Trial Outcomes & Findings for Analgesic Efficacy & Safety of Intravenous (IV) Acetaminophen Versus Placebo for the Treatment of Postop Pain (NCT NCT00564486)

Last Updated: 2016-10-21

Results Overview

Pain Intensity (PI) as measured by a 100 millimeter (mm) long Visual Analogue Scale (VAS) over 24 hours after treatment minus the Baseline VAS score. The 100 mm VAS was drawn on a pain ruler and labeled at its left end with '0 = No Pain' and with "100 = Worst Pain Imaginable' at its right end. Subjects placed a mark on the scale to represent their perceived pain. The score was the distance in mm from the left end of the VAS to the point where the subject's mark crossed the line. PI at baseline was compared to the PI at each timepoint and differences were summed over the 24 hour time period.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

244 participants

Primary outcome timeframe

Baseline to 24 hrs

Results posted on

2016-10-21

Participant Flow

The study was conducted at 17 sites across the US from 27 Nov 2007 to 12 September 2008.

On the morning of Post Operative Day 1, the subject was to have a pain intensity (PI) categorical score of moderate or severe and a visual analog scale (VAS) \>= 40 mm, but \<= 70 mm at rest on a 100 mm VAS.

Participant milestones

Participant milestones
Measure	Intravenous (IV) Placebo (100 ml) IV Placebo 100 ml dosed every every 6 hours for 24 hours (4 doses total).	IV Acetaminophen 1 gm IV Acetaminophen 1 gm dosed every every 6 hours for 24 hours (4 doses total).	IV Acetaminophen 650 mg IV Acetaminophen 650 mg dosed every every 4 hours for 24 hours (6 doses total).	IV Placebo (65 ml) IV Placebo 65 ml dosed every every 4 hours for 24 hours (6 doses total).
Overall Study STARTED	43	92	42	67
Overall Study COMPLETED	36	91	39	60
Overall Study NOT COMPLETED	7	1	3	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Intravenous (IV) Placebo (100 ml) IV Placebo 100 ml dosed every every 6 hours for 24 hours (4 doses total).	IV Acetaminophen 1 gm IV Acetaminophen 1 gm dosed every every 6 hours for 24 hours (4 doses total).	IV Acetaminophen 650 mg IV Acetaminophen 650 mg dosed every every 4 hours for 24 hours (6 doses total).	IV Placebo (65 ml) IV Placebo 65 ml dosed every every 4 hours for 24 hours (6 doses total).
Overall Study Adverse Event	0	1	0	0
Overall Study Withdrawal by Subject	4	0	0	5
Overall Study Subject refused to have blood drawn	0	0	1	0
Overall Study Lost to Follow-up	3	0	2	2

Baseline Characteristics

Analgesic Efficacy & Safety of Intravenous (IV) Acetaminophen Versus Placebo for the Treatment of Postop Pain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IV Placebo n=110 Participants All subjects randomized to receive IV Placebo 100 ml and IV placebo 65 ml groups combined	IV Acetaminophen 1 gm n=92 Participants All subjects randomized to receive IV Acetaminophen 1 gm	IV Acetaminophen 650 mg n=42 Participants All subjects randomized to receive IV Acetaminophen 650 mg	Total n=244 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	100 Participants n=5 Participants	86 Participants n=7 Participants	38 Participants n=5 Participants	224 Participants n=4 Participants
Age, Categorical >=65 years	10 Participants n=5 Participants	6 Participants n=7 Participants	4 Participants n=5 Participants	20 Participants n=4 Participants
Sex: Female, Male Female	91 Participants n=5 Participants	74 Participants n=7 Participants	33 Participants n=5 Participants	198 Participants n=4 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	18 Participants n=7 Participants	9 Participants n=5 Participants	46 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline to 24 hrs

Population: All efficacy analyses were conducted using the modified intent-to-treat (mITT) population, defined as those subjects who received at least one complete infusion of study medication prior to requesting rescue medication.Worst Observation Carried Forward (WOCF) imputation was applied after first rescue medication.

