Safety and Dose Determining Multi-dose Study of BT062 in Patients With Relapsed or Refractory Multiple Myeloma

• Sponsor: Biotest Pharmaceuticals Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01001442
• Collaborator: Biotest (Industry)
• Enrollment: 35
• Locations: 5
• Arm: 1
• Duration (Months): 67
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This Phase I/IIa clinical study is to test safety and anti-tumor activity of BT062 to define the best dose in treating patients with relapsed or refractory multiple myeloma with multiple doses of BT062.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: BT062	Phase 1/Phase 2

Detailed Description

Phase I/IIa, open-label, 3 + 3 multi-dose escalation study. The Phase I part of the study was to include the dose escalation cohort; a conventional dose escalation design, following 3 + 3 rules was chosen to define the MTD.

The Phase IIa part was to include the MTD/recommended phase II dose (RPTD) expansion cohort in which descriptive statistical methods for evaluation of response, time to event endpoints, and safety were to be performed.

35 subjects in the Safety population, 34 subjects in the ITT and PP populations.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/IIa Multi-Dose Escalation Study to Evaluate Maximum Tolerated Dose (MTD), Pharmacokinetics (PK), Safety and Efficacy of BT062 in Subjects With Relapsed or Relapsed/Refractory Multiple Myeloma
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: BT062 BT062 was to be administered as single-dose IV infusions via a 0.22 μm in-line filter preferably in a forearm vein, according to medically accepted procedures on Days 1, 8, and 15 of each 28-day cycle. Alternatively BT062 may have been administered through a central venous line or a peripherally inserted central catheter (PICC). Other administration routes were only to be allowed after approval from Biotest. Each subject was to be monitored carefully for the effects of exposure to BT062. No subject was to have received more than 3 doses of BT062 per 28-day treatment cycle.

Drug: BT062; intravenous administration; Other Names: Indatuximab ravtansine

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicities (DLT) - Number of Participants With at Least 1 DLT [Starting with first study drug administration until 30-day follow-up visit (average 4.99 months)]

   The primary safety variable was to determine the incidence of DLTs in subjects with relapsed or relapsed/refractory multiple myeloma treated with BT062.

2. Maximum Tolerated Dose (MTD) [First 28-day cycle]

   The Phase I part of the study was to include the dose escalation cohort; a conventional dose escalation design, following 3 + 3 rules was chosen to define the MTD. Only DLTs occurring in cycle 1 for each subject were counted in the dose escalation decisions. Three subjects were treated at the first or newest dose level as available. If none of the 3 subjects experienced a DLT during Cycle 1, three subjects could be treated at the next dose level as available. In case of a DLT the cohort was expanded to up to 6 subjects. If not more than 1 of these 6 subjects experienced a DLT during Cycle 1, a first subject could be treated at the next dose level. If 2 or more of the 6 subjects experienced a DLT during Cycle 1 the dose escalation was stopped. The highest dose level at which < 2 of 6 subjects experienced a DLT is defined as the MTD.

Secondary Outcome Measures

1. Qualitative and Quantitative Toxicities of BT062 [Starting with first study drug administration until 30-day follow-up visit (average 4.99 months)]

   Qualitative and quantitative toxicities assessed by incidence of adverse events and by clinically significant changes in the patient's physical examination, vital signs, and clinical laboratory results. The incidence of treatment emergent adverse events (TEAEs), including serious adverse events (SAEs).

2. Multi-dose Pharmacokinetics Properties of BT062 - Cmax [Starting with first study drug administration until 30-day follow-up visit (average 4.99 months).]

   Multi-dose Pharmacokinetics properties of BT062 after intravenous (IV) Administration of escalating doses of BT062 as assessed by measuring intact BT062 conjugate. Please note that not all subjects reached Cycle 4 due to early termination . A lower number of samples could be analyzed for Cycle 4.

