Trial Outcomes & Findings for Phase II A Trial of Curcumin Among Patients With Prevalent Subclinical Neoplastic Lesions (Aberrant Crypt Foci) (NCT NCT00365209)

NCT ID: NCT00365209

Last Updated: 2015-08-27

Results Overview

Baseline prostaglandin E2 (PGE2) values found in rectal aberrant crypt foci (ACF) tissue

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 44 participants
• Primary outcome timeframe: Baseline
• Results posted on: 2015-08-27

Participant Flow

This is a 2-stage study. In Stage1, there are 23 enrolled participants who received 2 g curcumin. In Stage2, there are addictional 21 enrolled participants who received 4 g curcumin.

Participant milestones

Measure	Curcumin Stage 1: Particpants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Particpants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Stage 1: Receiving 2g Curcumin STARTED	23
Stage 1: Receiving 2g Curcumin COMPLETED	21
Stage 1: Receiving 2g Curcumin NOT COMPLETED	2
Stage 2: Receiving 4g Curcumin STARTED	21
Stage 2: Receiving 4g Curcumin COMPLETED	19
Stage 2: Receiving 4g Curcumin NOT COMPLETED	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Phase II A Trial of Curcumin Among Patients With Prevalent Subclinical Neoplastic Lesions (Aberrant Crypt Foci)

Baseline characteristics by cohort

Measure	Curcumin n=43 Participants Stage 1: Patients receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Patients receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Age, Continuous Stage1 2 g (curcumin) N=22	57.1 years STANDARD_DEVIATION 5.0 • n=5 Participants
Age, Continuous Stage2 4 g (curcumin) N=21	52.2 years STANDARD_DEVIATION 6.8 • n=5 Participants
Sex/Gender, Customized Stage1 2 g (curcumin): Female	13 participants n=5 Participants
Sex/Gender, Customized Stage1 2 g (curcumin): Male	9 participants n=5 Participants
Sex/Gender, Customized Stage2 4 g (curcumin): Female	12 participants n=5 Participants
Sex/Gender, Customized Stage2 4 g (curcumin): Male	9 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 21 participants) and Stage2 4 g curcumin: (N = 19 participants)

Baseline prostaglandin E2 (PGE2) values found in rectal aberrant crypt foci (ACF) tissue

Outcome measures

Measure	Curcumin n=40 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Baseline in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF) Stage1 2 g (curcumin) N=21	1.1 µg/g protein Standard Deviation 1.8
Baseline in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF) Stage2 4 g (curcumin) N=19	3.4 µg/g protein Standard Deviation 4.8

PRIMARY outcome

Timeframe: At 30 day

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2g curcumin: (N = 21 participants), Stage2 4 g curcumin: (N = 19 participants)

Post-treatment prostaglandin E2 (PGE2) values found in rectal aberrant crypt foci (ACF) tissue

Outcome measures

Measure	Curcumin n=40 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Post-treatment in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF) Stage1 2 g (curcumin) N=21	1.6 µg/g protein Standard Deviation 1.8
Post-treatment in Prostaglandin E2 (PGE2) Within Aberrant Crypt Foci (ACF) Stage2 4 g (curcumin) N=19	3.7 µg/g protein Standard Deviation 3.2

SECONDARY outcome

Timeframe: Baseline

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 21 participants), Stage2 4 g curcumin: (N = 19 participants)

Baseline 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in rectal aberrant crypt foci (ACF) tissue

Outcome measures

Measure	Curcumin n=40 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF) Stage1 2 g (curcumin) N=21	1.4 µg/g protein Standard Deviation 0.9
Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF) Stage2 4 g (curcumin) N=19	2.3 µg/g protein Standard Deviation 1.6

SECONDARY outcome

Timeframe: At 30 Day

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 21 participants), Stage2 4 g curcumin: (N = 19 participants)

Post-treatment 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in rectal aberrant crypt foci (ACF) tissue

Outcome measures

Measure	Curcumin n=40 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF) Stage1 2 g (curcumin) N=21	1.4 µg/g protein Standard Deviation 1.0
Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Within Aberrant Crypt Foci (ACF) Stage2 4 g (curcumin) N=19	1.9 µg/g protein Standard Deviation 0.9

SECONDARY outcome

Timeframe: Baseline

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 21 participants), Stage2 4 g curcumin: (N = 19 participants)

