Trial Outcomes & Findings for Study of Vaniprevir Plus PegIntron®/Ribavirin in Japanese Participants With Chronic Hepatitis C Who Relapsed After Treatment (MK-7009-044) (NCT NCT01405937)

Last Updated: 2018-10-18

Results Overview

SVR24 was defined as having an undetectable HCV RNA level 24 weeks after completion of all study therapy. The percentage of participants achieving SVR24 were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

51 participants

Primary outcome timeframe

24 weeks after 24 weeks of study therapy (up to 48 weeks)

Results posted on

2018-10-18

Participant Flow

Japanese patients 20-70 years old (inclusive) with chronic, compensated, genotype 1 Hepatitis C (HCV) infection and HCV ribonucleic acid (RNA) levels ≥5.0 log IU/mL in peripheral blood at screening, who had failed to respond to prior treatment, were recruited from 22 sites in Japan.

51 participants were randomized to receive 12 or 24 weeks of vaniprevir in combination with 24 weeks of peg-IFN α-2b (peg-IFN) and ribavirin (RBV).

Participant milestones

Participant milestones
Measure	Vaniprevir 12 Week Arm Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Overall Study STARTED	25	26
Overall Study COMPLETED	25	26
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of Vaniprevir Plus PegIntron®/Ribavirin in Japanese Participants With Chronic Hepatitis C Who Relapsed After Treatment (MK-7009-044)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Total n=51 Participants Total of all reporting groups
Age, Continuous	57.8 years STANDARD_DEVIATION 9.0 • n=93 Participants	60.3 years STANDARD_DEVIATION 7.5 • n=4 Participants	59.1 years STANDARD_DEVIATION 8.3 • n=27 Participants
Sex: Female, Male Female	13 Participants n=93 Participants	14 Participants n=4 Participants	27 Participants n=27 Participants
Sex: Female, Male Male	12 Participants n=93 Participants	12 Participants n=4 Participants	24 Participants n=27 Participants

PRIMARY outcome

Timeframe: 24 weeks after 24 weeks of study therapy (up to 48 weeks)

Population: Full Analysis Set (FAS) population; all randomized participants who received at least one dose of study treatment.

Outcome measures

Outcome measures
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Completion of All Study Therapy (SVR24)	92.0 percentage of participants Interval 74.0 to 99.0	96.2 percentage of participants Interval 80.4 to 99.9

PRIMARY outcome

Timeframe: From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)

Population: All Participants Treated (APaT) Population; all participants receiving at least one dose of study treatment

An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, was also an AE. For this study, safety parameters or AEs of special interest that were identified a priori included serious rash, anemia (anemia plus haemoglobin decreased), neutropenia (neutropenia plus neutrophil count decreased), bilirubin increased and gastrointestinal (GI) adverse experiences (vomiting, nausea, and diarrhea). The percentage of participants with ≥1 specific AEs were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.

Outcome measures

Outcome measures
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study With ≥1 specific AEs	88.0 percentage of participants Interval 68.8 to 97.5	84.6 percentage of participants Interval 65.1 to 95.6
Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study anaemia	56.0 percentage of participants Interval 34.9 to 75.6	61.5 percentage of participants Interval 40.6 to 79.8
Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study bilirubin increased	8.0 percentage of participants Interval 1.0 to 26.0	3.8 percentage of participants Interval 0.1 to 19.6
Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study GI AEs	64.0 percentage of participants Interval 42.5 to 82.0	65.4 percentage of participants Interval 44.3 to 82.8
Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study neutropenia	40.0 percentage of participants Interval 21.1 to 61.3	42.3 percentage of participants Interval 23.4 to 63.1

PRIMARY outcome

Timeframe: From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)

Population: All Participants Treated (APaT) Population; all participants receiving at least one dose of study treatment

Outcome measures

Outcome measures
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Percentage of Participants Who Discontinued Study Drug Due to an AE	4.0 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: 12 weeks after 24 weeks of study therapy (up to 36 weeks)

Population: FAS population; all randomized participants who received at least one dose of study treatment.

SVR12 was defined as having an undetectable HCV RNA level 12 weeks after completion of all study therapy. The percentage of participants achieving SVR12 were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.

Outcome measures

Outcome measures
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Percentage of Participants Achieving SVR12	88.0 percentage of participants Interval 68.8 to 97.5	92.3 percentage of participants Interval 74.9 to 99.1

SECONDARY outcome

Timeframe: At Week 4

Population: FAS population; all randomized participants who received at least one dose of study treatment.