3. Anti-tumor Activity of BT062 in Subjects With Relapsed or Relapsed/Refractory Multiple Myeloma by Number of Participants With Objective Response(ORR) and/or Clinial Benefit(CBR) Based on the International Myeloma Working Group Uniform Response Criteria [On day 1 of each treatment cycle (on a monthly basis) starting with first study drug administration until Close Out visit (average 3.84 months).]

   sCR:CR+normal FLC+absence of clonal cells in BM; CR:Negative immunofixation,disappearance of soft tissue plasmacytomas +≤5% plasma cells in BM+normal FLC; VGPR:M-protein detectable by immunofixation,not on electrophoresis or 90% or greater reduction in serum M-protein+urine M-protein level <100mg per 24h,>90% decrease in the difference between involved/uninvolved FLC; PR:≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h or ≥50% decrease in the difference between involved/uninvolved FLC or ≥50% reduction in plasma cells, provided baseline bone marrow plasma cell percentage was ≥30%, ≥50% size reduction of soft tissue plasmacytomas; MR:25%-49% reduction of serum M-protein+reduction in 24h urinary M-protein by 50-89%(still >200 mg/24h),25-49% soft tissue plasmacytomas size reduction,no increase in size or number of lytic bone lesions; SD:no response or PD ORR: %of subjects with MR+PR+VGPR+CR+sCR CBR:ORR + %of subjects with SD.

4. Time to Progression (TTP), Progression Free Survival (PFS) and Overall Survival (OS) [Starting with first study drug administration until death or 3 years from first study treatment.]

   Progressive disease Requires any one or more of the following: Increase of ≥ 25% from baseline in Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL) (increases of ≥ 1 g/dL are sufficient to define relapse if starting M-component is ≥ 5 g/dL). Urine M-component and/or (the absolute increase must be ≥ 200mg/24h). Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL. Bone marrow plasma cell percentage: the absolute % must be ≥ 10% (relapse form CR as a 5% cutoff instead of 10%). Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of active multiple myeloma according to the International Myeloma Working Group diagnostic criteria

• Relapsed or relapsed/refractory multiple myeloma

• Previous treatment with both an immunomodulator and a proteosome inhibitor therapy

• Age ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status (Zubrod) ≤ 2

• Ability to understand and willingness to sign a written informed consent document

• Ability to adhere with the study visit schedule and other protocol procedures

• Life expectancy of ≥ 12 weeks

• Normal organ and marrow function

Exclusion Criteria:

• Chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to day 1 or those who have not recovered from AEs due to agents administered more than 3 weeks earlier

• Treatment with another investigational agent during the study or within 4 weeks before day 1

• Major surgery within 4 weeks before day 1 (this does not include placement of vascular access device or tumor biopsies)

• Antineoplastic therapy with biological agents within 2 weeks before day 1

• Known HAHAs, HACAs, or HAMAs in response to previous MAb therapy

• Previous treatment with BT062

• Malignancy within 3 years before day 1, other than the trial indication multiple myeloma and excluding treated non-melanoma skin cancer, superficial bladder cancer and carcinoma in-situ of the cervix

• Severe diseases of skin, colon, esophagus, or eye within 1 year before day 1, as judged by the Investigator

• Severe infections necessitating use of antibiotics / antivirals during the screening period

• Clinically relevant active infection including active hepatitis B or C or human immunodeficiency virus (HBV, HCV, or HIV) or any other concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for enrollment into this study

• Acute or relevant abnormalities in electrocardiogram (ECG), as judged by the Investigator. These abnormalities can be defined as recent myocardial infarction, uncontrolled cardiac arrhythmias and/or pronounced disturbances of the electrical conduction system of the heart.

• Significant cardiac disease such as recent myocardial infarction (≤ 6 months prior to day 1), unstable angina, uncontrolled congestive heart failure, uncontrolled hypertension (recurrent or persistent increases in systolic blood pressure ≥ 180 mm Hg or diastolic blood pressure ≥ 110 mm Hg), uncontrolled cardiac arrhythmias, grade 3 (Lown Criteria) or greater cardiac toxicity from prior chemotherapy

• History of clinically significant drug or alcohol abuse

• Unwillingness or inability to adhere to the requirements of the study

• Concomitant therapy with corticosteroids (except as indicated in low dose for other medical conditions such as inhaled steroid for asthma, topical use, or as premedication for administration of certain medications (including BT062) or blood products and for treatment of infusion reactions if needed)

• Concomitant antineoplastic therapies including chemotherapy, radiotherapy, or biological agents during the study

• Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the subject at unacceptable risk if he or she are included in the study

• Breast-feeding

• Unwillingness to use an effective contraceptive method during the study and at least 3 months after administration of study drug - unless subject is naturally infertile. (Acceptable contraceptive methods include oral or injectable contraceptives, intrauterine devices (IUD), double-barrier method, contraceptive patch, surgical sterilization, or condoms).

