration of 24 months.]

   Defined as the time elapsed between randomization and resistant disease or relapse or death from any cause

3. Patient Quality of Life [Each patient will be followed for a duration of 24 months.]

   Collecting survey about patients quality of life

4. Safety of GRASPA Adverse Events and Serious Adverse Events [Each patient will be followed for a duration of 24 months.]

   Number of incidences, type, severity and causality of adverse events / serious adverse events

5. Relapse Free Survival [Each patient will be followed for a duration of 24 months.]

   Defined only for patients who achieve CR or CRi as the time elapsed between date of CR/CRi and date of disease relapse or death from any cause

6. Number of Hospitalizations [Each patient will be followed for a duration of 24 months.]

   Hospitalizations (except schedule protocol visit during the study)

7. Percentage of Patients Who Need Transfusions [Until patient stops treatment (expected average of 8 months)]

   Number of transfusions per patient (red blood cells and or platelets)

8. Pharmacodynamic and Pharmacokinetic Parameters of GRASPA [Until patient stops treatment (expected average of 8 months)]

   Plasma concentrations of asparagine, aspartate, glutamine, glutamate, whole blood L- asparaginase activity

9. Immunogenicity [Until patient stops treatment (expected average of 8 months)]

   Titer of anti L-asparaginase antibodies

10. Asparagine Synthetase (Optional) [Until patient stops treatment (expected average of 8 months)]

    Asparagine synthetase and in vitro sensitivity to aspariginase on the harvested bone marrow cells

11. Biomarker Cytogenetic Testing (Optional) [Until patient stops treatment (expected average of 8 months)]

    Defined as cytogenetic biomarker testing

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Patient > 65 years old and < 85 years old

• Newly diagnosed Acute Myeloid Leukemia (AML) or post myelodysplastic syndrome diagnosed within 6 months prior to study enrollment

• Unfit for intensive chemotherapy (at risk to suffer treatment related pejorative toxicities /early death) due to the presence of one or more of the following criteria: Dependence in activities of daily living owing to the presence of comorbidities other than those resulting from the deterioration caused by the neoplastic disease. Presence in the patient's medical history of three or more of the following comorbidities, even if they are under control with proper treatment: Congestive heart failure, other chronic cardiovascular diseases, chronic obstructive pulmonary disease, cerebrovascular disease, peripheral neuropathy, chronic kidney failure, hypertension, diabetes mellitus, systemic vasculitis, severe arthritis

• Presence of geriatric syndromes such as fecal or urinary incontinence, spontaneous bone fractures, mild and moderate dementia, or patients who fall repeatedly, or, patient unwilling to receive intensive chemotherapy

• Eligible to receive low-dose cytarabine treatment

• ECOG performance status ≤ 2

• Female patients of childbearing potential and males must agree to use adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) for the duration of study treatment and for 6 months after the last dose of Cytarabine or 3 months after last dose of GRASPA (whichever is the longest).

• Negative serum pregnancy test at study entry for female subjects of childbearing potential

• Subscription to social security insurance (if applicable, in accordance with local regulations)

• Ability to understand, and willingness to sign, a written informed consent document and to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

Exclusion criteria:

• Patients with M3 AML of FAB classification (APL, acute promyelocytic leukemia)

• Patients with AML involving chromosome 16 abnormalities or translocation (8:21) (CBF-AML)

• Patient with secondary AML subsequent to prior malignant blood disorder such as: Myelodysplastic syndrome diagnosed more than 6 months before study entry or Myeloproliferative syndrome

• Prior therapy to AML (standard therapy or investigational agents)

• Inadequate organ function : Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis, Serum creatinine concentration > 2 x ULN (Upper Limit of Normal), AST or ALT levels > 3.5xULN or 5xULN if related to AML, Total bilirubin > 2 x ULN, INR > 1.5, unless patient under chronic treatment with anticoagulants (in this case, INR should be within expected ranges for the specific condition), Insulin-dependent or uncontrolled diabetes mellitus

• Concurrent malignancies other than AML requiring chemotherapy

• Severe active infection, HIV seropositivity, or known active type B or C viral hepatitis

