Trial Outcomes & Findings for Temozolomide 12 Cycles Versus 6 Cycles of Standard First-line Treatment in Patients With Glioblastoma. (NCT NCT02209948)

NCT ID: NCT02209948

Last Updated: 2021-01-12

Results Overview

Percentage of patients without progression of disease and time between start of treatment and progression of disease. The progression disease is defined as the time from the date of randomization to the date of progression defined according to the RANO criteria.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

166 participants

Primary outcome timeframe

6 month

Results posted on

2021-01-12

Participant Flow

7 patients do not meet inclusion criteria. Only 159 patients were randomized

Participant milestones

Participant milestones
Measure	Temozolomide Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment No treatment (total 6 cycles of adjuvant Temozolomide).
Overall Study STARTED	80	79
Overall Study Recieved Alocated Intervention	80	79
Overall Study Lost to Follow up	0	1
Overall Study Discontinued Due to Progression	31	39
Overall Study COMPLETED	80	79
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Temozolomide n=80 Participants Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=79 Participants No treatment (total 6 cycles of adjuvant Temozolomide).	Total n=159 Participants Total of all reporting groups
Age, Continuous	60.7 Years n=80 Participants	60.4 Years n=79 Participants	60.4 Years n=159 Participants
Sex: Female, Male Female	38 Participants n=80 Participants	38 Participants n=79 Participants	76 Participants n=159 Participants
Sex: Female, Male Male	42 Participants n=80 Participants	41 Participants n=79 Participants	83 Participants n=159 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Spain	80 participants n=80 Participants	79 participants n=79 Participants	159 participants n=159 Participants
Residual disease (>10mm) Yes	41 Participants n=80 Participants	42 Participants n=79 Participants	83 Participants n=159 Participants
Residual disease (>10mm) No	39 Participants n=80 Participants	37 Participants n=79 Participants	76 Participants n=159 Participants
Karnofski Performance Status (KPS) index <70%	2 Participants n=80 Participants	2 Participants n=79 Participants	4 Participants n=159 Participants
Karnofski Performance Status (KPS) index >=70%	78 Participants n=80 Participants	77 Participants n=79 Participants	155 Participants n=159 Participants
Residual Neurological symptom Yes	19 Participants n=80 Participants	8 Participants n=79 Participants	27 Participants n=159 Participants
Residual Neurological symptom No	60 Participants n=80 Participants	71 Participants n=79 Participants	131 Participants n=159 Participants
Residual Neurological symptom NA	1 Participants n=80 Participants	0 Participants n=79 Participants	1 Participants n=159 Participants
Dexamethasone (DXM) dose at inclusion 0 mg	67 Participants n=80 Participants	70 Participants n=79 Participants	137 Participants n=159 Participants
Dexamethasone (DXM) dose at inclusion 0.5-2 mg	9 Participants n=80 Participants	6 Participants n=79 Participants	15 Participants n=159 Participants
Dexamethasone (DXM) dose at inclusion >2 mg	4 Participants n=80 Participants	3 Participants n=79 Participants	7 Participants n=159 Participants
Barthel index 0	12 Participants n=80 Participants	9 Participants n=79 Participants	21 Participants n=159 Participants
Barthel index 1	68 Participants n=80 Participants	70 Participants n=79 Participants	138 Participants n=159 Participants
Mini-mental status examinaion (MMSE) <27	16 Participants n=80 Participants	10 Participants n=79 Participants	26 Participants n=159 Participants
Mini-mental status examinaion (MMSE) ≥27	51 Participants n=80 Participants	60 Participants n=79 Participants	111 Participants n=159 Participants
Mini-mental status examinaion (MMSE) NP/ND	13 Participants n=80 Participants	9 Participants n=79 Participants	22 Participants n=159 Participants
Anticonvulsant therapy Yes	37 Participants n=80 Participants	38 Participants n=79 Participants	75 Participants n=159 Participants
Anticonvulsant therapy No	43 Participants n=80 Participants	41 Participants n=79 Participants	84 Participants n=159 Participants
Initial surgery- Treatment at diagnosis. Biopsy	7 Participants n=80 Participants	10 Participants n=79 Participants	17 Participants n=159 Participants
Initial surgery- Treatment at diagnosis. Complete resection by post-op MRI)	28 Participants n=80 Participants	35 Participants n=79 Participants	63 Participants n=159 Participants
Initial surgery- Treatment at diagnosis. Complete resection without post-op MRI	20 Participants n=80 Participants	14 Participants n=79 Participants	34 Participants n=159 Participants
Initial surgery- Treatment at diagnosis. Subtotal resection	25 Participants n=80 Participants	20 Participants n=79 Participants	45 Participants n=159 Participants
O6-methylguanine DNA methyltransferase (MGMT) Methylation status Methylated	49 Participants n=80 Participants	48 Participants n=79 Participants	97 Participants n=159 Participants
O6-methylguanine DNA methyltransferase (MGMT) Methylation status Unmethylated	31 Participants n=80 Participants	31 Participants n=79 Participants	62 Participants n=159 Participants
Isocitrate dehydrogenase 1 (IDH1) Mutation status IDH1-R132 mutated by ICH	1 Participants n=80 Participants	7 Participants n=79 Participants	8 Participants n=159 Participants
Isocitrate dehydrogenase 1 (IDH1) Mutation status IDH1-R132 non mutated by ICH	71 Participants n=80 Participants	66 Participants n=79 Participants	137 Participants n=159 Participants
Isocitrate dehydrogenase 1 (IDH1) Mutation status not determined	8 Participants n=80 Participants	6 Participants n=79 Participants	14 Participants n=159 Participants