• Positive serum or urine pregnancy test

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322
2	The University of Chicago	Chicago	Illinois	United States	60637
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
4	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
5	The Mount Sinai School of Medicine	New York	New York	United States	10029

Sponsors and Collaborators

• Biotest Pharmaceuticals Corporation
• Biotest

Investigators

• Study Director: Kenneth C. Anderson, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Biotest Pharmaceuticals Corporation
• ClinicalTrials.gov Identifier: NCT01001442
• Other Study ID Numbers: 975
• First Posted: Oct 26, 2009
• Last Update Posted: Jul 30, 2019
• Last Verified: Jan 1, 2018

• Keywords provided by Biotest Pharmaceuticals Corporation: Multiple myeloma; Relapsed; Refractory
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Maytansine

Study Results

Participant Flow

Pre-assignment Detail	The Intention-to-treat (ITT) population included all subjects who were enrolled in the study and received at least 1 dose of BT062 and who had any post-Baseline evaluations or data. One subject did not have at least one post-injection assessment of the treatment response and was excluded from both the ITT and PP populations (n = 34).

Arm/Group Title	BT062 40 mg/m²	BT062 50 mg/m²	BT062 65 mg/m²	BT062 80 mg/m²	BT062 100 mg/m²	BT062 120 mg/m²	BT062 140 mg/m²	BT062 160 mg/m²
Arm/Group Description	40 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	50 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	65 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	80 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	100 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	120 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	140 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	160 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.
Period Title: Overall Study
STARTED	4	3	4	3	4	3	10	4
COMPLETED	4	3	4	3	2	3	6	2
NOT COMPLETED	0	0	0	0	2	0	4	2

Baseline Characteristics

Arm/Group Title	BT062 40 mg/m²	BT062 50 mg/m²	BT062 65 mg/m²	BT062 80 mg/m²	BT062 100 mg/m²	BT062 120 mg/m²	BT062 140 mg/m²	BT062 160 mg/m²	Total
Arm/Group Description	40 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	50 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	65 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	80 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	100 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	120 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	140 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	160 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	Total of all reporting groups
Overall Participants	4	3	4	3	3	3	10	4	34
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 25%	3 100%	2 50%	2 66.7%	1 33.3%	3 100%	2 20%	3 75%	17 50%
>=65 years	3 75%	0 0%	2 50%	1 33.3%	2 66.7%	0 0%	8 80%	1 25%	17 50%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.3 (15.56)	55.3 (7.64)	64.3 (9.39)	60.7 (4.51)	64.3 (8.02)	55.3 (5.03)	66.8 (8.80)	61.5 (9.98)	63.5 (9.63)
Sex: Female, Male (Count of Participants)
Female	2 50%	3 100%	2 50%	1 33.3%	2 66.7%	1 33.3%	5 50%	2 50%	18 52.9%
Male	2 50%	0 0%	2 50%	2 66.7%	1 33.3%	2 66.7%	5 50%	2 50%	16 47.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 10%	1 25%	2 5.9%
Not Hispanic or Latino	4 100%	3 100%	3 75%	3 100%	3 100%	3 100%	9 90%	3 75%	31 91.2%
Unknown or Not Reported	0 0%	0 0%	1 25%	0 0%	0 0%	0 0%	0 0%	0 0%	1 2.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	1 33.3%	1 33.3%	4 40%	1 25%	7 20.6%
White	4 100%	3 100%	3 75%	3 100%	2 66.7%	2 66.7%	6 60%	3 75%	26 76.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 25%	0 0%	0 0%	0 0%	0 0%	0 0%	1 2.9%
Region of Enrollment (participants) [Number]
United States	4 100%	3 100%	4 100%	3 100%	3 100%	3 100%	10 100%	4 100%	34 100%