Baseline prostaglandin E2 (PGE2) values found in normal mucosa rectal tissue

Outcome measures

Measure	Curcumin n=40 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Baseline in Prostaglandin E2 (PGE2) Level in Normal Mucosa Stage1 2 g (curcumin) N=21	2.1 µg/g protein Standard Deviation 3.2
Baseline in Prostaglandin E2 (PGE2) Level in Normal Mucosa Stage2 4 g (curcumin) N=19	2.7 µg/g protein Standard Deviation 1.9

SECONDARY outcome

Timeframe: At 30 day

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 21 participants), Stage2 4 g curcumin: (N = 19 participants)

Post-treatment prostaglandin E2 (PGE2) values found in normal mucosa rectal tissue

Outcome measures

Measure	Curcumin n=40 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Post-treatment in Prostaglandin E2 (PGE2) Level in Normal Mucosa Stage1 2 g (curcumin) N=21	2.7 µg/g protein Standard Deviation 3.7
Post-treatment in Prostaglandin E2 (PGE2) Level in Normal Mucosa Stage2 4 g (curcumin) N=19	2.6 µg/g protein Standard Deviation 2.9

SECONDARY outcome

Timeframe: Baseline

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 21 participants), Stage2 4 g curcumin: (N = 19 participants)

Baseline 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in normal mucosa rectal tissue

Outcome measures

Measure	Curcumin n=40 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa Stage1 2 g (curcumin) N=21	2.3 µg/g protein Standard Deviation 1.3
Baseline in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa Stage2 4 g (curcumin) N=19	2.5 µg/g protein Standard Deviation 1.5

SECONDARY outcome

Timeframe: At 30 day

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 21 participants), Stage2 4 g curcumin: (N = 19 participants)

Post-treatment 5-hydroxy-eicosatetraenoic acid (5-HETE) values found in normal mucosa rectal tissue

Outcome measures

Measure	Curcumin n=40 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa Stage1 2 g (curcumin) N=21	2.4 µg/g protein Standard Deviation 1.2
Post-treatment in 5-hydroxy-eicosatetraenoic Acid (5-HETE) Level in Normal Mucosa Stage2 4 g (curcumin) N=19	2.2 µg/g protein Standard Deviation 1.6

SECONDARY outcome

Timeframe: Baseline to 30 days

Population: There is not enough tissue for the analysis, so no data is provided.

The protein levels for each enzyme will be expressed as an absolute change from baseline and graphed against % change of its enzyme product in the same individual. The degree of correlation between these parameters will be assessed by either Pearson's correlation coefficient or Spearman's rank order correlation coefficient.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to 30 days

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 22 participants), Stage2 4 g curcumin: (N = 19 participants)

Changes in total aberrant crypt foci (ACF) number = Number of ACF at pre-treatment - Number of ACF at post-treatment

Outcome measures

Measure	Curcumin n=41 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Changes in Total Aberrant Crypt Foci (ACF) Number Stage1 2 g (curcumin) N=22	0.0 Number of ACF Interval -18.0 to 15.0
Changes in Total Aberrant Crypt Foci (ACF) Number Stage2 4 g (curcumin) N=19	6.0 Number of ACF Interval -1.0 to 14.0

SECONDARY outcome

Timeframe: Baseline

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 22 participants), Stage2 4 g curcumin: (N = 17 participants)

Outcome measures

Measure	Curcumin n=39 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third Stage1 2 g (curcumin) N=22	0.5 percentage of labeled cells Standard Deviation 0.9
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third Stage2 4 g (curcumin) N=17	0.3 percentage of labeled cells Standard Deviation 0.6

SECONDARY outcome

Timeframe: At 30 day

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g crucumin: (N = 22 participants), Stage2 4 g curcumin: (N = 19 participants)

Outcome measures

Measure	Curcumin n=41 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third Stage1 2 g (curcumin) N=22	0.6 percentage of labeled cells Standard Deviation 1.4
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Proximal Third Stage 2 4 g (curcumin) N=19	0.3 percentage of labeled cells Standard Deviation 0.8

SECONDARY outcome

Timeframe: Baseline

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 22 participants), Stage2 4 g curcumin : (N = 17 participants).

