Trial Outcomes & Findings for Short Duration Combination Therapy With Daclatasvir, Asunaprevir, BMS-791325 and Sofosbuvir in Subjects Infected With Chronic Hepatitis-C (FOURward Study) (NCT NCT02175966)

Last Updated: 2020-08-11

Results Overview

SVR12 was defined as hepatitis C virus ribonucleic acid (HCV RNA) \< lower limit of quantitation (LLOQ) target detected (TD) or not detected (TND) at post-treatment follow-up Week 12. Imputed SVR12 was based on Next Value Carried Backwards approach.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

35 participants

Primary outcome timeframe

12 Weeks after treatment discontinuation (Follow-up Week 12)

Results posted on

2020-08-11

Participant Flow

35 participants enrolled in the study, 28 were randomized. Of the 7 not randomized, 1 participant withdrew consent and 6 no longer met study criteria

Participant milestones

Participant milestones
Measure	4 Weeks DCV 3DAA + SOF Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Treatment Period STARTED	14	14
Treatment Period COMPLETED	14	14
Treatment Period NOT COMPLETED	0	0
Follow-up Period STARTED	14	14
Follow-up Period COMPLETED	4	8
Follow-up Period NOT COMPLETED	10	6

Reasons for withdrawal

Reasons for withdrawal
Measure	4 Weeks DCV 3DAA + SOF Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Follow-up Period Lack of Efficacy	10	6

Baseline Characteristics

Short Duration Combination Therapy With Daclatasvir, Asunaprevir, BMS-791325 and Sofosbuvir in Subjects Infected With Chronic Hepatitis-C (FOURward Study)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	Total n=28 Participants Total of all reporting groups
Age, Continuous	58.0 years n=5 Participants	59.0 years n=7 Participants	58.5 years n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	8 Participants n=7 Participants	17 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	12 Participants n=5 Participants	13 Participants n=7 Participants	25 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 12 Weeks after treatment discontinuation (Follow-up Week 12)

Population: It included treated participants (randomized participants) who received at least 1 dose of study therapy (DCV 3DAA or SOF).

Outcome measures

Outcome measures
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Percentage of Participants With Sustained Virologic Response 12 (SVR12)	28.6 Percentage of participants Interval 13.1 to 49.2	57.1 Percentage of participants Interval 36.9 to 75.7

PRIMARY outcome

Timeframe: From signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)

Population: Safety population included participants who received at least 1 dose of study therapy (DCV 3DAA or SOF).

SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/ birth defect.

Outcome measures

Outcome measures
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Number of Participants With Deaths, Serious Adverse Events (SAEs) and AEs Leading to Discontinuation From Treatment Death	0 Participants	0 Participants
Number of Participants With Deaths, Serious Adverse Events (SAEs) and AEs Leading to Discontinuation From Treatment Serious Adverse Events	1 Participants	0 Participants
Number of Participants With Deaths, Serious Adverse Events (SAEs) and AEs Leading to Discontinuation From Treatment AEs Leading to Discontinuation	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)

Population: Safety analysis population included participants who received at least 1 dose of study therapy.

Grade 3/4 laboratory abnormalities (hematology, electrolyte, lipase, liver function, metabolic, renal function, urinalysis). The Week 24 data set was used to evaluate the Week-24 on-treatment safety. The cumulative data set was used to evaluate the safety while on treatment. Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Grades:1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death.

Outcome measures

Outcome measures
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Number of Participants With Selected Grade 3/4 Laboratory Abnormalities	0 Participants	0 Participants

SECONDARY outcome

Timeframe: End of the treatment

Population: All treated participants.

EOTR was defined as HCV RNA less than the lower limit of quantitation, target detected or not detected at end of treatment.

Outcome measures

Outcome measures
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Percentage of Participants With End of Treatment Response (EOTR)	92.9 Percentage of participants Interval 66.1 to 99.8	100.0 Percentage of participants Interval 76.8 to 100.0

SECONDARY outcome

Timeframe: Treatment Weeks 1, 2, 4 and 6; post-treatment Weeks 2 (SVR2), 4 (SVR4), 12 (SVR12) and 24 (SVR24)

Population: It included modified Intent-to-treat treated population.