Outcome Measures

1. Primary Outcome

Title	Dose Limiting Toxicities (DLT) - Number of Participants With at Least 1 DLT
Description	The primary safety variable was to determine the incidence of DLTs in subjects with relapsed or relapsed/refractory multiple myeloma treated with BT062.
Time Frame	Starting with first study drug administration until 30-day follow-up visit (average 4.99 months)

Outcome Measure Data

Analysis Population Description

The Safety population included all subjects who were enrolled and received at least 1 dose of BT062 (n = 35).

Arm/Group Title	BT062 40 mg/m²	BT062 50 mg/m²	BT062 65 mg/m²	BT062 80 mg/m²	BT062 100 mg/m²	BT062 120 mg/m²	BT062 140 mg/m²	BT062 160 mg/m²	Total
Arm/Group Description	40 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	50 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	65 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	80 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	100 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	120 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	140 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	160 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	BT062 administration (all dose levels)
Measure Participants	4	3	4	3	4	3	10	4	35
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%	2 20%	2 50%	5 14.7%

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
Description	The Phase I part of the study was to include the dose escalation cohort; a conventional dose escalation design, following 3 + 3 rules was chosen to define the MTD. Only DLTs occurring in cycle 1 for each subject were counted in the dose escalation decisions. Three subjects were treated at the first or newest dose level as available. If none of the 3 subjects experienced a DLT during Cycle 1, three subjects could be treated at the next dose level as available. In case of a DLT the cohort was expanded to up to 6 subjects. If not more than 1 of these 6 subjects experienced a DLT during Cycle 1, a first subject could be treated at the next dose level. If 2 or more of the 6 subjects experienced a DLT during Cycle 1 the dose escalation was stopped. The highest dose level at which < 2 of 6 subjects experienced a DLT is defined as the MTD.
Time Frame	First 28-day cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BT062
Arm/Group Description	BT062: intravenous administration
Measure Participants	35
Number [mg/m²]	140

3. Secondary Outcome

Title	Qualitative and Quantitative Toxicities of BT062
Description	Qualitative and quantitative toxicities assessed by incidence of adverse events and by clinically significant changes in the patient's physical examination, vital signs, and clinical laboratory results. The incidence of treatment emergent adverse events (TEAEs), including serious adverse events (SAEs).
Time Frame	Starting with first study drug administration until 30-day follow-up visit (average 4.99 months)

Outcome Measure Data

Analysis Population Description

Safety Population: The Safety population included all subjects who were enrolled and received at least 1 dose of BT062 (n = 35).

Arm/Group Title	BT062 40 mg/m²	BT062 50 mg/m²	BT062 65 mg/m²	BT062 80 mg/m²	BT062 100 mg/m²	BT062 120 mg/m²	BT062 140 mg/m²	BT062 160 mg/m²	Total
Arm/Group Description	40 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	50 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	65 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	80 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	100 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	120 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	140 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	160 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	BT062 Administration (all dose levels)
Measure Participants	4	3	4	3	4	3	10	4	35
At least one SAE	2 50%	0 0%	0 0%	2 66.7%	2 66.7%	1 33.3%	5 50%	2 50%	14 41.2%
At least one treatment related SAE	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 20%	1 25%	3 8.8%

4. Secondary Outcome

Title	Multi-dose Pharmacokinetics Properties of BT062 - Cmax
Description	Multi-dose Pharmacokinetics properties of BT062 after intravenous (IV) Administration of escalating doses of BT062 as assessed by measuring intact BT062 conjugate. Please note that not all subjects reached Cycle 4 due to early termination . A lower number of samples could be analyzed for Cycle 4.
Time Frame	Starting with first study drug administration until 30-day follow-up visit (average 4.99 months).

Outcome Measure Data

Analysis Population Description

Safety Population: The Safety population included all subjects who were enrolled and received at least 1 dose of BT062 (n = 35).

