Safety and Efficacy of Pimavanserin in Adults With Parkinson's Disease and Depression

• Sponsor: ACADIA Pharmaceuticals Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03482882
• Collaborator: (none)
• Enrollment: 47
• Locations: 21
• Arm: 1
• Actual Duration (Months): 16.5
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy of pimavanserin for the treatment of depression in adults with Parkinson's disease.

Condition or Disease	Intervention/Treatment	Phase
Treatment of Depression in Adults With Parkinson's Disease (PD)	Drug: Pimavanserin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, 8-Week Study of Safety and Efficacy of Pimavanserin Treatment in Adults With Parkinson's Disease and Depression
• Actual Study Start Date: Mar 9, 2018
• Actual Primary Completion Date: Jul 9, 2019
• Actual Study Completion Date: Jul 24, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Drug - pimavanserin	Drug: Pimavanserin; Pimavanserin 34 mg total daily dose, tablets, once daily by mouth (provided as two 17 mg NUPLAZID® tablets)

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 8 in HAMD-17 (Hamilton Depression Scale -17 Items) Total Score [From baseline to Week 8]

   The HAMD-17 is a multiple-item questionnaire to assess the severity of depression, including items of mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. Each of the 17 items is scored on a 3- or 5-point scale (depending on the item). The minimum total score is 0; the maximum total score is 52. A higher total score signifies more severe depression.

Secondary Outcome Measures

1. Change From Baseline (CFB) in HAMD-17 Total Score at Weeks 2, 4, and 6 [2, 4, and 6 weeks from baseline]

   The HAMD-17 is a multiple-item questionnaire to assess the severity of depression, including items of mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. Each of the 17 items is scored on a 3- or 5-point scale (depending on the item). The minimum total score is 0; the maximum total score is 52. A higher total score signifies more severe depression.

2. Clinical Global Impression-Improvement (CGI-I) [At Week 8]

   The CGI-I is a clinician-rated 7-point scale to rate the improvement in the patient's depression at the time of assessment relative baseline. The CGI-I ranges from 1 (very much improved) to 7 (very much worse)

3. Change From Baseline (CFB) in Clinical Global Impression-Severity (CGI-S) [From baseline to Week 8]

   The CGI-S is a clinician-rated 7-point scale to rate the severity of the patient's depression at the time of assessment. The CGI-S ranges from 1 (normal) to 7 (patient is among the most severely ill).

4. Change From Baseline (CFB) in Scale of Outcomes in PD-Sleep Scale (SCOPA) Nighttime Sleep (NS)Score [From baseline to Week 8]

   The SCOPA-NS subscale addresses problems in nighttime sleep and consists of 5 items (sleep initiation, sleep fragmentation, sleep efficiency, sleep duration, early wakening). Each item has 4 response options (ranging from 0=not at all to 3=a lot). The SCOPA-NS score ranges from 0 to 15, with a higher score indicating more severe nighttime sleep problems.

5. Change From Baseline (CFB) in SCOPA Daytime Sleepiness (DS) Score [From baseline to Week 8]

   The SCOPA-DS subscale addresses problems in daytime sleepiness and consists of 6 items (falling asleep unexpectedly, falling asleep peacefully, falling asleep watching TV/reading, falling asleep while talking to someone, having difficulty staying awake, whether falling asleep in the daytime is considered a Problem). Each item has 4 response options (from 0=never to 3=often). The SCOPA-DS subscale score ranges from 0 to 18, with a higher score indicating more severe DS problems.

6. The Number (or Percentage) of Responders [From baseline to Week 8]

   The HAMD-17 is a multiple-item questionnaire to assess the severity of depression, including items of mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. Each of the 17 items is scored on a 3- or 5-point scale (depending on the item). The minimum total score is 0; the maximum total score is 52. A higher total score signifies more severe Depression. Response was defined as ≥50% reduction from baseline in HAMD-17 total score. Patients without Week-8 score were counted as nonresponders.

7. Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) [From baseline to Week 8]

   The EQ-5D-5L is a standardized measure of health status. The questionnaire consists of 2 components: the EQ-5D-5L descriptive system and the EQ-5D-5L Visual Analogue scale (EQ-5D-5L VAS). The descriptive system consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels (from 1=no problem to 5=extreme Problems). The digits for the 5 dimensions are combined into a 5-digit code that describes the patient's health state, which is then converted into a single summary index value. Health state index scores generally range from less than 0 (where 0 is the value of a health state equivalent to dead; negative values representing values as worse than dead) to 1 (the value of full health), with higher scores indicating higher health utility. The EQ-5D-5L VAS records the patient's health on a vertical visual analogue scale, ranging from 100 (=the best health you can imagine) to 0 (=the worst health you can imagine).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Can understand and provide signed informed consent, request for medical records and/or subject privacy form if applicable according to local regulations

2. Has a clinical diagnosis of idiopathic Parkinson's disease with a minimum duration of 1 year, defined as the presence of at least three of the following cardinal features, in the absence of alternative explanations or atypical features:

3. rest tremor

4. rigidity

5. bradykinesia and/or akinesia

6. postural and gait abnormalities

7. Meets clinical criteria for depression with Parkinson's disease as listed in the NINDS/NIMH Guidelines

8. If currently taking an anti-depressant, is being treated with only one SSRI or SNRI antidepressant at a dose within the US FDA-approved dose range. Subjects who are currently taking a second antidepressant or antidepressant augmentation agent at a sub-therapeutic dose or for an inadequate duration at Screening, and can be discontinued from this agent before the Baseline visit (in the opinion of the Investigator), may be eligible for the study.

9. Is on a stable dose of anti-Parkinson's medication for 1 month prior to Screening

10. If the subject is female, she must be of non-childbearing potential or agree to use two methods of clinically acceptable contraception

Exclusion Criteria:

1. Use of an antipsychotic within 3 weeks or 5 half-lives of Baseline (whichever is longer)

2. Had a myocardial infarction within the 6 months prior to Screening

3. Has a known personal or family history or symptoms of long QT syndrome

4. Evidence of severe or medically significant hepatic or renal impairment on laboratory tests as assessed by the Investigator or Medical Monitor

5. Has a history of PD psychosis, schizophrenia, or other psychotic disorder, or bipolar I or II disorder.

6. Actively suicidal at Visit 1 (Screening) or Visit 2 (Baseline)

7. Is pregnant or breastfeeding

8. Has previously been treated with pimavanserin or is currently taking pimavanserin

9. Has a sensitivity to pimavanserin or its excipients

10. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study

Additional inclusion/exclusion criteria apply. Subjects will be evaluated at screening to ensure that all criteria for study participation are met.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ATP Clinical Research, Inc.	Costa Mesa	California	United States	92626
2	The Parkinson's and Movement Disorder Institute	Fountain Valley	California	United States	92708
3	SC3 Research-Reseda	Pasadena	California	United States	91105
4	The Neurology Group	Pomona	California	United States	91767
5	SC3 Research-Reseda	Reseda	California	United States	91335
6	CNS Network	Torrance	California	United States	90502
7	Associated Neurologists, P.C.	Danbury	Connecticut	United States	06810
8	Parkinson's Disease and Movement Disorder Center of Boca Raton	Boca Raton	Florida	United States	33486
9	University of Florida	Gainesville	Florida	United States	32607
10	Parkinson's Disease Treatment Center of SW Florida	Port Charlotte	Florida	United States	33980
11	Infinity Clinical Research, LLC	Sunrise	Florida	United States	33351
12	Tallahassee Neurological Clinic, P.A.	Tallahassee	Florida	United States	32308
13	SRI Biosciences, Clinical Trials and Strategic Development Services	Plymouth	Michigan	United States	48170
14	Washington University School of medicine	Saint Louis	Missouri	United States	63110
15	Bio Behavioral Health	Toms River	New Jersey	United States	08755
16	Albany Medical College	Albany	New York	United States	12208
17	David L. Kreitzman, MD, PC	Commack	New York	United States	11725
18	Asheville Neurology Specialists, PA	Asheville	North Carolina	United States	28806
19	Neurology/Neurophysiology	Johnstown	Pennsylvania	United States	15904
20	Booth Gardner Parkinson's Care Center	Kirkland	Washington	United States	98034
21	Inland Northwest Research	Spokane	Washington	United States	99202

Sponsors and Collaborators

• ACADIA Pharmaceuticals Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jan 8, 2019
• Statistical Analysis Plan - Jan 31, 2019

More Information

Publications

None provided.

