Trial Outcomes & Findings for Efficacy and Safety Study of PDT Using Photofrin in Unresectable Advanced Perihilar Cholangiocarcinoma (OPUS) (NCT NCT02082522)

NCT ID: NCT02082522

Last Updated: 2019-08-28

Results Overview

Time from the date of randomization until the date of death or the last date the subject was known to be alive

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

28 participants

Primary outcome timeframe

Up to 26 months

Results posted on

2019-08-28

Participant Flow

An independent expert panel acted as central assessors for subjects across all sites. Central assessors prospectively interpreted all abdominal CT and cholangiogram images taken at screening to establish the final diagnosis and to confirm the randomization. Central assessors had the authority to overrule the investigator's diagnosis.

Participant milestones

Participant milestones
Measure	Photodynamic Therapy-Photofrin Plus SMC Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Overall Study STARTED	15	13
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	15	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Photodynamic Therapy-Photofrin Plus SMC Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Overall Study Sponsor termination	5	3
Overall Study Withdrawal by Subject	2	4
Overall Study Death	1	0
Overall Study Lost to Follow-up	1	0
Overall Study Physician Decision	3	1
Overall Study Disease progression	2	2
Overall Study Chemotherapy change	1	3

Baseline Characteristics

Efficacy and Safety Study of PDT Using Photofrin in Unresectable Advanced Perihilar Cholangiocarcinoma (OPUS)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Photodynamic Therapy-Photofrin Plus SMC n=15 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=13 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.	Total n=28 Participants Total of all reporting groups
Age, Continuous	63.4 years STANDARD_DEVIATION 11.84 • n=5 Participants	66.6 years STANDARD_DEVIATION 7.69 • n=7 Participants	64.9 years STANDARD_DEVIATION 10.08 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	8 Participants n=7 Participants	20 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	12 Participants n=5 Participants	10 Participants n=7 Participants	22 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	3 Participants n=7 Participants	6 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	5 Participants n=5 Participants	8 Participants n=7 Participants	13 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	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants	4 Participants n=7 Participants	13 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	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment South Korea	5 participants n=5 Participants	8 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment United States	9 participants n=5 Participants	4 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment Germany	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 26 months

Population: All participants randomized (intent-to-treat population)

Time from the date of randomization until the date of death or the last date the subject was known to be alive

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=15 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=13 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Overall Survival Time	444 days Interval 111.0 to The value cannot be estimated because less than 50% of patients had a documented death by the time of premature study termination. Only 15 patients were enrolled, most did not complete the study and there was 1 death. Impossible to measure this.	387 days Interval 181.0 to Value cannot be estimated because \< 50% of patients had a documented death at time of premature study termination. Only 13 subjects were enrolled, most did not complete the study \& there were 0 deaths in the group. Impossible to measure this.

SECONDARY outcome

Timeframe: Up to 30 days

Population: Data not collected

From the date of randomization until the date of first documented bilirubin response

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 26 months

Population: Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

From the start of the treatment until disease progression or recurrence the RECIST 1.1 criteria are applied (Response Evaluation Criteria in Solid Tumors)

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=9 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=8 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Best Overall Tumor Response as Measured by the RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumors)	56 percentage of participants	75 percentage of participants

SECONDARY outcome

Timeframe: Up to 26 months

Population: Not collected

From the date of first documented response until the date that tumor progression was assessed

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 7 days

Population: At Day 7, all 15 subjects in the PDT +SMC group were analysed and 9/13 in the SMC Alone group were analysed.

The Karnofsky Performance Scale scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. However, the premature termination of the study does not allow for a meaningful analysis of the scale where 100% means no complaints with no evidence of disease, 80% is normal activity with effort and some signs or symptoms of disease.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=15 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=9 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline on Karnofsky Performance Scale (KPS)	-0.7 score on a scale Standard Deviation 7.99	0 score on a scale Standard Deviation 0

SECONDARY outcome

Timeframe: Baseline, up to 4 weeks

Population: At 4 weeks, 12 subjects in the PDT +SMC group were analysed and 9 in the SMC Alone group were analysed.

The Karnofsky Performance Scale (KPS) scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. A score of 100% means there are no complaints and no evidence of disease. A score of 80% means there is normal activity with effort and some signs or symptoms of disease. A score of 0% means death.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=12 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=9 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS)	1.7 score on a scale Standard Deviation 5.77	0 score on a scale Standard Deviation 0

SECONDARY outcome

Timeframe: Baseline, 13 weeks

Population: At 13 weeks, 8 subjects in the PDT +SMC group were analysed and 8 in the SMC Alone group were analysed. Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=8 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=8 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS)	0.0 score on a scale Standard Deviation 7.56	2.5 score on a scale Standard Deviation 4.63

SECONDARY outcome

Timeframe: Baseline, 16 weeks

Population: At 16 weeks, 9 subjects in the PDT +SMC group were analysed and 9 in the SMC Alone group were analysed. Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=9 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=9 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS)	-6.7 score on a scale Standard Deviation 15.00	3.3 score on a scale Standard Deviation 5.00