• Known or suspected hypersensitivity or intolerance to mannitol

• Breastfeeding or lactating women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hôpital l'Archet 1	Nice	Alpes Maritimes	France	06200
2	Institut Paoli Calmettes	Marseille	Bouche Du Rhone	France	13000
3	Hôpital JEAN MINJOZ	Besancon	Doubs	France	25000
4	Hopital Morvan	Brest	Finistere	France	29200
5	Hôpital Haut-Lévèque	Pessac	Gironde	France	33600
6	CHRU de Nîmes	Nimes	Guard	France	30000
7	Hopital de Hautepierre	Strasbourg	Haut Rhin	France	67000
8	Hopital De Purpan CHU Toulouse	Toulouse	Haute Garonne	France	31500
9	Hopital Région d'Annecy	Pringy	Haute Savoie	France	74000
10	Hôpital Saint Eloi	Montpellier	Hérault	France	34295
11	Hôtel Dieu - CHU de NANTES	Nantes	Loire Atlantique	France	44200
12	Institut de Cancérologie de la Loire	Saint-priest-en-jarez	Loire	France	42270
13	Chu D'Angers	Angers	Maine Et Loire	France	49000
14	Hopital de Brabois	Vandoeuvre Les Nancy	Meurthe Et Moselle	France	54500
15	Hôpital Claude-Huriez	Lille	Nord	France	59800
16	CHU Estaing	Clermont-ferrand	Puy De Dome	France	63000
17	hopital de Perpignan	Perpignan	Pyrénées Orientales	France	66100
18	Centre Léon Bérard	Lyon	Rhone Alpes	France	69008
19	Centre hospitalier Lyon Sud	Pierre Benite	Rhone Alpes	France	69310
20	Centre Henri Becquerel	Rouen	Seine Maritime	France	76100
21	Groupe Hospitalier Sud	Amiens	Somme	France	80090

Sponsors and Collaborators

• ERYtech Pharma

Investigators

• Principal Investigator: X Thomas, Doctor,

Study Documents (Full-Text)

• Study Protocol - Oct 5, 2015
• Statistical Analysis Plan - Oct 26, 2017

More Information

Publications

None provided.

• Responsible Party: ERYtech Pharma
• ClinicalTrials.gov Identifier: NCT01810705
• Other Study ID Numbers: GRASPA-AML2012-01
• First Posted: Mar 13, 2013
• Last Update Posted: Feb 21, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by ERYtech Pharma: myeloid; leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Asparaginase

Study Results

Participant Flow

Arm/Group Title	GRASPA	Control
Arm/Group Description	patients will receive one injection of GRASPA (100 IU/kg) after each course of low-dose cytarabine (see Arm "Control") GRASPA: Patients receiving Intervention (experimental group) will be treated with one injection of graspa per cycle of treatment, each cycle during 28 days, for a duration up to 24 cycles maximum	patients will receive successive courses of low intensive chemotherapy, as subcutaneous low-dose cytarabine 20mg twice daily for 10 days per course (from day 1 to day 10), each course occurring every 28 days, for a duration up to 24 months
Period Title: Overall Study
STARTED	83	40
COMPLETED	10	5
NOT COMPLETED	73	35

Baseline Characteristics

Arm/Group Title	GRASPA	Control	Total
Arm/Group Description	In the experimental group, the patients will receive one administration of GRASPA (100 IU/kg) at Day 11 in combination with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months	In the control arm, patients will be treated with subcutaneous low-dose cytarabine as 40 mg daily (either one single dose of 40 mg or 20 mg twice daily according to local practice) for 10 consecutive days, every 28 days, for duration up to 24 months. Each period of 28 days constitute a cycle of chemotherapy.	Total of all reporting groups
Overall Participants	83	40	123
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	83 100%	40 100%	123 100%
Sex: Female, Male (Count of Participants)
Female	37 44.6%	16 40%	53 43.1%
Male	46 55.4%	24 60%	70 56.9%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	OS is defined as the time elapsed between randomization and death from any cause.
Time Frame	Each patient will be followed for a duration of 24 months.