Outcome measures

Measure	Curcumin n=39 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third Stage1 2 g (curcumin) N=22	11.9 percentage of labeled cells Standard Deviation 4.2
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third Stage2 4 g (curcumin) N=17	12.8 percentage of labeled cells Standard Deviation 6.1

SECONDARY outcome

Timeframe: At 30 day

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 22 participants), Stage2 4 g curcumin: (N = 19 participants)

Outcome measures

Measure	Curcumin n=41 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third Stage1 2 g (curcumin) N=22	11.8 percentage of labeled cells Standard Deviation 7.2
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Middle Third Stage2 4 g (curcumin) N=19	16.4 percentage of labeled cells Standard Deviation 10.3

SECONDARY outcome

Timeframe: Baseline

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 22 participants), Stage2 4 g curcumin: (N = 17 participants)

Outcome measures

Measure	Curcumin n=39 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third Stage1 2 g (curcumin) N=22	25.2 percentage of labeled cells Standard Deviation 5.3
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third Stage2 4 g (curcumin) N=17	28.7 percentage of labeled cells Standard Deviation 9.1

SECONDARY outcome

Timeframe: At 30 day

Population: The analysis is based on participants whose data are evaluable and available. Stage1 2 g curcumin: (N = 22 participants), Stage2 4 g curcumin: (N = 19 participants)

Outcome measures

Measure	Curcumin n=41 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third Stage1 2 g (curcumin) N=22	23.5 percentage of labeled cells Standard Deviation 8.0
Proliferation by Ki-67 Immunohistochemical Assay (IHC) in Normal Mucosa - Distal Third Stage2 4 g (curcumin) N=19	30.9 percentage of labeled cells Standard Deviation 7.7

SECONDARY outcome

Timeframe: Baseline

Population: Samples from 21 participants in the 2g curcumin arm and 18 participants in the 4g curcumin arm were sent to be assayed. Detectable levels of curcumin in rectal mucosa were found in 1 participant in the 2g arm and none in participants on the 4g arm. Therefore, only 1 sample from the 2g arm and 0 samples from the 4g arm are reported here.

If detectable in the rectal mucosa, it is predicted that curcumin concentrations and potentially curcumin conjugate concentrations will be associated with reduction in PGE2 and 5-HETE measured from colorectal mucosal biopsies. Pearson correlation coefficients between changes in baseline levels in these 2 parameters and curcumin concentration in rectal mucosa will be calculated. Endpoints may be log transformed as appropriate prior to analysis.

Outcome measures

Measure

Curcumin n=1 samples with detectable levels Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally

Baseline Curcumin Concentration in Rectal Mucosa

4.03 µg/g protein

SECONDARY outcome

Timeframe: At 30 day

Population: The analysis is based on 39 participants (21 participants from 2g curcmin, and 18 participants from 4 g curcumin). In 2g group, a total of 5 samples with detectable levels were analyzed. In 4g group, a total of 3 samples with detectable levels were analyzed.

If detectable in the rectal mucosa, it is predicted that curcumin concentrations and potentially curcumin conjugate concentrations will be associated with reduction in PGE2 and 5-HETE measured from colorectal mucosal biopsies. Pearson correlation coefficients between changes in baseline levels in these 2 parameters and curcumin concentration in rectal mucosa will be calculated. Endpoints may be log transformed as appropriate prior to analysis.

Outcome measures

Measure	Curcumin n=8 samples with detectable levels Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Post-treatment Curcumin Concentration in Rectal Mucosa 2 g (curcumin) N=21 subjects, N=5 samples analyzed	8.2 µg/g protein Standard Deviation 2.9
Post-treatment Curcumin Concentration in Rectal Mucosa 4 g (curcumin) N=18 subjects, N=3 samples analyzed	3.8 µg/g protein Standard Deviation 0.6

SECONDARY outcome

Timeframe: Baseline

Population: Samples from 19 participants in the 4g curcumin arm were assayed. Detectable levels of curcumin in plasma were found in 4 participants in the 4g arm; therefore, 4 samples are reported here. Samples from participants in the 2g curcumin arm were not collected due to a delayed decision resulting with protocol modification and resource restrictions.

Baseline curcumin conjugate concentrations will be measured directly from the subject's plasma and then the change in concentrations after the last dose of study drug will be measured. Concentrations will be measured and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate.

Outcome measures

Measure

Curcumin n=4 samples with detectable levels Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally

Baseline Curcumin Plasma Concentrations

7.3 µg/mL Standard Deviation 8.1

SECONDARY outcome

Timeframe: At 30 day

Population: Samples from 19 participants in the 4g curcumin arm were assayed. Detectable levels of curcumin in plasma were found in 2 participants in the 4g arm; therefore, 2 samples are reported here. Samples from participants in the 2g curcumin arm were not collected due to a delayed decision resulting with protocol modification and resource restrictions.

Baseline curcumin conjugate concentrations will be measured directly from the subject's plasma and then the change in concentrations after the last dose of study drug will be measured. Concentrations will be measured and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate.

