Trial Outcomes & Findings for Long-term Effects of Thalidomide for Recurrent Gastrointestinal Bleeding Due to Vascular Malformation (NCT NCT00964496)

Last Updated: 2015-12-17

Results Overview

The primary end point was defined as the patients whose rebleeds decreased from baseline by ≥ 50% at 12 months. Reduction of rebleeds = \[(total bleeding episode at 12 months - total bleeding episodes at a year before randomization)/total bleeding episodes at a year before randomization(baseline)\]\*100%. Rebleeding was defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

55 participants

Primary outcome timeframe

baseline and 12 months

Results posted on

2015-12-17

Participant Flow

From November 2004 to November 2007, a total of 59 subjects were assessed for eligibility at Shanghai Ren Ji Hospital, China.

Among the 59 patients, two refused to enter the protocol and two other were excluded owing to severe associated disease with short life expectancy. Therefore, 55 patients were enrolled in our study.

Participant milestones

Participant milestones
Measure	Thalidomide Group interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Overall Study STARTED	28	27
Overall Study COMPLETED	26	26
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Long-term Effects of Thalidomide for Recurrent Gastrointestinal Bleeding Due to Vascular Malformation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Thalidomide Group n=28 Participants interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=27 Participants interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Total n=55 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	20 Participants n=99 Participants	20 Participants n=107 Participants	40 Participants n=206 Participants
Age, Categorical >=65 years	8 Participants n=99 Participants	7 Participants n=107 Participants	15 Participants n=206 Participants
Sex: Female, Male Female	24 Participants n=99 Participants	22 Participants n=107 Participants	46 Participants n=206 Participants
Sex: Female, Male Male	4 Participants n=99 Participants	5 Participants n=107 Participants	9 Participants n=206 Participants
Region of Enrollment China	28 participants n=99 Participants	27 participants n=107 Participants	55 participants n=206 Participants
Location Multiple	13 participants n=99 Participants	14 participants n=107 Participants	27 participants n=206 Participants
Location Single	15 participants n=99 Participants	13 participants n=107 Participants	28 participants n=206 Participants
Outcome Completion of study	26 participants n=99 Participants	26 participants n=107 Participants	52 participants n=206 Participants
Outcome Incomplete study	2 participants n=99 Participants	1 participants n=107 Participants	3 participants n=206 Participants
Transfusion dependence dependent	14 participants n=99 Participants	14 participants n=107 Participants	28 participants n=206 Participants
Transfusion dependence independent	14 participants n=99 Participants	13 participants n=107 Participants	27 participants n=206 Participants
Ways of diagnose Capsule endoscopy	24 participants n=99 Participants	24 participants n=107 Participants	48 participants n=206 Participants
Ways of diagnose Enteroscopies	2 participants n=99 Participants	2 participants n=107 Participants	4 participants n=206 Participants
Ways of diagnose Gastroscopy	2 participants n=99 Participants	1 participants n=107 Participants	3 participants n=206 Participants
Activated partial thromboplastin time (APTT)	27.4929 seconds STANDARD_DEVIATION 6.4430 • n=99 Participants	28.0667 seconds STANDARD_DEVIATION 5.9947 • n=107 Participants	27.7745 seconds STANDARD_DEVIATION 6.1760 • n=206 Participants
Follow-up time	34.9286 months STANDARD_DEVIATION 13.73810 • n=99 Participants	36.1481 months STANDARD_DEVIATION 13.49274 • n=107 Participants	35.5273 months STANDARD_DEVIATION 13.50563 • n=206 Participants
Glutamic-pyruvic transaminase (GPT)	24.8143 IU/L STANDARD_DEVIATION 13.4963 • n=99 Participants	25.2019 IU/L STANDARD_DEVIATION 14.1123 • n=107 Participants	25.0045 IU/L STANDARD_DEVIATION 12.4753 • n=206 Participants
History of bleeding time	5 years FULL_RANGE 4.1404 • n=99 Participants	3 years FULL_RANGE 4.4331 • n=107 Participants	5 years FULL_RANGE 4.2552 • n=206 Participants
Mean corpuscular volume (MCV)	76.8000 femtoliter STANDARD_DEVIATION 3.9711 • n=99 Participants	75.2444 femtoliter STANDARD_DEVIATION 4.4130 • n=107 Participants	76.0364 femtoliter STANDARD_DEVIATION 4.2282 • n=206 Participants
Mean Corpuscular Hemoglobin Concentration	295.8571 g/L STANDARD_DEVIATION 15.2624 • n=99 Participants	299.0000 g/L STANDARD_DEVIATION 13.3012 • n=107 Participants	297.4000 g/L STANDARD_DEVIATION 14.2888 • n=206 Participants
Platelet count (PLT)	206.4536 10^9/L STANDARD_DEVIATION 53.1686 • n=99 Participants	197.7111 10^9/L STANDARD_DEVIATION 60.0851 • n=107 Participants	202.1618 10^9/L STANDARD_DEVIATION 56.3131 • n=206 Participants
Pre- packed red cell units transfused per year	1928.57 milliliter STANDARD_DEVIATION 763.02 • n=99 Participants	1985.71 milliliter STANDARD_DEVIATION 766.47 • n=107 Participants	1957.14 milliliter STANDARD_DEVIATION 751.01 • n=206 Participants
Pre-bleeding duration	8.8214 days STANDARD_DEVIATION 3.0799 • n=99 Participants	8.7407 days STANDARD_DEVIATION 4.5029 • n=107 Participants	8.7818 days STANDARD_DEVIATION 3.8088 • n=206 Participants
Pre-treatment hemoglobin level	6.4000 g/dl STANDARD_DEVIATION 1.7904 • n=99 Participants	5.9919 g/dl STANDARD_DEVIATION 1.5304 • n=107 Participants	6.1996 g/dl STANDARD_DEVIATION 1.6652 • n=206 Participants
Prothrombin time-international normalized ratio (PT-INR)	1.0550 seconds STANDARD_DEVIATION 0.1530 • n=99 Participants	1.0989 seconds STANDARD_DEVIATION 0.1533 • n=107 Participants	1.0765 seconds STANDARD_DEVIATION 0.1534 • n=206 Participants
Serum creatinine	77.5536 mg/dl STANDARD_DEVIATION 20.9532 • n=99 Participants	88.9296 mg/dl STANDARD_DEVIATION 24.2665 • n=107 Participants	83.1382 mg/dl STANDARD_DEVIATION 23.1514 • n=206 Participants
Total bilirubin	9.1607 μmol/L STANDARD_DEVIATION 4.4212 • n=99 Participants	9.1407 μmol/L STANDARD_DEVIATION 4.1196 • n=107 Participants	9.1509 μmol/L STANDARD_DEVIATION 4.2361 • n=206 Participants
White blood cell (WBC)	6.4429 10^9/L STANDARD_DEVIATION 1.5704 • n=99 Participants	6.5926 10^9/L STANDARD_DEVIATION 1.7389 • n=107 Participants	6.5164 10^9/L STANDARD_DEVIATION 1.6416 • n=206 Participants
pre-bleeding episodes per year	13.96 bleeding episodes STANDARD_DEVIATION 3.383 • n=99 Participants	13.96 bleeding episodes STANDARD_DEVIATION 3.469 • n=107 Participants	13.96 bleeding episodes STANDARD_DEVIATION 3.394 • n=206 Participants