Outcome measures

Outcome measures
Measure	IV Placebo n=108 Participants mITT - IV Placebo 100 ml and IV placebo 65 ml groups combined	IV Acetaminophen 1 gm n=92 Participants mITT - IV Acetaminophen 1 gm	IV Acetaminophen 650 mg IV Acetaminophen 650 mg every 4 hours for 24 hours
Sum Pain Intensity Difference - Baseline to 24 Hours (SPID24), 1 g IV Acetaminophen vs. Placebo (PI Was Measured at the Timepoints of T0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, and 24 Hours.)	-45.2 Units on a scale Standard Deviation 513.25	-194.1 Units on a scale Standard Deviation 593.62	—

SECONDARY outcome

Timeframe: Baseline to 24 hrs

Population: Included modified Intent To Treat group (mITT), defined as randomized subjects who received at least one complete infusion of study medication prior to receiving rescue medication.

Sum of Pain Intensity (PI) as measured by the 100 mm long Visual Analogue Scale (VAS) over 24 hours after treatment subtracting the Baseline VAS score.The 100 mm VAS was drawn on a pain ruler and labeled at it's left end with "0 = No Pain' and its right end with '100 = Worst Pain Imaginable.' Subjects placed a mark on the scale to represent their perceived pain. The score was the distance in mm from the left end of the VAS to the point where the subject's mark crossed the line. PI difference from baseline was calculated at each assessment over a 24 hour period.

Outcome measures

Outcome measures
Measure	IV Placebo n=108 Participants mITT - IV Placebo 100 ml and IV placebo 65 ml groups combined	IV Acetaminophen 1 gm n=41 Participants mITT - IV Acetaminophen 1 gm	IV Acetaminophen 650 mg IV Acetaminophen 650 mg every 4 hours for 24 hours
Sum Pain Intensity Difference - Baseline to 24 Hours (SPID24), 650 mg IV Acetaminophen vs. Placebo (PI Was Measured at the Timepoints of T0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, and 24 Hours.)	-45.2 Units on a scale Standard Deviation 513.25	-323.1 Units on a scale Standard Deviation 619.27	—

SECONDARY outcome

Timeframe: First dose through 7 day follow up

Population: All analyses of safety were conducted on the safety population, which included those subjects who received any portion of a dose of study medication.

Number of subjects who experienced at least one treatment emergent adverse event (TEAE). A TEAE is an adverse event that occurs on or after the first dose of study medication (T0).

Outcome measures

Outcome measures
Measure	IV Placebo n=110 Participants mITT - IV Placebo 100 ml and IV placebo 65 ml groups combined	IV Acetaminophen 1 gm n=91 Participants mITT - IV Acetaminophen 1 gm	IV Acetaminophen 650 mg n=43 Participants IV Acetaminophen 650 mg every 4 hours for 24 hours
The Number of Subjects Reporting a Treatment Emergent Adverse Event	68 Subjects	65 Subjects	28 Subjects

SECONDARY outcome

Timeframe: First dose to 30 days after last dose of study medication.

Population: All analyses were conducted on the safety population, which included those subjects who received any portion of a dose of study medication.

The number of subjects who reported at least one treatment emergent SAE during the study. A Serious Adverse Event is defined as any untoward medical occurrence at any dose of blinded study medication that: * results in death * is life-threatening * requires inpatient hospitalization or causes prolongation of existing hospitalization * results in persistent or significant disability/incapacity * is a congenital anomaly/birth defect * is an important medical event

Outcome measures

Outcome measures
Measure	IV Placebo n=110 Participants mITT - IV Placebo 100 ml and IV placebo 65 ml groups combined	IV Acetaminophen 1 gm n=91 Participants mITT - IV Acetaminophen 1 gm	IV Acetaminophen 650 mg n=43 Participants IV Acetaminophen 650 mg every 4 hours for 24 hours
The Number of Subjects Reporting a Treatment Emergent Serious Adverse Event	2 Subjects	1 Subjects	3 Subjects

Adverse Events

Intravenous (IV) Placebo (100 ml)

