Trial Outcomes & Findings for Investigation of 1.2% Sodium Hyaluronate for Treatment of Painful Chronic Osteoarthritis of the Knee (NCT NCT00988091)

Last Updated: 2012-06-15

Results Overview

The level of pain is estimated by the participant following a walk of 50 feet in length which is observed by the investigator. Pain estimates were recorded on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain; a score of 100 millimeters means extreme pain. Change from baseline is calculated: week 26 VAS Pain Score - Baseline VAS Pain Score.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

596 participants

Primary outcome timeframe

Day 0 (baseline) through Week 26

Results posted on

2012-06-15

Participant Flow

A total of 1007 subjects were screened for the double-blind period of the study, and 596 subjects were randomized and treated (safety population).

Participant milestones

Participant milestones
Measure	IA-SA Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Double-blind Period STARTED	298	298
Double-blind Period Intent to Treat Population	294	295
Double-blind Period COMPLETED	255	251
Double-blind Period NOT COMPLETED	43	47
Open-label Period STARTED	229	225
Open-label Period COMPLETED	208	192
Open-label Period NOT COMPLETED	21	33

Reasons for withdrawal

Reasons for withdrawal
Measure	IA-SA Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Double-blind Period Withdrawal by Subject	15	13
Double-blind Period Lost to Follow-up	12	14
Double-blind Period Other	8	8
Double-blind Period Adverse Event	6	9
Double-blind Period Use of exclusionary medication	2	3
Open-label Period Adverse Event	4	7
Open-label Period Use of exclusionary medication	1	1
Open-label Period Protocol Violation	1	1
Open-label Period Withdrawal by Subject	10	16
Open-label Period Lost to Follow-up	3	5
Open-label Period Other	2	3

Baseline Characteristics

Investigation of 1.2% Sodium Hyaluronate for Treatment of Painful Chronic Osteoarthritis of the Knee

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IA-SA n=298 Participants Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA n=298 Participants Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.	Total n=596 Participants Total of all reporting groups
Age Continuous	60.30 years STANDARD_DEVIATION 11.180 • n=5 Participants	60.70 years STANDARD_DEVIATION 10.228 • n=7 Participants	60.50 years STANDARD_DEVIATION 10.708 • n=5 Participants
Sex: Female, Male Female	193 Participants n=5 Participants	168 Participants n=7 Participants	361 Participants n=5 Participants
Sex: Female, Male Male	105 Participants n=5 Participants	130 Participants n=7 Participants	235 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 0 (baseline) through Week 26

Population: Intent to treat population

Outcome measures

Outcome measures
Measure	IA-SA n=294 Participants Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA n=295 Participants Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Change From Baseline in the Visual Analogue Score (VAS) Pain Score of the 50-foot Walk Test at Week 26	-33.48 units on a scale Standard Error 1.81	-28.15 units on a scale Standard Error 1.82

SECONDARY outcome

Timeframe: Day 0 (baseline), week 26

Population: Intent to treat population

Adjusted mean of all WOMAC pain, stiffness and physical function subscores on Visual Analog Scale (VAS) of 100 mm; 0 mm = no pain, stiffness and difficulty; 100 mm = extreme pain, stiffness and difficulty. Change from baseline calculated as: Week 26 minus baseline.

Outcome measures

Outcome measures
Measure	IA-SA n=294 Participants Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA n=295 Participants Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Change From Baseline in Western Ontario McMaster University Osteoarthritis Index (WOMAC) Disability Scores at Week 26	-21.72 units on a scale Standard Error 1.55	-18.82 units on a scale Standard Error 1.57

SECONDARY outcome

Timeframe: Day 0 (baseline), Week 26

Population: Intent to treat population

Outcome measures

Outcome measures
Measure	IA-SA n=256 Participants Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA n=253 Participants Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Percentage of Participants With a >=20mm Improvement Between Baseline and Week 26 on the 50 Foot Walk Visual Analogue Scale (VAS) Pain Score.	66.8 percentage of participants	60.9 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: Intent to treat population

At the end of the double-blind period (week 26), participants were asked: "Are you satisfied with the results of the injection?" Answers could be: 1=dissatisfied; 2=slightly satisfied; 3=satisfied; or 4=very satisfied.