Arm/Group Title	BT062 40 mg/m²	BT062 50 mg/m²	BT062 65 mg/m²	BT062 80 mg/m²	BT062 100 mg/m²	BT062 120 mg/m²	BT062 140 mg/m²	BT062 160 mg/m²
Arm/Group Description	40 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	50 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	65 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	80 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	100 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	120 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	140 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	160 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.
Measure Participants	4	3	4	3	4	3	10	4
BT062 plasma concentration Cycle 1 - Cmax	13409.0	10156.0	26229.0	21498.0	51593.0	61190.0	48463.0	62876.5
BT062 plasma concentration Cycle 4 - Cmax	9427.0	14193.0	27770.5	38144.0	92046.0	96178.0	50073.0	79248.0

5. Secondary Outcome

Title	Anti-tumor Activity of BT062 in Subjects With Relapsed or Relapsed/Refractory Multiple Myeloma by Number of Participants With Objective Response(ORR) and/or Clinial Benefit(CBR) Based on the International Myeloma Working Group Uniform Response Criteria
Description	sCR:CR+normal FLC+absence of clonal cells in BM; CR:Negative immunofixation,disappearance of soft tissue plasmacytomas +≤5% plasma cells in BM+normal FLC; VGPR:M-protein detectable by immunofixation,not on electrophoresis or 90% or greater reduction in serum M-protein+urine M-protein level <100mg per 24h,>90% decrease in the difference between involved/uninvolved FLC; PR:≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h or ≥50% decrease in the difference between involved/uninvolved FLC or ≥50% reduction in plasma cells, provided baseline bone marrow plasma cell percentage was ≥30%, ≥50% size reduction of soft tissue plasmacytomas; MR:25%-49% reduction of serum M-protein+reduction in 24h urinary M-protein by 50-89%(still >200 mg/24h),25-49% soft tissue plasmacytomas size reduction,no increase in size or number of lytic bone lesions; SD:no response or PD ORR: %of subjects with MR+PR+VGPR+CR+sCR CBR:ORR + %of subjects with SD.
Time Frame	On day 1 of each treatment cycle (on a monthly basis) starting with first study drug administration until Close Out visit (average 3.84 months).

Outcome Measure Data

Analysis Population Description

ITT: The Intention-to-treat (ITT) population included all subjects who were enrolled in the study and received at least 1 dose of BT062 and who had any post-Baseline evaluations or data. One subject did not have at least one post-injection assessment of the treatment response and was excluded from both the ITT and PP populations (n = 34).

Arm/Group Title	BT062 40 mg/m²	BT062 50 mg/m²	BT062 65 mg/m²	BT062 80 mg/m²	BT062 100 mg/m²	BT062 120 mg/m²	BT062 140 mg/m²	BT062 160 mg/m²	Total
Arm/Group Description	40 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	50 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	65 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	80 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	100 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	120 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	140 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	160 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.	BT062 administration (all dose levels)
Measure Participants	4	3	4	3	3	3	10	4	34
yes	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	1 10%	0 0%	2 5.9%
no	4 100%	3 100%	4 100%	2 66.7%	3 100%	3 100%	9 90%	4 100%	32 94.1%
yes	0 0%	0 0%	0 0%	1 33.3%	0 0%	1 33.3%	1 10%	2 50%	5 14.7%
no	4 100%	3 100%	4 100%	2 66.7%	3 100%	2 66.7%	9 90%	2 50%	29 85.3%

6. Secondary Outcome

Title	Time to Progression (TTP), Progression Free Survival (PFS) and Overall Survival (OS)
Description	Progressive disease Requires any one or more of the following: Increase of ≥ 25% from baseline in Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL) (increases of ≥ 1 g/dL are sufficient to define relapse if starting M-component is ≥ 5 g/dL). Urine M-component and/or (the absolute increase must be ≥ 200mg/24h). Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL. Bone marrow plasma cell percentage: the absolute % must be ≥ 10% (relapse form CR as a 5% cutoff instead of 10%). Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder.
Time Frame	Starting with first study drug administration until death or 3 years from first study treatment.