Outcome Measure Data

Analysis Population Description

OS was to be assessed by measuring time elapsed between randomisation and death for any cause. Any patient not known to have died at the time of analysis is censored based on the last recorded date on which the patient was known to be alive

Arm/Group Title	GRASPA	Control
Arm/Group Description	patients will receive one injection of GRASPA (100 IU/kg) after each course of low-dose cytarabine (see Arm "Control") GRASPA: Patients receiving Intervention (experimental group) will be treated with one injection of graspa per cycle of treatment, each cycle during 28 days, for a duration up to 24 cycles maximum	patients will receive successive courses of low intensive chemotherapy, as subcutaneous low-dose cytarabine 20mg twice daily for 10 days per course (from day 1 to day 10), each course occurring every 28 days, for a duration up to 24 months
Measure Participants	83	40
Median (95% Confidence Interval) [months]	4.8	6.4

2. Secondary Outcome

Title	Response to Treatment
Description	Percentage of patients with Complete remission (CR), Complete remission with incomplete recovery (neutrophil or platelet regeneration, CRi), Partial remission (PR)
Time Frame	Each patient will be followed for a duration of 24 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Defined as the time elapsed between randomization and resistant disease or relapse or death from any cause
Time Frame	Each patient will be followed for a duration of 24 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Patient Quality of Life
Description	Collecting survey about patients quality of life
Time Frame	Each patient will be followed for a duration of 24 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Safety of GRASPA Adverse Events and Serious Adverse Events
Description	Number of incidences, type, severity and causality of adverse events / serious adverse events
Time Frame	Each patient will be followed for a duration of 24 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Relapse Free Survival
Description	Defined only for patients who achieve CR or CRi as the time elapsed between date of CR/CRi and date of disease relapse or death from any cause
Time Frame	Each patient will be followed for a duration of 24 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Number of Hospitalizations
Description	Hospitalizations (except schedule protocol visit during the study)
Time Frame	Each patient will be followed for a duration of 24 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Percentage of Patients Who Need Transfusions
Description	Number of transfusions per patient (red blood cells and or platelets)
Time Frame	Until patient stops treatment (expected average of 8 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Pharmacodynamic and Pharmacokinetic Parameters of GRASPA
Description	Plasma concentrations of asparagine, aspartate, glutamine, glutamate, whole blood L- asparaginase activity
Time Frame	Until patient stops treatment (expected average of 8 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Immunogenicity
Description	Titer of anti L-asparaginase antibodies
Time Frame	Until patient stops treatment (expected average of 8 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Asparagine Synthetase (Optional)