PRIMARY outcome

Timeframe: 6 month

Outcome measures

Outcome measures
Measure	Temozolomide n=80 Participants Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=79 Participants No treatment (total 6 cycles of adjuvant Temozolomide).
Progression Free Survival at 6 Month	61.3 percentage of patients Interval 51.5 to 72.9	55.7 percentage of patients Interval 45.8 to 67.8

SECONDARY outcome

Timeframe: Through the whole study. 4 years

Total number of patients presenting adverse events, stratified by type of event and grade. Adverse Events of special interest: Only relevant differences in toxicity by arm.

Outcome measures

Outcome measures
Measure	Temozolomide n=80 Participants Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=79 Participants No treatment (total 6 cycles of adjuvant Temozolomide).
Number of Participants With Adverse Effects Lymphopenia · Grade 1-2	52 Participants	33 Participants
Number of Participants With Adverse Effects Lymphopenia · Grade 3-4	3 Participants	0 Participants
Number of Participants With Adverse Effects Lymphopenia · not affected	25 Participants	46 Participants
Number of Participants With Adverse Effects Thrombocytopenia · Grade 1-2	36 Participants	17 Participants
Number of Participants With Adverse Effects Thrombocytopenia · Grade 3-4	2 Participants	0 Participants
Number of Participants With Adverse Effects Thrombocytopenia · not affected	42 Participants	62 Participants
Number of Participants With Adverse Effects Nausea and vomiting · Grade 1-2	30 Participants	10 Participants
Number of Participants With Adverse Effects Nausea and vomiting · Grade 3-4	0 Participants	0 Participants
Number of Participants With Adverse Effects Nausea and vomiting · not affected	50 Participants	69 Participants
Number of Participants With Adverse Effects Fatigue · Grade 1-2	35 Participants	21 Participants
Number of Participants With Adverse Effects Fatigue · Grade 3-4	0 Participants	0 Participants
Number of Participants With Adverse Effects Fatigue · not affected	45 Participants	58 Participants
Number of Participants With Adverse Effects Leucopenia · Grade 1-2	29 Participants	20 Participants
Number of Participants With Adverse Effects Leucopenia · Grade 3-4	1 Participants	0 Participants
Number of Participants With Adverse Effects Leucopenia · not affected	50 Participants	59 Participants