Outcome Measure Data

Analysis Population Description

The Intention-to-treat (ITT) population included all subjects who were enrolled in the study and received at least 1 dose of BT062 and who had any post-Baseline evaluations or data (n = 34).

Arm/Group Title	BT062
Arm/Group Description	BT062: intravenous administration
Measure Participants	34
TTP	3
PFS	3
OS	26.7

Adverse Events

Time Frame	Adverse events (AEs) were to be documented during the entire study period including the 30 day follow up (average 4.99 months).
Arm/Group Title	BT062 40 mg/m²		BT062 50 mg/m²		BT062 65 mg/m²		BT062 80 mg/m²		BT062 100 mg/m²		BT062 120 mg/m²		BT062 140 mg/m²		BT062 160 mg/m²		Total
Arm/Group Description	40 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.		50 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.		65 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.		80 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.		100 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.		120 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.		140 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.		160 mg/m² BT062 was administered by IV infusion on Days 1, 8, and 15 of every 28-day cycle.		BT062 administration (all dose levels)
All Cause Mortality
	BT062 40 mg/m²		BT062 50 mg/m²		BT062 65 mg/m²		BT062 80 mg/m²		BT062 100 mg/m²		BT062 120 mg/m²		BT062 140 mg/m²		BT062 160 mg/m²		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/3 (0%)		0/4 (0%)		0/3 (0%)		1/4 (25%)		1/3 (33.3%)		1/10 (10%)		1/4 (25%)		4/35 (11.4%)
Serious Adverse Events
	BT062 40 mg/m²		BT062 50 mg/m²		BT062 65 mg/m²		BT062 80 mg/m²		BT062 100 mg/m²		BT062 120 mg/m²		BT062 140 mg/m²		BT062 160 mg/m²		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/4 (50%)		0/3 (0%)		0/4 (0%)		2/3 (66.7%)		2/4 (50%)		1/3 (33.3%)		5/10 (50%)		2/4 (50%)		14/35 (40%)
Blood and lymphatic system disorders
NEUTROPENIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	1/4 (25%)	1	1/35 (2.9%)	1
Cardiac disorders
ATRIAL FIBRILLATION	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
Eye disorders
EXTRAOCULAR MUSCLE PARESIS	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
General disorders
PYREXIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/10 (20%)	2	0/4 (0%)	0	2/35 (5.7%)	2
Infections and infestations
PNEUMONIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/10 (20%)	2	1/4 (25%)	1	3/35 (8.6%)	3
Injury, poisoning and procedural complications
HEAD INJURY	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
HIP FRACTURE	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	1/4 (25%)	1	1/35 (2.9%)	1
PELVIC FRACTURE	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	1/35 (2.9%)	1
Investigations
TRANSAMINASES INCREASED	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
Musculoskeletal and connective tissue disorders
BONE PAIN	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
Nervous system disorders
BRAIN MASS	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
HAEMORRHAGE INTRACRANIAL	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	1/4 (25%)	1	1/35 (2.9%)	1
Renal and urinary disorders
RENAL FAILURE ACUTE	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
Respiratory, thoracic and mediastinal disorders
ALVEOLITIS ALLERGIC	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
PULMONARY EMBOLISM	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
Skin and subcutaneous tissue disorders
PALMAR-PLANTAR / ERYTHRODYSAESTHESIA SYNDROME	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	1/35 (2.9%)	1
STEVENS-JOHNSON SYNDROME	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
Vascular disorders
DEEP VEIN THROMBOSIS	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	BT062 40 mg/m²		BT062 50 mg/m²		BT062 65 mg/m²		BT062 80 mg/m²		BT062 100 mg/m²		BT062 120 mg/m²		BT062 140 mg/m²		BT062 160 mg/m²		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		3/3 (100%)		3/4 (75%)		2/3 (66.7%)		3/4 (75%)		3/3 (100%)		8/10 (80%)		3/4 (75%)		28/35 (80%)