Description	Asparagine synthetase and in vitro sensitivity to aspariginase on the harvested bone marrow cells
Time Frame	Until patient stops treatment (expected average of 8 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Biomarker Cytogenetic Testing (Optional)
Description	Defined as cytogenetic biomarker testing
Time Frame	Until patient stops treatment (expected average of 8 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events were collected from signature of the informed consent from first patient and until 4 months after last GRASPA/ low-dose cytarabine administration of last patient i.e. up to 28 months for the longuest study drug exposure and on a total of 46 months of AE collection period throughout the study.
Arm/Group Title	GRASPA		Control
Arm/Group Description	Patients having received at least one injection of GRASPA (100 IU/kg) i.e. 81 in GRASPA arm		Patients having received at least one dose of study treatment i.e. 39 in control arm
All Cause Mortality
	GRASPA		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/81 (86.4%)		34/39 (87.2%)
Serious Adverse Events
	GRASPA		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/81 (91.4%)		32/39 (82.1%)
Blood and lymphatic system disorders
Febrile bone marrow aplasia	8/81 (9.9%)	8	2/39 (5.1%)	2
Febrile neutropenia	7/81 (8.6%)	7	3/39 (7.7%)	5
Anaemia	7/81 (8.6%)	8	1/39 (2.6%)	1
Hemorrhagic Events	6/81 (7.4%)	6	1/39 (2.6%)	1
Pancytopenia	5/81 (6.2%)	7	1/39 (2.6%)	1
General disorders
General physical health deterioration	10/81 (12.3%)	12	2/39 (5.1%)	2
Pyrexia	7/81 (8.6%)	7	2/39 (5.1%)	2
Immune system disorders
Hypersensitivity	6/81 (7.4%)	6	0/39 (0%)	0
Infections and infestations
Sepsis	12/81 (14.8%)	13	6/39 (15.4%)	6
Septic shock	7/81 (8.6%)	7	6/39 (15.4%)	6
Bronchopulmonary aspergillosis	4/81 (4.9%)	5	2/39 (5.1%)	2
Lung infection	1/81 (1.2%)	2	2/39 (5.1%)	2
Infection	0/81 (0%)	0	2/39 (5.1%)	2
Respiratory, thoracic and mediastinal disorders
Lung disorder	6/81 (7.4%)	6	3/39 (7.7%)	3
Other (Not Including Serious) Adverse Events
	GRASPA		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	80/81 (98.8%)		39/39 (100%)
Blood and lymphatic system disorders
thrombocytopenia	59/81 (72.8%)	149	32/39 (82.1%)	84
Leukopenia	41/81 (50.6%)	87	19/39 (48.7%)	31
Neutropenia	35/81 (43.2%)	98	18/39 (46.2%)	34
Lymphopenia	8/81 (9.9%)	9	6/39 (15.4%)	6
Leukocytosis	8/81 (9.9%)	8	2/39 (5.1%)	2
Bone marrow failure	2/81 (2.5%)	2	2/39 (5.1%)	2
Anaemia	62/81 (76.5%)	170	34/39 (87.2%)	74
Hemorrhagic Events	21/81 (25.9%)	23	9/39 (23.1%)	11
Febrile neutropenia	7/81 (8.6%)	8	1/39 (2.6%)	1
Febrile bone marrow aplasia	4/81 (4.9%)	4	2/39 (5.1%)	2
Cardiac disorders
Atrial fibrillation	2/81 (2.5%)	2	5/39 (12.8%)	5
Cardiac failure	4/81 (4.9%)	4	1/39 (2.6%)	1
Ear and labyrinth disorders
Vertigo	4/81 (4.9%)	4	2/39 (5.1%)	2
Gastrointestinal disorders
Nausea	24/81 (29.6%)	57	15/39 (38.5%)	21
Diarrhoea	24/81 (29.6%)	32	10/39 (25.6%)	12
Constipation	18/81 (22.2%)	22	10/39 (25.6%)	11
Vomiting	14/81 (17.3%)	27	5/39 (12.8%)	14
Stomatitis	7/81 (8.6%)	7	3/39 (7.7%)	4
Aphthous ulcer	9/81 (11.1%)	11	1/39 (2.6%)	1
Abdominal pain	4/81 (4.9%)	4	2/39 (5.1%)	2
Abdominal pain upper	4/81 (4.9%)	4	3/39 (7.7%)	4