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

IV Acetaminophen 1 gm

Serious events: 1 serious events

Other events: 42 other events

Deaths: 0 deaths

IV Acetaminophen 650 mg

Serious events: 3 serious events

Other events: 16 other events

Deaths: 0 deaths

IV Placebo (65 ml)

Serious events: 2 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Intravenous (IV) Placebo (100 ml) n=43 participants at risk IV Placebo 100 ml dosed every every 6 hours for 24 hours (4 doses total).	IV Acetaminophen 1 gm n=91 participants at risk IV Acetaminophen 1 gm dosed every every 6 hours for 24 hours (4 doses total).	IV Acetaminophen 650 mg n=43 participants at risk IV Acetaminophen 650 mg dosed every every 4 hours for 24 hours (6 doses total).	IV Placebo (65 ml) n=67 participants at risk IV Placebo 65 ml dosed every every 4 hours for 24 hours (6 doses total).
Gastrointestinal disorders Impaired gastric emptying	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	2.3% 1/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	2.3% 1/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Gastrointestinal disorders Vomiting	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	1.1% 1/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Infections and infestations Postoperative abscess	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	1.5% 1/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Injury, poisoning and procedural complications Postoperative ileus	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	4.7% 2/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	1.5% 1/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.

Other adverse events

Other adverse events
Measure	Intravenous (IV) Placebo (100 ml) n=43 participants at risk IV Placebo 100 ml dosed every every 6 hours for 24 hours (4 doses total).	IV Acetaminophen 1 gm n=91 participants at risk IV Acetaminophen 1 gm dosed every every 6 hours for 24 hours (4 doses total).	IV Acetaminophen 650 mg n=43 participants at risk IV Acetaminophen 650 mg dosed every every 4 hours for 24 hours (6 doses total).	IV Placebo (65 ml) n=67 participants at risk IV Placebo 65 ml dosed every every 4 hours for 24 hours (6 doses total).
Respiratory, thoracic and mediastinal disorders Dypsnoea	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	7.0% 3/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Gastrointestinal disorders Constipation	16.3% 7/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	17.6% 16/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	11.6% 5/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	16.4% 11/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Gastrointestinal disorders Flatulence	9.3% 4/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	15.4% 14/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	9.3% 4/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	9.0% 6/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Gastrointestinal disorders Nausea	7.0% 3/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	17.6% 16/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	9.3% 4/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	13.4% 9/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Gastrointestinal disorders Vomiting	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	7.7% 7/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	9.3% 4/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	3.0% 2/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Nervous system disorders Headache	9.3% 4/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	13.2% 12/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	9.3% 4/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	11.9% 8/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Gastrointestinal disorders Diarrhoea	2.3% 1/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	3.3% 3/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	7.5% 5/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
General disorders Infusion site pain	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	5.5% 5/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	2.3% 1/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	1.5% 1/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
General disorders Pyrexia	11.6% 5/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	2.2% 2/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	3.0% 2/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Injury, poisoning and procedural complications Incision site pain	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	5.5% 5/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	0.00% 0/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Musculoskeletal and connective tissue disorders Back pain	2.3% 1/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	1.1% 1/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	4.7% 2/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	9.0% 6/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.
Psychiatric disorders Insomnia	2.3% 1/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	2.2% 2/91 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	7.0% 3/43 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.	6.0% 4/67 • Adverse Events were collected from T0 (on or after start of study drug) to Day 7 after surgery. Serious Adverse Events were collected from T0 to 30 days after the last dose of study medication.

Additional Information

Lawrence Hill

Mallinckrodt Pharmaceuticals

Phone: 908-238-6370

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Institution or Investigator may publish the results of the study (without raw data, detailed patient Case Report Forms, or patient identification) only after such cooperative publication, or 18 months after Cadence's final evaluation of all study data from all sites, whichever occurs first. At least 60 days prior to submission, or prior to any public presentation, a copy of the abstract, manuscript or presentation will be provided to Cadence who will have 60 days to respond with comments.
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