PRIMARY outcome

Timeframe: baseline and 12 months

Outcome measures

Outcome measures
Measure	Thalidomide Group n=28 Participants interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=27 Participants interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Participants Whose Rebleeds Decreased From Baseline by ≥ 50% at 12 Months	20 participants	1 participants

PRIMARY outcome

Timeframe: 52 months

The cessation of bleeding was defined as repeated negative faecal occult blood test (FOBT) (monoclonal colloidal gold color technology) during our observation period. Rebleeding was defined based on a positive FOBT at any visit after treatment.

Outcome measures

Outcome measures
Measure	Thalidomide Group n=28 Participants interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=27 Participants interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Cessation of Bleeding	13 participants	0 participants

SECONDARY outcome

Timeframe: baseline and 12 months

The change from baseline in average hemoglobin (Hb) level(tested every month) at 12 months.

Outcome measures

Outcome measures
Measure	Thalidomide Group n=28 Participants interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=27 Participants interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Change From Baseline in Hemoglobin (Hb) Level at 12 Months	3.06 g/L Standard Deviation 2.08	-0.01 g/L Standard Deviation 1.32

SECONDARY outcome

Timeframe: baseline and 12 months

The Change from baseline in bleeding episodes at 12 months

Outcome measures

Outcome measures
Measure	Thalidomide Group n=28 Participants interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=27 Participants interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Change From Baseline in Bleeding Episodes at 12 Months	-9.36 bleeding episodes Standard Deviation 4.31	1.41 bleeding episodes Standard Deviation 2.74

SECONDARY outcome

Timeframe: baseline and 12 months

The change from baseline in bleeding duration at 12 months

Outcome measures

Outcome measures
Measure	Thalidomide Group n=28 Participants interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=27 Participants interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Change From Baseline in Bleeding Duration at 12 Months	5.2 days Standard Deviation 3.0	0.8 days Standard Deviation 5.1

SECONDARY outcome

Timeframe: 52 months

Population: 55 patients were enrolled in our study. One in iron-controlled group refused to continue for personal reason after 8 months, two other in thalidomide plus iron group refused to take study medications after 4 weeks treatment due to leukopenia and unexplained somnolence. Analysis was performed according to Intention-to-Treat principle.