Blood and lymphatic system disorders
ANAEMIA	1/4 (25%)	1	2/3 (66.7%)	2	0/4 (0%)	0	1/3 (33.3%)	2	2/4 (50%)	2	1/3 (33.3%)	2	3/10 (30%)	4	1/4 (25%)	1	11/35 (31.4%)	14
LEUKOPENIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/10 (10%)	1	1/4 (25%)	2	3/35 (8.6%)	4
LYMPHOPENIA	0/4 (0%)	0	2/3 (66.7%)	2	1/4 (25%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	5/35 (14.3%)	5
NEUTROPENIA	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/10 (10%)	1	1/4 (25%)	2	4/35 (11.4%)	5
THROMBOCYTOPENIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	2/3 (66.7%)	3	1/10 (10%)	1	0/4 (0%)	0	4/35 (11.4%)	5
Gastrointestinal disorders
ABDOMINAL DISTENSION	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
ABDOMINAL PAIN	0/4 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	1/4 (25%)	1	3/35 (8.6%)	3
CONSTIPATION	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/10 (10%)	1	1/4 (25%)	1	5/35 (14.3%)	5
DIARRHOEA	1/4 (25%)	1	2/3 (66.7%)	3	1/4 (25%)	2	1/3 (33.3%)	1	0/4 (0%)	0	2/3 (66.7%)	7	3/10 (30%)	3	3/4 (75%)	4	13/35 (37.1%)	21
DYSPEPSIA	0/4 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
HAEMATOCHEZIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
NAUSEA	1/4 (25%)	1	2/3 (66.7%)	2	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	3/10 (30%)	4	0/4 (0%)	0	8/35 (22.9%)	9
General disorders
FATIGUE	3/4 (75%)	5	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	2/4 (50%)	2	3/3 (100%)	5	2/10 (20%)	2	1/4 (25%)	2	12/35 (34.3%)	17
INFLUENZA LIKE ILLNESS	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	2	0/10 (0%)	0	1/4 (25%)	1	2/35 (5.7%)	3
INFUSION SITE ERYTHEMA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	2/4 (50%)	2	2/35 (5.7%)	2
NON-CARDIAC CHEST PAIN	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
OEDEMA PERIPHERAL	1/4 (25%)	1	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	2/4 (50%)	2	1/3 (33.3%)	1	1/10 (10%)	1	0/4 (0%)	0	7/35 (20%)	7
PYREXIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
Infections and infestations
PNEUMONIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	1/4 (25%)	1	2/35 (5.7%)	2
UPPER RESPIRATORY TRACT INFECTION	0/4 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/3 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	0/10 (0%)	0	0/4 (0%)	0	4/35 (11.4%)	4
Injury, poisoning and procedural complications
FALL	0/4 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
INFUSION RELATED	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	1/4 (25%)	1	2/35 (5.7%)	2
SKIN ABRASION	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/3 (66.7%)	4	3/10 (30%)	4	1/4 (25%)	2	6/35 (17.1%)	10
AMYLASE INCREASED	0/4 (0%)	0	1/3 (33.3%)	2	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/10 (20%)	3	0/4 (0%)	0	3/35 (8.6%)	5
ASPARTATE AMINOTRANSFERASE INCREASED	1/4 (25%)	1	0/3 (0%)	0	2/4 (50%)	3	0/3 (0%)	0	0/4 (0%)	0	2/3 (66.7%)	2	3/10 (30%)	4	1/4 (25%)	1	9/35 (25.7%)	11
BLOOD CREATINE PHOSPHOKINASE INCREASED	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/10 (20%)	2	0/4 (0%)	0	2/35 (5.7%)	2
BLOOD CREATININE INCREASED	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
BLOOD LACTATE DEHYDROGENASE INCREASED	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	2/10 (20%)	2	1/4 (25%)	1	4/35 (11.4%)	4
BLOOD URIC ACID INCREASED	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
GAMMA-GLUTAMYLTRANSFERASE INCREASED	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	1	2/10 (20%)	2	0/4 (0%)	0	4/35 (11.4%)	4
LIPASE INCREASED	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/10 (20%)	2	0/4 (0%)	0	2/35 (5.7%)	2
LYMPHOCYTE COUNT DECREASED	0/4 (0%)	0	2/3 (66.7%)	6	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	3/35 (8.6%)	7
NEUTROPHIL COUNT DECREASED	0/4 (0%)	0	2/3 (66.7%)	5	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	5
OCCULT BLOOD POSITIVE	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	1	1/10 (10%)	1	0/4 (0%)	0	4/35 (11.4%)	4