• Responsible Party: ACADIA Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT03482882
• Other Study ID Numbers: ACP-103-048
• First Posted: Mar 29, 2018
• Last Update Posted: Aug 31, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Parkinson Disease; Depression; Depressive Disorder; Pimavanserin

Study Results

Participant Flow

Arm/Group Title	Pimavanserin
Arm/Group Description	Pimavanserin 34 mg, taken as 2 tablets of pimavanserin 17 mg as a single dose once daily
Period Title: Overall Study
STARTED	47
COMPLETED	40
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Pimavanserin Safety Analysis Set
Arm/Group Description	The Safety Analysis Set (SAS) includes all subjects (47 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth)
Overall Participants	47
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.6 (8.25)
Sex: Female, Male (Count of Participants)
Female	23 48.9%
Male	24 51.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 4.3%
White	43 91.5%
More than one race	0 0%
Unknown or Not Reported	1 2.1%
Region of Enrollment (participants) [Number]
United States	47 100%
Duration of Parkinson's Disease (PD) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.8 (5.39)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 8 in HAMD-17 (Hamilton Depression Scale -17 Items) Total Score
Description	The HAMD-17 is a multiple-item questionnaire to assess the severity of depression, including items of mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. Each of the 17 items is scored on a 3- or 5-point scale (depending on the item). The minimum total score is 0; the maximum total score is 52. A higher total score signifies more severe depression.
Time Frame	From baseline to Week 8

Outcome Measure Data

Analysis Population Description

Patients treated with study drug and with at least one post-baseline assessment of the HAMD-17. The Full Analysis Set had 45 participants at baseline. The Full Analysis Set at Week 8 had 39 participants.

Arm/Group Title	Pimavanserin Full Analysis Set
Arm/Group Description	The Full Analysis Set (FAS) includes all subjects (45 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth) and who have both a baseline value and post-baseline value for the Hamilton Depression Scales (17 items; HAMD-17)
Measure Participants	45
Baseline HAMD-17 total score	19.2 (0.46)
Week 8 HAMD-17 total score	8.1 (0.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pimavanserin Full Analysis Set
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effect model repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM
	Estimated Value	-10.8
	Confidence Interval	(2-Sided) 95%; -12.0 to -9.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.63
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline (CFB) in HAMD-17 Total Score at Weeks 2, 4, and 6
Description	The HAMD-17 is a multiple-item questionnaire to assess the severity of depression, including items of mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. Each of the 17 items is scored on a 3- or 5-point scale (depending on the item). The minimum total score is 0; the maximum total score is 52. A higher total score signifies more severe depression.
Time Frame	2, 4, and 6 weeks from baseline

Outcome Measure Data

Analysis Population Description

Patients treated with study drug and with at least one post-baseline assessment of the HAMD-17

Arm/Group Title	Pimavanserin Full Analysis Set
Arm/Group Description	The Full Analysis Set (FAS) includes all subjects (45 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth) and who have both a baseline value and post-baseline value for the Hamilton Depression Scales (17 items; HAMD-17)
Measure Participants	45
Baseline HAMD-17 total score	19.2 (0.46)
Week 2 HAMD-17 total score CFB	-7.5 (0.89)
Week 4 HAMD-17 total score CFB	-9.7 (0.69)
Week 6 HAMD-17 total score CFB	-9.6 (0.69)

3. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I)
Description	The CGI-I is a clinician-rated 7-point scale to rate the improvement in the patient's depression at the time of assessment relative baseline. The CGI-I ranges from 1 (very much improved) to 7 (very much worse)
Time Frame	At Week 8

Outcome Measure Data

Analysis Population Description

Patients treated with study drug and with at least one post-baseline assessment of the HAMD-17

Arm/Group Title	Pimavanserin Full Analysis Set
Arm/Group Description	The Full Analysis Set (FAS) includes all subjects (45 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth) and who have both a baseline value and post-baseline value for the Hamilton Depression Scales (17 items; HAMD-17)
Measure Participants	39
Mean (Standard Error) [score on a scale]	2.0 (0.16)