Numbers of participants dependent on blood transfusions

Outcome measures

Outcome measures
Measure	Thalidomide Group n=28 Participants interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=27 Participants interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Participants Dependent on Blood Transfusions	3 participants	13 participants

SECONDARY outcome

Timeframe: baseline and 12 months

Population: There are 14 participants depended on blood transfusion in each group

Change of total transfused red cell requirements at 12 months after randomization from one year before baseline in transfusion dependent patients

Outcome measures

Outcome measures
Measure	Thalidomide Group n=14 Participants interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=14 Participants interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Change From Baseline in Total Transfused Red Cell Requirements at 12 Months	-1585.71 milliliter Standard Deviation 446.97	-28.57 milliliter Standard Deviation 106.90

Adverse Events

Thalidomide Group

Serious events: 0 serious events

Other events: 20 other events

Deaths: 0 deaths

Iron-controlled Group

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Zhizheng Ge, MD. Ph.D. Director of the Clinical Trials

Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine

Phone: 86-21-68383015

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Thalidomide Group n=28 participants at risk interventions administered (dosage, 100mg; dosage form, 25mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)	Iron-controlled Group n=27 participants at risk interventions administered (dosage, 400mg; dosage form, 100mg; frequency of administration, 4 times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m)
Gastrointestinal disorders Abdominal distension	3.6% 1/28 • Number of events 9 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	3.7% 1/27 • Number of events 12 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Gastrointestinal disorders Abdominal pain	0.00% 0/28 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	3.7% 1/27 • Number of events 7 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Gastrointestinal disorders Bitter taste	7.1% 2/28 • Number of events 10 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Eye disorders Blurred vision	3.6% 1/28 • Number of events 5 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Cardiac disorders Bradycardia	3.6% 1/28 • Number of events 1 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Gastrointestinal disorders Constipation	25.0% 7/28 • Number of events 92 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	11.1% 3/27 • Number of events 18 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
General disorders Dizziness	21.4% 6/28 • Number of events 82 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	7.4% 2/27 • Number of events 10 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Eye disorders Dryness of eye	3.6% 1/28 • Number of events 5 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
General disorders Fatigue	32.1% 9/28 • Number of events 72 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	11.1% 3/27 • Number of events 12 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Nervous system disorders Hands tremble	3.6% 1/28 • Number of events 4 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Nervous system disorders Headache	3.6% 1/28 • Number of events 8 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Endocrine disorders Increase in vaginal discharge	3.6% 1/28 • Number of events 60 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Blood and lymphatic system disorders Leukopenia	3.6% 1/28 • Number of events 2 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Gastrointestinal disorders Nuasea	0.00% 0/28 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	3.7% 1/27 • Number of events 5 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Nervous system disorders Numb limb	3.6% 1/28 • Number of events 6 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Ear and labyrinth disorders Otalgia	3.6% 1/28 • Number of events 5 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Vascular disorders Peripheral edema	14.3% 4/28 • Number of events 16 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Skin and subcutaneous tissue disorders Pruritus	3.6% 1/28 • Number of events 4 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Skin and subcutaneous tissue disorders Rash	3.6% 1/28 • Number of events 1 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Infections and infestations Shingles zoster Infection	3.6% 1/28 • Number of events 1 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Nervous system disorders Somnolence	3.6% 1/28 • Number of events 8 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Gastrointestinal disorders Stomach discomfort	0.00% 0/28 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	11.1% 3/27 • Number of events 18 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Blood and lymphatic system disorders Thrombopenia	3.6% 1/28 • Number of events 1 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	0.00% 0/27 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Gastrointestinal disorders Vomiting	0.00% 0/28 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	3.7% 1/27 • Number of events 3 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.
Gastrointestinal disorders Diarrhea	0.00% 0/28 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.	3.7% 1/27 • Number of events 4 • Adverse events were recorded during 4-month treatment and thereafter medium 39 months (range: 8 to 52 months) of follow-up. Adverse events were considered if any uncomfortable symptoms occur and relevant to our study medications. Severe adverse events (SAE's) were considered if the complained symptoms resulted in more hospitalization or that threaten the patients lives.