Outcome measures

Outcome measures
Measure	IA-SA n=266 Participants Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA n=269 Participants Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Subjective Patient Assessment of Treatment at Week 26	2.71 units on a scale Standard Deviation 1.096	2.70 units on a scale Standard Deviation 1.115

SECONDARY outcome

Timeframe: Day 1 to week 26

Acetaminophen (500-mg tablets) was provided to study participants as a rescue medication in case they needed a pain medication during the study. The mean number of tablets of rescue medication should have been summarized, however the data was not captured in a reliable way and is therefore not reported.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 0 (baseline), Week 26

Population: Intent to treat population

Participants were asked to mark along a 100mm visual analog scale (VAS) indicating the point best representing the severity of the knee pain that day. The left side of the VAS was 0=no pain and the right side was 100 = extreme pain. Change from baseline was calculated as Week 26 - Baseline.

Outcome measures

Outcome measures
Measure	IA-SA n=294 Participants Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA n=295 Participants Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Change From Baseline in Patient Global Assessment at Week 26	-27.41 units on a scale Standard Error 1.83	-23.41 units on a scale Standard Error 1.85

SECONDARY outcome

Timeframe: Day 0 (baseline), week 26

Population: Intent to treat population

Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function (WOMAC Disability score) and global assessment (Patient Global Assessment Score) scales. Each of the individual scales was completed by the participant. A responder showed considerable improvement in pain or function (\>=50 percent and absolute change of \>=20 millimeters), or improvement in at least two of three categories: Pain and/or Function and/or Patient Global Assessment scales of \>=20 percent and absolute change \>=10 millimeter. Response at Week 26 is compared to baseline.

Outcome measures

Outcome measures
Measure	IA-SA n=253 Participants Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	IA-BioHA n=249 Participants Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Percentage of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Visual Analogue Scale (VAS) to Assess Pain Following a 50-foot Walk at Week 26	70.0 percentage of participants	62.2 percentage of participants

Adverse Events

IA-SA: Double-blind Period

Serious events: 6 serious events

Other events: 25 other events

Deaths: 0 deaths

IA-BioHA: Double-blind Period

Serious events: 13 serious events

Other events: 29 other events

Deaths: 0 deaths

IA-BioHA: Open-label Period

Serious events: 12 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	IA-SA: Double-blind Period n=298 participants at risk Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period.	IA-BioHA: Double-blind Period n=298 participants at risk Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period.	IA-BioHA: Open-label Period n=454 participants at risk Participants had the option of continuing into the open-label period in which their target knee received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) and they were followed for an additional 26 weeks.
Musculoskeletal and connective tissue disorders Arthralgia	8.4% 25/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	9.7% 29/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	7.0% 32/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.

Additional Information

Clinical Development Support

Ferring Pharmaceuticals

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.
Publication restrictions are in place

Restriction type: OTHER

Measure	IA-SA: Double-blind Period n=298 participants at risk Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period.	IA-BioHA: Double-blind Period n=298 participants at risk Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period.	IA-BioHA: Open-label Period n=454 participants at risk Participants had the option of continuing into the open-label period in which their target knee received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) and they were followed for an additional 26 weeks.
Cardiac disorders Bradycardia	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Cardiac disorders Cardiac failure congestive	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Cardiac disorders Myopericarditis	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Cardiac disorders Angina pectoris	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Cardiac disorders Atrial fibrillation	0.67% 2/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Cardiac disorders Myocardial infarction	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Congenital, familial and genetic disorders Urethral intrinsic sphincter deficiency	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
General disorders Chest pain	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
General disorders Death	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Infections and infestations Intraspinal abscess	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Infections and infestations Pneumonia	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Infections and infestations Diverticulitis	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Infections and infestations Urosepsis	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Injury, poisoning and procedural complications Upper limb fracture	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Injury, poisoning and procedural complications Joint injury	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Investigations Heart rate irregular	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Musculoskeletal and connective tissue disorders Back pain	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Nervous system disorders Headache	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Nervous system disorders Syncope	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Nervous system disorders Transient ischaemic attack	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Renal and urinary disorders Urinary incontinence	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Renal and urinary disorders Renal failure acute	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Reproductive system and breast disorders Pelvic prolapse	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Surgical and medical procedures Nephrectomy	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Surgical and medical procedures Spinal fusion surgery	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.34% 1/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Surgical and medical procedures Knee arthroplasty	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Hepatobiliary disorders Cholecystitis	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Metabolism and nutrition disorders Obesity	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Psychiatric disorders Psychotic disorder	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.00% 0/298 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.	0.22% 1/454 • Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.