4. Secondary Outcome

Title	Change From Baseline (CFB) in Clinical Global Impression-Severity (CGI-S)
Description	The CGI-S is a clinician-rated 7-point scale to rate the severity of the patient's depression at the time of assessment. The CGI-S ranges from 1 (normal) to 7 (patient is among the most severely ill).
Time Frame	From baseline to Week 8

Outcome Measure Data

Analysis Population Description

Patients treated with study drug and with at least one post-baseline assessment of the HAMD-17

Arm/Group Title	Pimavanserin Full Analysis Set
Arm/Group Description	The Full Analysis Set (FAS) includes all subjects (45 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth) and who have both a baseline value and post-baseline value for the Hamilton Depression Scales (17 items; HAMD-17)
Measure Participants	45
Baseline CGI-S	4.1 (0.08)
8 Week CGI-S CFB	-1.8 (0.17)

5. Secondary Outcome

Title	Change From Baseline (CFB) in Scale of Outcomes in PD-Sleep Scale (SCOPA) Nighttime Sleep (NS)Score
Description	The SCOPA-NS subscale addresses problems in nighttime sleep and consists of 5 items (sleep initiation, sleep fragmentation, sleep efficiency, sleep duration, early wakening). Each item has 4 response options (ranging from 0=not at all to 3=a lot). The SCOPA-NS score ranges from 0 to 15, with a higher score indicating more severe nighttime sleep problems.
Time Frame	From baseline to Week 8

Outcome Measure Data

Analysis Population Description

Patients treated with study drug and with at least one post-baseline assessment of the HAMD-17

Arm/Group Title	Pimavanserin Full Analysis Set
Arm/Group Description	The Full Analysis Set (FAS) includes all subjects (45 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth) and who have both a baseline value and post-baseline value for the Hamilton Depression Scales (17 items; HAMD-17)
Measure Participants	45
Baseline SCOPA-NS	6.1 (0.51)
Week 8 SCOPA-NS CFB	-2.1 (0.57)

6. Secondary Outcome

Title	Change From Baseline (CFB) in SCOPA Daytime Sleepiness (DS) Score
Description	The SCOPA-DS subscale addresses problems in daytime sleepiness and consists of 6 items (falling asleep unexpectedly, falling asleep peacefully, falling asleep watching TV/reading, falling asleep while talking to someone, having difficulty staying awake, whether falling asleep in the daytime is considered a Problem). Each item has 4 response options (from 0=never to 3=often). The SCOPA-DS subscale score ranges from 0 to 18, with a higher score indicating more severe DS problems.
Time Frame	From baseline to Week 8

Outcome Measure Data

Analysis Population Description

Patients treated with study drug and with at least one post-baseline assessment of the HAMD-17

Arm/Group Title	Pimavanserin Full Analysis Set
Arm/Group Description	The Full Analysis Set (FAS) includes all subjects (45 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth) and who have both a baseline value and post-baseline value for the Hamilton Depression Scales (17 items; HAMD-17)
Measure Participants	45
Baseline SCOPA-DS	5.2 (0.56)
8 Week SCOPA-DS CFB	-2.2 (0.50)

7. Secondary Outcome

Title	The Number (or Percentage) of Responders
Description	The HAMD-17 is a multiple-item questionnaire to assess the severity of depression, including items of mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. Each of the 17 items is scored on a 3- or 5-point scale (depending on the item). The minimum total score is 0; the maximum total score is 52. A higher total score signifies more severe Depression. Response was defined as ≥50% reduction from baseline in HAMD-17 total score. Patients without Week-8 score were counted as nonresponders.
Time Frame	From baseline to Week 8

Outcome Measure Data

Analysis Population Description

Patients treated with study drug and with at least one post-baseline assessment of the HAMD-17

Arm/Group Title	Pimavanserin Full Analysis Set
Arm/Group Description	The Full Analysis Set (FAS) includes all subjects (45 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth) and who have both a baseline value and post-baseline value for the Hamilton Depression Scales (17 items; HAMD-17)
Measure Participants	45
Count of Participants [Participants]	27 57.4%