SECONDARY outcome

Timeframe: Through the whole study. 4 years. The median follow up for each patient was 33.4 months

It will be measured following Response assessment in neuro-oncology (RANO) guidelines: progression-free survival

Outcome measures

Outcome measures
Measure	Temozolomide n=80 Participants Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=79 Participants No treatment (total 6 cycles of adjuvant Temozolomide).
Progresion Free Survival Median Values	9.5 months Interval 5.93 to 13.07	7.77 months Interval 5.7 to 9.83

SECONDARY outcome

Timeframe: Through the whole study. 4 years. The median follow up for each patient was 33.4 months

Time between start of treatment and death

Outcome measures

Outcome measures
Measure	Temozolomide n=80 Participants Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=79 Participants No treatment (total 6 cycles of adjuvant Temozolomide).
Overall Survival	18.2 months Interval 16.7 to 23.8	23.3 months Interval 17.9 to 28.7

SECONDARY outcome

Timeframe: Through the whole study. 4 years. The median follow up for each patient was 33.4 months

Population: Patients with MGMT methylation

Median Progression Free Survival depending on treatment arm in patients with MGMT methylation

Outcome measures

Outcome measures
Measure	Temozolomide n=49 Participants Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=48 Participants No treatment (total 6 cycles of adjuvant Temozolomide).
Median Progression-free Survival (PFS) by Arm and MGMT Methylation Status	11.4 months Interval 9.2 to 13.6	8.5 months Interval 6.5 to 10.4

SECONDARY outcome

Timeframe: Through the whole study. 4 years. The median follow up for each patient was 33.4 months

Population: Patients with MGMT methylation

Median OS depending on treatment arm in patients with methylated MGMT

Outcome measures

Outcome measures
Measure	Temozolomide n=49 Participants Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=48 Participants No treatment (total 6 cycles of adjuvant Temozolomide).
Median Overall Survival (OS) by Arm and MGMT Methylation Status	20.7 months Interval 14.7 to 26.7	27.1 months Interval 20.3 to 33.9

SECONDARY outcome

Timeframe: baseline

partial immunoreactivity of MSH6 in patients by treatment arm. Tumor samples were stained by immuno-histochemical techniques.

Outcome measures

Outcome measures
Measure	Temozolomide n=80 Participants Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=79 Participants No treatment (total 6 cycles of adjuvant Temozolomide).
Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity MSH6 partial immunoreactivity	5 Participants	6 Participants
Translational Sub-study - Biomarkers: mutS Homolog 6 (MSH6) Immunoreactivity no MSH6 partial immunoreactivity	75 Participants	73 Participants

Adverse Events

Temozolomide

Serious events: 9 serious events

Other events: 80 other events

Deaths: 63 deaths

Without Treatment

Serious events: 5 serious events

Other events: 79 other events

Deaths: 52 deaths

Serious adverse events

Serious adverse events
Measure	Temozolomide n=80 participants at risk Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=79 participants at risk No treatment (total 6 cycles of adjuvant Temozolomide).
Nervous system disorders Dysarthria	0.00% 0/80 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	1.3% 1/79 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Nervous system disorders Neurological impairment	2.5% 2/80 • Number of events 2 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	0.00% 0/79 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
General disorders Syncope	0.00% 0/80 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	1.3% 1/79 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/80 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	1.3% 1/79 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Vascular disorders Intracraneal hypertension	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	0.00% 0/79 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Nervous system disorders Epileptic crisis	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	0.00% 0/79 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Infections and infestations Respiratory infection	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	0.00% 0/79 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Cardiac disorders Claudication	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	0.00% 0/79 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Musculoskeletal and connective tissue disorders Femur fracture	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	0.00% 0/79 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
General disorders General deterioration	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	1.3% 1/79 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Nervous system disorders Seizure	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	0.00% 0/79 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Vascular disorders Pulmonary embolism	0.00% 0/80 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	1.3% 1/79 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).