Metabolism and nutrition disorders
DECREASED APPETITE	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	3/35 (8.6%)	3
HYPERCALCAEMIA	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	3/35 (8.6%)	3
HYPERGLYCAEMIA	0/4 (0%)	0	2/3 (66.7%)	6	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	3/10 (30%)	4	0/4 (0%)	0	6/35 (17.1%)	11
HYPERKALAEMIA	0/4 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
HYPOKALAEMIA	0/4 (0%)	0	0/3 (0%)	0	2/4 (50%)	3	1/3 (33.3%)	1	0/4 (0%)	0	1/3 (33.3%)	4	1/10 (10%)	1	2/4 (50%)	2	7/35 (20%)	11
HYPONATRAEMIA	1/4 (25%)	2	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	3
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/4 (25%)	2	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/10 (0%)	0	0/4 (0%)	0	3/35 (8.6%)	4
BACK PAIN	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/3 (0%)	0	0/10 (0%)	0	1/4 (25%)	1	4/35 (11.4%)	4
BONE PAIN	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	1/3 (33.3%)	1	1/10 (10%)	1	0/4 (0%)	0	5/35 (14.3%)	5
FLANK PAIN	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
MUSCULOSKELETAL CHEST PAIN	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
MUSCULOSKELETAL PAIN	1/4 (25%)	1	0/3 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	3/35 (8.6%)	3
MYALGIA	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	1/4 (25%)	1	2/35 (5.7%)	2
PAIN IN EXTREMITY	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/10 (10%)	1	0/4 (0%)	0	3/35 (8.6%)	3
Nervous system disorders
HYPOAESTHESIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	1/4 (25%)	1	2/35 (5.7%)	2
NEURALGIA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	3/4 (75%)	3	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	3/35 (8.6%)	3
NEUROPATHY PERIPHERAL	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/3 (66.7%)	2	0/10 (0%)	0	1/4 (25%)	1	4/35 (11.4%)	4
Psychiatric disorders
ANXIETY	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
INSOMNIA	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
Renal and urinary disorders
DYSURIA	1/4 (25%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
Respiratory, thoracic and mediastinal disorders
COUGH	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	1/4 (25%)	1	3/35 (8.6%)	3
DYSPNOEA	1/4 (25%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
DYSPNOEA EXERTIONAL	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	0/10 (0%)	0	1/4 (25%)	1	3/35 (8.6%)	3
PRODUCTIVE COUGH	2/4 (50%)	2	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	3/35 (8.6%)	3
UPPER-AIRWAY COUGH SYNDROME	0/4 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	0/4 (0%)	0	2/35 (5.7%)	2
Skin and subcutaneous tissue disorders
BLISTER	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
DRY SKIN	2/4 (50%)	2	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	2/4 (50%)	3	0/3 (0%)	0	0/10 (0%)	0	1/4 (25%)	2	5/35 (14.3%)	7
ERYTHEMA	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/3 (66.7%)	5	0/10 (0%)	0	1/4 (25%)	1	3/35 (8.6%)	6
PRURITUS	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/10 (10%)	1	0/4 (0%)	0	2/35 (5.7%)	2
RASH	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	3	0/4 (0%)	0	1/3 (33.3%)	1	2/10 (20%)	2	1/4 (25%)	1	5/35 (14.3%)	7
RASH ERYTHEMATOUS	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	1/10 (10%)	1	1/4 (25%)	1	2/35 (5.7%)	2
Vascular disorders
HOT FLUSH	0/4 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/10 (0%)	0	1/4 (25%)	1	2/35 (5.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Part of CTA:The Investigator or any Site employee, consultant or admitting physician to the Site or Study Team member is not allowed to make any publication of any Study Data, information, results, or similar information without the review and comment of SPONSOR. As the Study is part of a multi-center trial, and the Investigator/site agree that no publication by Site/Investigator of the results of the Study conducted at the Site shall be made before the first multi-centre publication.