8. Secondary Outcome

Title	Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L)
Description	The EQ-5D-5L is a standardized measure of health status. The questionnaire consists of 2 components: the EQ-5D-5L descriptive system and the EQ-5D-5L Visual Analogue scale (EQ-5D-5L VAS). The descriptive system consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels (from 1=no problem to 5=extreme Problems). The digits for the 5 dimensions are combined into a 5-digit code that describes the patient's health state, which is then converted into a single summary index value. Health state index scores generally range from less than 0 (where 0 is the value of a health state equivalent to dead; negative values representing values as worse than dead) to 1 (the value of full health), with higher scores indicating higher health utility. The EQ-5D-5L VAS records the patient's health on a vertical visual analogue scale, ranging from 100 (=the best health you can imagine) to 0 (=the worst health you can imagine).
Time Frame	From baseline to Week 8

Outcome Measure Data

Analysis Population Description

Patients treated with study drug and with at least one post-baseline assessment of the HAMD-17

Arm/Group Title	Pimavanserin Full Analysis Set
Arm/Group Description	The Full Analysis Set (FAS) includes all subjects (45 participants) who received at least one dose of study drug (34mg pimavanserin taken as two 17mg tablets, once daily by mouth) and who have both a baseline value and post-baseline value for the Hamilton Depression Scales (17 items; HAMD-17)
Measure Participants	45
Baseline EQ-5D-5L index score	0.6750 (0.02551)
8 Week EQ-5D-5L index score CFB	0.0712 (0.02629)
Baseline EQ-5D-5L VAS	63.9 (2.43)
8 Week EQ-5D-5L VAS CFB	6.7 (2.61)

Adverse Events

Time Frame	From the time of informed consent through a safety follow-up visit at Week 10
Arm/Group Title	Pimavanserin
Arm/Group Description	Pimavanserin 34 mg, taken as 2 tablets of pimavanserin 17 mg as a single dose once daily
All Cause Mortality
	Pimavanserin
	Affected / at Risk (%)	# Events
Total	0/47 (0%)
Serious Adverse Events
	Pimavanserin
	Affected / at Risk (%)	# Events
Total	1/47 (2.1%)
Gastrointestinal disorders
Colitis	1/47 (2.1%)	1
Other (Not Including Serious) Adverse Events
	Pimavanserin
	Affected / at Risk (%)	# Events
Total	21/47 (44.7%)
Cardiac disorders
Palpitations	1/47 (2.1%)	1
Supraventricular extrasystoles	1/47 (2.1%)	1
Endocrine disorders
Hypothyroidism	1/47 (2.1%)	1
Gastrointestinal disorders
Nausea	3/47 (6.4%)	3
Diarrhoea	2/47 (4.3%)	2
Abdominal pain	1/47 (2.1%)	1
Constipation	1/47 (2.1%)	1
Gastritis	1/47 (2.1%)	1
Vomiting	1/47 (2.1%)	1
General disorders
Oedema	2/47 (4.3%)	2
Non-cardiac chest pain	1/47 (2.1%)	1
Peripheral swelling	1/47 (2.1%)	1
Infections and infestations
Urinary tract infection	2/47 (4.3%)	2
Injury, poisoning and procedural complications
Fall	4/47 (8.5%)	4
Skin abrasion	2/47 (4.3%)	2
Contusion	1/47 (2.1%)	1
Laceration	1/47 (2.1%)	1
Muscle strain	1/47 (2.1%)	1
Investigations
Blood glucose increased	1/47 (2.1%)	1
Blood pressure increased	1/47 (2.1%)	1
Metabolism and nutrition disorders
Gout	1/47 (2.1%)	1
Nervous system disorders
Dizziness	1/47 (2.1%)	1
Hypertonia	1/47 (2.1%)	1
Mental impairment	1/47 (2.1%)	1
Presyncope	1/47 (2.1%)	1
Psychiatric disorders
Abnormal dreams	1/47 (2.1%)	1
Hallucination, auditory	1/47 (2.1%)	1
Hallucination, visual	1/47 (2.1%)	1
Illusion	1/47 (2.1%)	1
Insomnia	1/47 (2.1%)	1
Rapid eye movement sleep behaviour disorder	1/47 (2.1%)	1
Suicidal ideation	1/47 (2.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigator may publish the study results, relative to his/her own patients, only after review, comment and approval by the sponsor. No publication of confidential information shall be made without the sponsor's prior written consent. At least 60 days prior to submitting a manuscript or prior to any public presentation, a copy of the manuscript or presentation will be provided to the sponsor for review and comment. The sponsor has 60 days to review and comment.