RVR was defined as having an undetectable HCV RNA level at Week 4. The percentage of participants achieving RVR were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.

Outcome measures

Outcome measures
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Percentage of Participants Achieving Rapid Virologic Response (RVR)	88.0 percentage of participants Interval 68.8 to 97.5	88.5 percentage of participants Interval 69.8 to 97.6

SECONDARY outcome

Timeframe: At Week 12

Population: FAS population; all randomized participants who received at least one dose of study treatment.

cEVR was defined as having an undetectable HCV RNA level at Week 12. The percentage of participants achieving cEVR were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.

Outcome measures

Outcome measures
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Percentage of Participants Achieving Complete Early Virologic Response (cEVR)	100.0 Percentage of participants Interval 86.3 to 100.0	100.0 Percentage of participants Interval 86.8 to 100.0

SECONDARY outcome

Timeframe: At Week 24

Population: FAS population; all randomized participants who received at least one dose of study treatment.

Participants were assessed for undetectable HCV RNA levels at the end of all study therapy. The percentage of participants with undetectable HCV RNA levels at EOT were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.

Outcome measures

Outcome measures
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Percentage of Participants Achieving Undetectable HCV RNA at the End of Treatment (EOT)	100.0 Percentage of participants Interval 86.3 to 100.0	100.0 Percentage of participants Interval 86.8 to 100.0

SECONDARY outcome

Timeframe: Baseline, Week 2, Week 4, Week 8, Week 12, Week 24

Population: Participants in the FAS population (all randomized participants who received at least one dose of study treatment) that had HCV RNA data available.

HCV RNA levels were assessed at baseline (BL) and during treatment weeks 2, 4, 8, 12, and 24 using the Roche TaqMan HCV assay, and transformed to Log 10 values. HCV RNA values below the limit of reliable quantification (LoQ) or the limit of detection (LoD) at any time point were handled as follows (imputations done for computational purposes): values below the LoQ but above the LoD were imputed with the LoQ minus 0.1; values below the LoD were imputed with the value of 0 Log IU/mL. HCV RNA levels below the LoD were considered "undetectable".

Outcome measures

Outcome measures
Measure	Vaniprevir 12 Week Arm n=25 Participants Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 Participants Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Mean Change From Baseline in HCV RNA (Log 10) Change From BL at Week 2 (n=25, 26)	-5.7 Log IU/ml Standard Deviation 0.5	-5.7 Log IU/ml Standard Deviation 0.7
Mean Change From Baseline in HCV RNA (Log 10) Change From BL at Week 4 (n=25, 26)	-6.5 Log IU/ml Standard Deviation 0.6	-6.3 Log IU/ml Standard Deviation 0.9
Mean Change From Baseline in HCV RNA (Log 10) Change From BL at Week 8 (n=25, 26)	-6.6 Log IU/ml Standard Deviation 0.5	-6.5 Log IU/ml Standard Deviation 0.7
Mean Change From Baseline in HCV RNA (Log 10) Change From BL at Week 12 (n=25, 26)	-6.6 Log IU/ml Standard Deviation 0.5	-6.5 Log IU/ml Standard Deviation 0.7
Mean Change From Baseline in HCV RNA (Log 10) Change From BL at Week 24 (n=24, 26)	-6.7 Log IU/ml Standard Deviation 0.5	-6.5 Log IU/ml Standard Deviation 0.7

Adverse Events

Vaniprevir 12 Week Arm

Serious events: 2 serious events

Other events: 24 other events

Deaths: 0 deaths

Vaniprevir 24 Week Arm

Serious events: 3 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Vaniprevir 12 Week Arm n=25 participants at risk Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 participants at risk Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Gastrointestinal disorders Vomiting	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Chills	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Infections and infestations Appendicitis	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	0.00% 0/26 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Injury, poisoning and procedural complications Contusion	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Injury, poisoning and procedural complications Rib fracture	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Injury, poisoning and procedural complications Sternal fracture	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Psychiatric disorders Depression	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	0.00% 0/26 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	0.00% 0/26 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Vascular disorders Pallor	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)

Other adverse events

Additional Information

Vice President, Late Stage Development

Merck Sharp & Dohme Corp

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission.
Publication restrictions are in place