Haemorrhoids	5/81 (6.2%)	5	2/39 (5.1%)	2
Gastrooesophageal reflux disease	1/81 (1.2%)	1	4/39 (10.3%)	4
Odynophagia	1/81 (1.2%)	1	2/39 (5.1%)	2
Gingival pain	0/81 (0%)	0	2/39 (5.1%)	2
General disorders
asthenia	28/81 (34.6%)	34	18/39 (46.2%)	20
asthenia	13/81 (16%)	17	9/39 (23.1%)	10
Pain	8/81 (9.9%)	8	2/39 (5.1%)	2
Injection site haematoma	5/81 (6.2%)	5	2/39 (5.1%)	2
Pyrexia	26/81 (32.1%)	50	13/39 (33.3%)	27
General physical health deterioration	4/81 (4.9%)	4	3/39 (7.7%)	3
Hepatobiliary disorders
Hyperbilirubinaemia	15/81 (18.5%)	25	5/39 (12.8%)	5
Hepatocellular injury	5/81 (6.2%)	5	1/39 (2.6%)	2
Immune system disorders
Alloimmunisation	16/81 (19.8%)	16	1/39 (2.6%)	1
Alloimmunisation	5/81 (6.2%)	5	2/39 (5.1%)	2
Hypersensitivity	8/81 (9.9%)	14	0/39 (0%)	0
Injury, poisoning and procedural complications
fall	10/81 (12.3%)	12	3/39 (7.7%)	3
Transfusion reaction	7/81 (8.6%)	8	1/39 (2.6%)	1
Traumatic haematoma	2/81 (2.5%)	2	3/39 (7.7%)	3
Food poisoning	0/81 (0%)	0	2/39 (5.1%)	2
Investigations
Blood albumin decreased	24/81 (29.6%)	29	6/39 (15.4%)	8
Pancreatic enzymes abnormal	20/81 (24.7%)	31	5/39 (12.8%)	5
Transaminases increased	15/81 (18.5%)	40	6/39 (15.4%)	10
Antithrombin III decreased	17/81 (21%)	22	3/39 (7.7%)	3
Gamma-glutamyltransferase increased	15/81 (18.5%)	18	5/39 (12.8%)	5
Weight decreased	8/81 (9.9%)	9	7/39 (17.9%)	7
Blood Creatinine increased	12/81 (14.8%)	15	3/39 (7.7%)	3
Blood chloride increased	11/81 (13.6%)	15	2/39 (5.1%)	3
Blood urea increased	9/81 (11.1%)	9	4/39 (10.3%)	6
Blood lactate dehydrogenase increased	7/81 (8.6%)	8	2/39 (5.1%)	2
Blood alkaline phosphatase increased	5/81 (6.2%)	5	3/39 (7.7%)	3
Blood chloride decreased	5/81 (6.2%)	6	3/39 (7.7%)	3
Prothrombin time ratio decreased	8/81 (9.9%)	10	0/39 (0%)	0
Activated partial thromboplastin time prolonged	6/81 (7.4%)	7	5/39 (12.8%)	5
Metabolism and nutrition disorders
Hypocalcaemia	16/81 (19.8%)	19	9/39 (23.1%)	13
Decreased appetite	5/81 (6.2%)	5	6/39 (15.4%)	8
Hyperglycaemia	8/81 (9.9%)	10	3/39 (7.7%)	4
Hypertriglyceridaemia	8/81 (9.9%)	9	2/39 (5.1%)	2
Hyperkalaemia	6/81 (7.4%)	8	2/39 (5.1%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	5/81 (6.2%)	7	4/39 (10.3%)	5
Pain in extremity	8/81 (9.9%)	10	2/39 (5.1%)	2
Back pain	5/81 (6.2%)	6	3/39 (7.7%)	3
Myalgia	4/81 (4.9%)	5	2/39 (5.1%)	2
Nervous system disorders
Headache	12/81 (14.8%)	13	6/39 (15.4%)	6
Psychiatric disorders
Anxiety	11/81 (13.6%)	12	4/39 (10.3%)	4
Depression	5/81 (6.2%)	5	3/39 (7.7%)	3
Confusional state	4/81 (4.9%)	5	0/39 (0%)	0
Renal and urinary disorders
Renal failure	12/81 (14.8%)	13	5/39 (12.8%)	5
Respiratory, thoracic and mediastinal disorders
Dyspnoea	11/81 (13.6%)	14	8/39 (20.5%)	9
Cough	9/81 (11.1%)	10	7/39 (17.9%)	7
Acute pulmonary oedema	0/81 (0%)	0	2/39 (5.1%)	2
Oropharyngeal pain	0/81 (0%)	0	2/39 (5.1%)	2
Lung disorder	3/81 (3.7%)	3	3/39 (7.7%)	3
Skin and subcutaneous tissue disorders
Erythema	8/81 (9.9%)	10	3/39 (7.7%)	3
Pruritus	4/81 (4.9%)	4	3/39 (7.7%)	3
Vascular disorders
Epistaxis	10/81 (12.3%)	12	6/39 (15.4%)	6
Hypertension	10/81 (12.3%)	12	4/39 (10.3%)	5
Purpura	5/81 (6.2%)	5	2/39 (5.1%)	2
Haematoma	4/81 (4.9%)	4	2/39 (5.1%)	2
Petechiae	3/81 (3.7%)	3	2/39 (5.1%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.