Other adverse events

Additional Information

Pau Doñate

MFAR Clinical Research

Phone: 0034934344412

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Temozolomide n=80 participants at risk Temozolomide dose 150/200 mg/m2/d for 5 days every 28 days for 6 cycles (total 12 cycles of adjuvant temozolomide).	Without Treatment n=79 participants at risk No treatment (total 6 cycles of adjuvant Temozolomide).
Blood and lymphatic system disorders Leukopenia	37.5% 30/80 • Number of events 30 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	25.3% 20/79 • Number of events 20 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders Neutropenia	3.8% 3/80 • Number of events 3 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	2.5% 2/79 • Number of events 2 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders Anemia	5.0% 4/80 • Number of events 4 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	10.1% 8/79 • Number of events 8 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders Lymphopenia	68.8% 55/80 • Number of events 55 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	41.8% 33/79 • Number of events 33 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders Thrombocytopenia	47.5% 38/80 • Number of events 38 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	21.5% 17/79 • Number of events 17 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Renal and urinary disorders Creatinine high	3.8% 3/80 • Number of events 3 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	7.6% 6/79 • Number of events 6 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders Alkaline Phosphatase High	3.8% 3/80 • Number of events 3 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	5.1% 4/79 • Number of events 4 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders Potasium High	3.8% 3/80 • Number of events 3 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	7.6% 6/79 • Number of events 6 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders Sodium High	8.8% 7/80 • Number of events 7 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	6.3% 5/79 • Number of events 5 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders GGT High	5.0% 4/80 • Number of events 4 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	7.6% 6/79 • Number of events 6 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders GOT High	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	3.8% 3/79 • Number of events 3 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders GPT High	6.2% 5/80 • Number of events 5 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	8.9% 7/79 • Number of events 7 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Blood and lymphatic system disorders Bilirubin High	8.8% 7/80 • Number of events 7 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	10.1% 8/79 • Number of events 8 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Metabolism and nutrition disorders Hyperglicemia	17.5% 14/80 • Number of events 14 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	24.1% 19/79 • Number of events 19 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Nervous system disorders Neurologic	47.5% 38/80 • Number of events 38 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	51.9% 41/79 • Number of events 41 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Gastrointestinal disorders Nausea and Vomiting	37.5% 30/80 • Number of events 30 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	12.7% 10/79 • Number of events 10 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
General disorders Asthenia	43.8% 35/80 • Number of events 35 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	26.6% 21/79 • Number of events 21 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Metabolism and nutrition disorders Anorexia	5.0% 4/80 • Number of events 4 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	1.3% 1/79 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Ear and labyrinth disorders Hearing loss	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	2.5% 2/79 • Number of events 2 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Skin and subcutaneous tissue disorders Skin disorders	5.0% 4/80 • Number of events 4 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	3.8% 3/79 • Number of events 3 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Nervous system disorders Anxiety	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	2.5% 2/79 • Number of events 2 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
General disorders Pain	16.2% 13/80 • Number of events 13 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	12.7% 10/79 • Number of events 10 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Infections and infestations Constipation	7.5% 6/80 • Number of events 6 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	2.5% 2/79 • Number of events 2 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Respiratory, thoracic and mediastinal disorders Respiratory disorders	1.2% 1/80 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	2.5% 2/79 • Number of events 2 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Infections and infestations Infection	13.8% 11/80 • Number of events 11 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	6.3% 5/79 • Number of events 5 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Vascular disorders Thromboembolism	0.00% 0/80 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	2.5% 2/79 • Number of events 2 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Musculoskeletal and connective tissue disorders Bone Events	3.8% 3/80 • Number of events 3 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	5.1% 4/79 • Number of events 4 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).
Cardiac disorders Cardiac Events	0.00% 0/80 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).	1.3% 1/79 • Number of events 1 • Through the clinical study. About 4 years In addition, clinically relevant changes on physical examination and abnormal parameters found on complementary examinations (eg radiography, ECG) should also be reported like Adverse Event (AE).