Outcome measures

Measure

Curcumin n=2 samples with detectable levels Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally

Post-treatment Curcumin Plasma Concentrations

3.8 µg/mL Standard Deviation 1.3

SECONDARY outcome

Timeframe: Baseline

Population: Samples from 21 participants in the 2g curcumin arm and 19 participants in the 4g curcumin arm were sent to be assayed. Detectable levels of curcumin conjugates in rectal mucosa were found in 0 participants in the 2g arm and 1 participant on the 4g arm. Therefore, 0 samples from the 2g arm and 1 sample from the 4g arm are reported here.

If detectable in the rectal mucosa, it is predicted that curcumin concentrations and potentially curcumin conjugate concentrations will be associated with reduction in PGE2 and 5-HETE measured from colorectal mucosal biopsies. Pearson correlation coefficients between changes in baseline levels in these 2 parameters and curcumin concentration in rectal mucosa will be calculated. Endpoints may be log transformed as appropriate prior to analysis.

Outcome measures

Measure

Curcumin n=1 samples with detectable levels Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally

Baseline Curcumin Conjugates Concentration in Rectal Mucosa

4.21 µg/g protein

SECONDARY outcome

Timeframe: At 30 day

Population: The analysis is based on 39 participants (21 participants from 2g curcumin group and 18 participatns from 4g curcumin group). In 2g group, a total of 13 samples with detectable levels were analyzed. In 4g group, a total of 12 samples with detectable levels were analyzed.

If detectable in the rectal mucosa, it is predicted that curcumin concentrations and potentially curcumin conjugate concentrations will be associated with reduction in PGE2 and 5-HETE measured from colorectal mucosal biopsies. Pearson correlation coefficients between changes in baseline levels in these 2 parameters and curcumin concentration in rectal mucosa will be calculated. Endpoints may be log transformed as appropriate prior to analysis.

Outcome measures

Measure	Curcumin n=25 samples with detectable levels Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Post-treatment Curcumin Conjugates Concentration in Rectal Mucosa 2 g (curcumin) N=21 subjects, N=13 samples	5.9 µg/g protein Standard Deviation 2.6
Post-treatment Curcumin Conjugates Concentration in Rectal Mucosa 4 g (curcumin) N=18 subjects, N=12 samples	4.5 µg/g protein Standard Deviation 1.7

SECONDARY outcome

Timeframe: Baseline

Population: Samples from 19 participants in the 4g curcumin arm were assayed. Detectable levels of curcumin in plasma were found in 19 participants in the 4g arm; therefore, 19 samples are reported here. Samples from participants in the 2g curcumin arm were not collected due to a delayed decision resulting with protocol modification and resource restrictions.

Baseline curcumin conjugate concentrations will be measured directly from the subject's plasma and then the change in concentrations after the last dose of study drug will be measured. Concentrations will be measured and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate.

Outcome measures

Measure

Curcumin n=19 samples with detectable levels Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally

Baseline Curcumin Conjugates Plasma Concentrations

15.8 µg/mL Standard Deviation 14.8

SECONDARY outcome

Timeframe: At 30 day

Population: Samples from 19 participants in the 4g curcumin arm were assayed. Detectable levels of curcumin in plasma were found in 19 participants in the 4g arm; therefore, 19 samples are reported here. Samples from participants in the 2g curcumin arm were not collected due to a delayed decision resulting with protocol modification and resource restrictions.

Post-treatment curcumin conjugate concentrations will be measured directly from the subject's plasma and then the change in concentrations after the last dose of study drug will be measured. Concentrations will be measured and statistically evaluated by paired t-test or Wilcoxon matched-pairs signed-ranks test, as appropriate.

Outcome measures

Measure

Curcumin n=19 samples with detectable levels Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally

Post-treatment Curcumin Conjugates Plasma Concentrations

78.5 µg/mL Standard Deviation 84.3

SECONDARY outcome

Timeframe: Baseline to 30 days

Population: These participants completed the study. The data is from the final dataset which was available in 2013 following the publication.