Percentage of Participants with hepatitis C virus(HCV) ribonucleic acid (RNA) \< lower limit of quantitation (LLOQ), target detected (TD) or target not detected (TND) were presented at treatment Weeks 1, 2, 4, 6, and follow-up Weeks 2 (SVR2), 4 (SVR4), 12 (SVR12) and 24 (SVR24).

Outcome measures

Outcome measures
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Percentage of Participants Who Achieved HCV RNA <LLOQ TD/TND Week 1	35.7 Percentage of Participants Interval 12.8 to 64.9	71.4 Percentage of Participants Interval 41.9 to 91.6
Percentage of Participants Who Achieved HCV RNA <LLOQ TD/TND Week 2	78.6 Percentage of Participants Interval 49.2 to 95.3	100.0 Percentage of Participants Interval 76.8 to 100.0
Percentage of Participants Who Achieved HCV RNA <LLOQ TD/TND Week 4	100.0 Percentage of Participants Interval 76.8 to 100.0	100.0 Percentage of Participants Interval 76.8 to 100.0
Percentage of Participants Who Achieved HCV RNA <LLOQ TD/TND Week 6	NA Percentage of Participants NA signifies data was not estimable due to lesser number of events.	100.0 Percentage of Participants Interval 76.8 to 100.0
Percentage of Participants Who Achieved HCV RNA <LLOQ TD/TND Follow-Up Week 2	78.6 Percentage of Participants Interval 49.2 to 95.3	100.0 Percentage of Participants Interval 76.8 to 100.0
Percentage of Participants Who Achieved HCV RNA <LLOQ TD/TND Follow-Up Week 4	42.9 Percentage of Participants Interval 17.7 to 71.1	78.6 Percentage of Participants Interval 49.2 to 95.3
Percentage of Participants Who Achieved HCV RNA <LLOQ TD/TND Follow-Up Week 12	28.6 Percentage of Participants Interval 8.4 to 58.1	57.1 Percentage of Participants Interval 28.9 to 82.3
Percentage of Participants Who Achieved HCV RNA <LLOQ TD/TND Follow-Up Week 24	28.6 Percentage of Participants Interval 8.4 to 58.1	57.1 Percentage of Participants Interval 28.9 to 82.3

SECONDARY outcome

Timeframe: Treatment Weeks 1, 2, 4 and 6; post-treatment Weeks 2, 4, 12 and 24

Population: It included modified ITT treated population.

Percentage of Participants with hepatitis C virus(HCV) ribonucleic acid (RNA) \< lower limit of quantitation (LLOQ), target not detected (TND) were presented at treatment Weeks 1, 2, 4, 6, and follow-up Weeks 2 (SVR2), 4 (SVR4), and 24 (SVR24).

Outcome measures

Outcome measures
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Percentage of Participants Who Achieved HCV RNA < LLOQ TND Week 1	21.4 Percentage of participants Interval 4.7 to 50.8	7.1 Percentage of participants Interval 0.2 to 33.9
Percentage of Participants Who Achieved HCV RNA < LLOQ TND Week 2	42.9 Percentage of participants Interval 17.7 to 71.1	64.3 Percentage of participants Interval 35.1 to 87.2
Percentage of Participants Who Achieved HCV RNA < LLOQ TND Week 4	92.9 Percentage of participants Interval 66.1 to 99.8	100.0 Percentage of participants Interval 76.8 to 100.0
Percentage of Participants Who Achieved HCV RNA < LLOQ TND Week 6	NA Percentage of participants NA signifies data was not reported due to lesser number of events.	100.0 Percentage of participants Interval 76.8 to 100.0
Percentage of Participants Who Achieved HCV RNA < LLOQ TND Follow-Up Week 2	71.4 Percentage of participants Interval 41.9 to 91.6	92.9 Percentage of participants Interval 66.1 to 99.8
Percentage of Participants Who Achieved HCV RNA < LLOQ TND Follow-Up Week 4	42.9 Percentage of participants Interval 17.7 to 71.1	71.4 Percentage of participants Interval 41.9 to 91.6
Percentage of Participants Who Achieved HCV RNA < LLOQ TND Follow-Up Week 12	28.6 Percentage of participants Interval 8.4 to 58.1	57.1 Percentage of participants Interval 28.9 to 82.3
Percentage of Participants Who Achieved HCV RNA < LLOQ TND Follow-Up Week 24	28.6 Percentage of participants Interval 8.4 to 58.1	57.1 Percentage of participants Interval 28.9 to 82.3

SECONDARY outcome

Timeframe: Post-treatment Week 12

Population: All included treated participants. Here n' signifies number of participants analysed for specific category.