Restriction type: OTHER

Measure	Vaniprevir 12 Week Arm n=25 participants at risk Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV	Vaniprevir 24 Week Arm n=26 participants at risk Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV
Blood and lymphatic system disorders Anaemia	12.0% 3/25 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	15.4% 4/26 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Blood and lymphatic system disorders Neutropenia	12.0% 3/25 • Number of events 5 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Ear and labyrinth disorders Tinnitus	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Abdominal discomfort	20.0% 5/25 • Number of events 5 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	26.9% 7/26 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Abdominal pain upper	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Cheilitis	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	15.4% 4/26 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Constipation	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Dental caries	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Diarrhoea	40.0% 10/25 • Number of events 10 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	26.9% 7/26 • Number of events 9 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Dyspepsia	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Nausea	36.0% 9/25 • Number of events 11 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	38.5% 10/26 • Number of events 10 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Stomatitis	28.0% 7/25 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	15.4% 4/26 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Gastrointestinal disorders Vomiting	28.0% 7/25 • Number of events 12 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	19.2% 5/26 • Number of events 5 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Chest pain	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	0.00% 0/26 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Chills	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Fatigue	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Influenza like illness	12.0% 3/25 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Injection site erythema	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Injection site pruritus	12.0% 3/25 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	0.00% 0/26 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Injection site reaction	12.0% 3/25 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	26.9% 7/26 • Number of events 9 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Malaise	40.0% 10/25 • Number of events 10 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	26.9% 7/26 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Pyrexia	80.0% 20/25 • Number of events 22 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	73.1% 19/26 • Number of events 40 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
General disorders Thirst	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Hepatobiliary disorders Hepatic function abnormal	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Infections and infestations Nasopharyngitis	28.0% 7/25 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	23.1% 6/26 • Number of events 10 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Infections and infestations Periodontitis	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Infections and infestations Pharyngitis	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Blood bilirubin increased	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Blood calcium decreased	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	15.4% 4/26 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Blood lactate dehydrogenase increased	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	15.4% 4/26 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Blood phosphorus decreased	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Blood thyroid stimulating hormone increased	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Gamma-glutamyltransferase increased	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Haematocrit decreased	12.0% 3/25 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Haemoglobin decreased	48.0% 12/25 • Number of events 14 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	46.2% 12/26 • Number of events 13 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Lymphocyte count decreased	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Neutrophil count decreased	28.0% 7/25 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	38.5% 10/26 • Number of events 10 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Platelet count decreased	20.0% 5/25 • Number of events 5 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	19.2% 5/26 • Number of events 5 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Red blood cell count decreased	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations Weight decreased	16.0% 4/25 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Investigations White blood cell count decreased	32.0% 8/25 • Number of events 8 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	38.5% 10/26 • Number of events 10 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Metabolism and nutrition disorders Decreased appetite	28.0% 7/25 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	30.8% 8/26 • Number of events 8 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Musculoskeletal and connective tissue disorders Arthralgia	16.0% 4/25 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Musculoskeletal and connective tissue disorders Back pain	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Musculoskeletal and connective tissue disorders Myalgia	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Nervous system disorders Dizziness	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Nervous system disorders Dysgeusia	4.0% 1/25 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	15.4% 4/26 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Nervous system disorders Headache	44.0% 11/25 • Number of events 12 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	42.3% 11/26 • Number of events 12 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Psychiatric disorders Insomnia	24.0% 6/25 • Number of events 6 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	19.2% 5/26 • Number of events 5 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Respiratory, thoracic and mediastinal disorders Cough	20.0% 5/25 • Number of events 5 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Respiratory, thoracic and mediastinal disorders Dyspnoea	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Respiratory, thoracic and mediastinal disorders Oropharyngeal discomfort	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	4.0% 1/25 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	11.5% 3/26 • Number of events 3 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Skin and subcutaneous tissue disorders Alopecia	28.0% 7/25 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	38.5% 10/26 • Number of events 10 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Skin and subcutaneous tissue disorders Dry skin	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	3.8% 1/26 • Number of events 1 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Skin and subcutaneous tissue disorders Eczema	12.0% 3/25 • Number of events 4 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Skin and subcutaneous tissue disorders Erythema	0.00% 0/25 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Skin and subcutaneous tissue disorders Pruritus	24.0% 6/25 • Number of events 7 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	42.3% 11/26 • Number of events 11 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Skin and subcutaneous tissue disorders Rash	24.0% 6/25 • Number of events 6 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	23.1% 6/26 • Number of events 6 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Vascular disorders Hypertension	8.0% 2/25 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)	7.7% 2/26 • Number of events 2 • From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)