Outcome measures

Measure	Curcumin n=41 Participants Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Number of Participants at Each Adverse Event Grade Level 4 g (curcumin) N=19: AE with a grade of 1 or 2	10 participants
Number of Participants at Each Adverse Event Grade Level 4 g (curcumin) N=19: AE with a grade of 3	1 participants
Number of Participants at Each Adverse Event Grade Level 2 g (curcumin) N=22: No AE reported	10 participants
Number of Participants at Each Adverse Event Grade Level 2 g (curcumin) N=22: AE with a grade of 1 or 2	12 participants
Number of Participants at Each Adverse Event Grade Level 2 g (curcumin) N=22: AE with a grade of 3	0 participants
Number of Participants at Each Adverse Event Grade Level 4 g (curcumin) N=19: No AE reported	8 participants

Adverse Events

Stage1 2 g Curcumin

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Stage2 4 g Curcumin

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Measure	Stage1 2 g Curcumin n=22 participants at risk Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally	Stage2 4 g Curcumin n=21 participants at risk Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
General disorders ATYPICAL CHEST PAIN	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.

Other adverse events

Measure	Stage1 2 g Curcumin n=22 participants at risk Stage 1: Participants receive 2 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally	Stage2 4 g Curcumin n=21 participants at risk Stage 2: Participants receive 4 grams of oral curcumin once daily. Treatment continues for up to 30 days in the absence of unacceptable toxicity or disease progression. laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies curcumin: Given orally
Gastrointestinal disorders YELLOW, SOFTER POO	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders ABDOMINAL CRAMPING	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders ABDOMINAL DISCOMFORT	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
General disorders BEGINNING OF INFLUENZA	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Renal and urinary disorders BURNING WHEN PEE	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders CALMED MY STOMACH	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Respiratory, thoracic and mediastinal disorders COLD/SINUSES	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders CONSTIPATION	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders CURBED APPETITE	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Metabolism and nutrition disorders DECREASED APPETITE	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders DIARRHEA	9.1% 2/22 • Number of events 2 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Investigations ELEVATED CREATININE	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Eye disorders EYE VISION IS BLURRY	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders FULLNESS	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders GAS	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Nervous system disorders HEADACHE	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Nervous system disorders HEADACHE AT NIGHT	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders HELPED BOWEL MOVEMENTS, MORE FREQUENT, LOOSER	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders IMPROVED, EASIER BOWEL MOVEMENTS	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders IMPROVED, SOFTER STOOL	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders IMPROVED; CURCUMIN HELPED CONSTIPATION; BEFORE GOING EVERY 3-4 DAYS, NOW EVERY 2 DAYS	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders IMPROVED; CURCUMIN WAS BETTER FOR BOWEL MOVEMENT, SOFTER STOOL	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Musculoskeletal and connective tissue disorders IMPROVED; LESS ACHEY	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders IMPROVED; MORE FREQUENT BOWEL MOVEMENTS	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders IMPROVED; NO LONGER CONSTIPATED, CONSTIPATION BEGAN IN 2006; NOW MORE FREQUENT BOWEL MOVEMENTS	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders IMPROVED; NOT TOO MUCH GAS IN THE STOMACH	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Skin and subcutaneous tissue disorders ITCHING	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Skin and subcutaneous tissue disorders ITCHING ALL OVER	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Musculoskeletal and connective tissue disorders LEFT AND RIGHT LEG LOWER EDEMA	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders LITTLE BLOATED	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders LITTLE BURNING IN STOMACH	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders LITTLE GAS	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Metabolism and nutrition disorders LOSS OF APPETITE	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Musculoskeletal and connective tissue disorders LOWER BACK PAIN	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders MILD HEART BURN	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders NAUSEA	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders NO MORE CONSTIPATION, PILL REALLY HELPED	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Renal and urinary disorders PEEING A LOT	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Nervous system disorders PEPPER TASTE	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders SIDE HURTS	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Renal and urinary disorders SLOW URINATION	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Respiratory, thoracic and mediastinal disorders SORE THROAT	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Musculoskeletal and connective tissue disorders STIFFNESS IN NECK	0.00% 0/22 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	4.8% 1/21 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders STOMACH UPSET AND RELATED PAINS	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Musculoskeletal and connective tissue disorders STRAINED SORE CHEST MUSCLES	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Psychiatric disorders UNUSUAL DREAM STATE	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders VOMITTED AFTER TAKING PILLS	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Psychiatric disorders WEIRD DREAMS	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	0.00% 0/21 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.
Gastrointestinal disorders YELLOW STOOL	4.5% 1/22 • Number of events 1 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.	9.5% 2/21 • Number of events 2 • All adverse events are reported and documented from 43 treated participants from the final 2013 dataset. Participants were followed for the duration of the study, an average of 45 days.

Additional Information

Dr. Frank L. Meyskens, Jr.

University of California, Irvine

Phone: 714-456-6310

Email: flmeyske@uci.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60