Percentage of Participants who Achieved SVR12 Associated with HCV geno subtype 1a or 1b

Outcome measures

Outcome measures
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Percentage of Participants Who Achieved SVR12 Associated With HCV Geno Subtype 1a vs 1b Genotype 1a	27.3 Percentage of Participants	54.5 Percentage of Participants
Percentage of Participants Who Achieved SVR12 Associated With HCV Geno Subtype 1a vs 1b Genotype 1b	33.3 Percentage of Participants	66.7 Percentage of Participants

SECONDARY outcome

Timeframe: Post-treatment Week 12

Population: All included treated participants. Here, n' signifies number of participants analysed for specific category.

Percentage of Participants who Achieved SVR12 Associated with IL28B rs12979860 Single Nucleotide Polymorphisms (SNP) status (CC genotype or non CC genotype) were reported.

Outcome measures

Outcome measures
Measure	4 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 Participants Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Percentage of Participants Who Achieved SVR12 Associated With Interleukin-28B (IL28B) rs12979860 SNP Status (CC Genotype or Non-CC Genotype) CC genotype	40.0 Percentage of Participants	66.7 Percentage of Participants
Percentage of Participants Who Achieved SVR12 Associated With Interleukin-28B (IL28B) rs12979860 SNP Status (CC Genotype or Non-CC Genotype) Non-CC Genotype	22.2 Percentage of Participants	50.0 Percentage of Participants

Adverse Events

4 Weeks DCV 3DAA + SOF

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

6 Weeks DCV 3DAA + SOF

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	4 Weeks DCV 3DAA + SOF n=14 participants at risk Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 participants at risk Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
Injury, poisoning and procedural complications Overdose	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period \<=60 days from submitting for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	4 Weeks DCV 3DAA + SOF n=14 participants at risk Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir (referred to as DCV 3DAA), plus sofosbuvir 400 mg 1 tablet daily for 4 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.	6 Weeks DCV 3DAA + SOF n=14 participants at risk Oral dose of a fixed dose combination regimen administered as 1 tablet BID comprising of 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg beclabuvir, plus sofosbuvir 400 mg 1 tablet daily for 6 weeks (treatment period). Thereafter, participants entered a follow-up period of 24 weeks after completion of study treatment or upon early discontinuation of treatment.
General disorders FATIGUE	21.4% 3/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	28.6% 4/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
General disorders CHEST DISCOMFORT	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
General disorders CHILLS	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
General disorders OEDEMA PERIPHERAL	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
General disorders PYREXIA	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Gastrointestinal disorders NAUSEA	14.3% 2/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Gastrointestinal disorders DIARRHOEA	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Gastrointestinal disorders CONSTIPATION	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Gastrointestinal disorders DRY MOUTH	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Gastrointestinal disorders DYSPEPSIA	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Gastrointestinal disorders FLATULENCE	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Gastrointestinal disorders TOOTHACHE	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Nervous system disorders HEADACHE	14.3% 2/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	21.4% 3/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Nervous system disorders DIZZINESS	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Infections and infestations URINARY TRACT INFECTION	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Infections and infestations ORAL HERPES	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Infections and infestations SINUSITIS	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Musculoskeletal and connective tissue disorders ARTHRALGIA	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Musculoskeletal and connective tissue disorders INTERVERTEBRAL DISC PROTRUSION	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Musculoskeletal and connective tissue disorders MUSCULOSKELETAL PAIN	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Ear and labyrinth disorders VERTIGO	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Injury, poisoning and procedural complications TOOTH FRACTURE	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Psychiatric disorders INSOMNIA	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	14.3% 2/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Psychiatric disorders AFFECT LABILITY	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Skin and subcutaneous tissue disorders RASH	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Skin and subcutaneous tissue disorders RASH PRURITIC	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Respiratory, thoracic and mediastinal disorders OROPHARYNGEAL PAIN	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)
Vascular disorders FLUSHING	0.00% 0/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)	7.1% 1/14 • All AEs were collected from signature of the informed consent until 4 weeks after last treatment administration.(Approximately 17 months)