SECONDARY outcome

Timeframe: Baseline, 29 weeks

Population: At 29 weeks, 6 subjects in the PDT +SMC group were analysed and 5 in the SMC Alone group were analysed. Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=6 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=5 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS)	0.0 score on a scale Standard Deviation 8.94	2.0 score on a scale Standard Deviation 4.47

SECONDARY outcome

Timeframe: Baseline, 41 weeks

Population: At 41 weeks, 2 subjects in the PDT +SMC group were analysed and 1 in the SMC Alone group was analysed. Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=2 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=1 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS)	10.0 score on a scale Standard Deviation 14.14	0.0 score on a scale Standard Deviation 0.0

SECONDARY outcome

Timeframe: Baseline, 54 weeks

Population: At 54 weeks, only 1 subject in each group was measured. Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=1 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=1 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS)	0.0 score on a scale Standard Deviation 0.0	0.0 score on a scale Standard Deviation 0.0

SECONDARY outcome

Timeframe: Baseline, 66 weeks

Population: Data not collected

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 78 weeks

Population: Not collected

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 7 days

Population: Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=15 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=9 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Health-related Quality of Life on the 4- and 7-point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30)	-2.2 score on a scale Standard Deviation 30.29	0.0 score on a scale Standard Deviation 0.0

SECONDARY outcome

Timeframe: Baseline, up to 4 weeks

Population: Not collected

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 13 weeks

Population: Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=7 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=8 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30	-7.1 score on a scale Standard Deviation 30.59	6.2 score on a scale Standard Deviation 35.84

SECONDARY outcome

Timeframe: Baseline, 16 weeks

Population: Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=9 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=8 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30	-21.3 score on a scale Standard Error 33.88	10.4 score on a scale Standard Error 31.10

SECONDARY outcome

Timeframe: Baseline, 29 weeks

Population: Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=4 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=5 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30	-12.5 score on a scale Standard Deviation 35.03	5.0 score on a scale Standard Deviation 18.26

SECONDARY outcome

Timeframe: Baseline, 41 weeks

Population: Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=2 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=2 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30	8.3 score on a scale Standard Deviation 11.79	-16.7 score on a scale Standard Deviation 23.57

SECONDARY outcome

Timeframe: Baseline, 54 weeks

Population: Due to the premature termination of the study, there was insufficient data to allow statistical analysis.

Outcome measures

Outcome measures
Measure	Photodynamic Therapy-Photofrin Plus SMC n=1 Participants Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=1 Participants Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30	-8.3 score on a scale Standard Deviation NA Only 1 patient so no SD	-33.3 score on a scale Standard Deviation NA Only 1 patient so no SD

SECONDARY outcome

Timeframe: Baseline, 66 weeks

Population: No data collected

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline, 78 weeks

Population: No data collected

Outcome measures

Outcome data not reported

Adverse Events

Photodynamic Therapy-Photofrin Plus SMC

Serious events: 11 serious events

Other events: 13 other events

Deaths: 1 deaths

Standard Medical Care (SMC)

Serious events: 10 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Michelle Depot

At the request of Concordia Laboratories Inc.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Photodynamic Therapy-Photofrin Plus SMC n=15 participants at risk Photodynamic therapy (PDT) involved the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) was applied to the tumor. A second light application was given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients underwent stenting. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) could be given at 3-month intervals. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity.	Standard Medical Care (SMC) n=10 participants at risk Standard Medical Care (SMC) was defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen comprised gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen could be administered if there was no disease progression or intolerable toxicity. As per SMC, stenting procedure consisted of the placement of stents above the main tumors of the right and left hepatic bile ducts.
Hepatobiliary disorders Portal vein thrombosis	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Blood and lymphatic system disorders Anemia	0.00% 0/15 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Gastrointestinal disorders Ascites	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Blood and lymphatic system disorders Pancytopenia	13.3% 2/15 • Number of events 2 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/15 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	20.0% 2/10 • Number of events 2 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Gastrointestinal disorders Abdominal pain	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
General disorders Catheter site pain	0.00% 0/15 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
General disorders Pyrexia	13.3% 2/15 • Number of events 2 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Injury, poisoning and procedural complications Post-procedural complications	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Infections and infestations Sepsis	33.3% 5/15 • Number of events 8 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	30.0% 3/10 • Number of events 4 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Infections and infestations Septic shock	20.0% 3/15 • Number of events 3 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Infections and infestations Liver abcess	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Hepatobiliary disorders Biloma	0.00% 0/15 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Hepatobiliary disorders Cholangitis	40.0% 6/15 • Number of events 6 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	90.0% 9/10 • Number of events 9 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Hepatobiliary disorders Cholecystitis	0.00% 0/15 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Hepatobiliary disorders Haemobilia	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Hepatobiliary disorders Hepatitis cholestatic	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Hepatobiliary disorders Jaundice	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/15 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Vascular disorders Deep vein thrombosis	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Vascular disorders Embolism	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	0.00% 0/10 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.
Hepatobiliary disorders Cholangitis acute	6.7% 1/15 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.	10.0% 1/10 • Number of events 1 • 26 months The SMC alone group enrolled 13 subjects but only 10 were treated thus there were only 10 subjects at risk for adverse events.