Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT)

• Sponsor: USWM, LLC (dba US WorldMeds) (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01770145
• Collaborator: (none)
• Enrollment: 127
• Locations: 12
• Arm: 1
• Duration (Months): 16
• Patients Per Site: 10.6
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This study is designed to assess the effect of APOKYN treatment in rapid and reliable improvement of motor symptoms in Parkinson's disease (PD) subjects suffering from delayed or unreliable onset of levodopa (L-dopa) action.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease; Motor Symptoms; Akinesia; Hypomobility; Delayed Levodopa Onset	Drug: APOKYN; Drug: L-dopa; Drug: Trimethobenzamide	Phase 4

Detailed Description

This Phase IV, Open-Label, Efficacy and Safety Study of APOKYN® is intended to assess the effect of APOKYN treatment in rapid and reliable improvement of motor symptoms in PD subjects suffering from delayed or unreliable onset of L-dopa action. The study will also include a sub-group of 8 subjects to evaluate their gastroparesis and assess their gastric empty with other measures to explore if APOKYN has any influence on gastric empty rather than just bypassing the stomach with a subcutaneous route of administration.

The primary objective of this study is to assess the effect of APOKYN treatment in rapid and reliable improvement of motor symptoms in PD subjects suffering from delayed or unreliable onset of L-dopa action (defined below). APOKYN treatment will also be assessed in a sub-group of PD subjects suffering from gastroparesis and delayed onset of L-dopa action.

Delayed or unreliable onset to L-dopa for the study population is defined as impaired motor function (tremor, bradykinesia, rigidity, and/or postural instability) persisting for a minimum of 45 minutes after taking a dose of L-dopa because of its delay in onset of action. The impaired motor function resulting from delay in L-dopa onset is referred to as "delayed ON" and when it occurs upon awakening is referred to as "morning akinesia."

Main Study:

This is a multicenter, multiple-treatment, open-label, outpatient study to evaluate the efficacy and safety of APOKYN in PD subjects with delayed onset of L dopa action. The study will have:

• Screening - 1-5 days (Visit 1);

• Baseline L-Dopa Period - 7 days, continuation of L dopa treatment;

• Antiemetic Treatment Period - 3-days; initiation of trimethobenzamide 300 mg tid orally;

• APOKYN Initiation/optimum dose identification Period (Visit 2)- variable, not more than 11 days;

• APOKYN Treatment Period - 7 days, immediately upon identification of optimum dose;

• Study Discharge (Visit 3)- within 2 days of completion of the APOKYN treatment period.

Gastroparesis Sub-Study:

A sub-group of subjects (n=8) from 1 study site that have symptoms of gastroparesis will be admitted to the clinic on 2 occasions to undergo gastroparesis procedures and assessments (once at the conclusion of the baseline L-dopa period and once at the conclusion of the APOKYN treatment period). Note, to do the second gastroparesis assessment, this sub-group of subjects will have an extension for one extra day beyond the designated 7 day APOKYN treatment period (i.e., it will be 8 days) in order to keep the 7 day diary recording outpatient scope of work the same as the rest of the subjects in the study. The second inpatient period will be also considered the end-of-study visit for this sub group.

Study Design

• Study Type: Interventional
• Actual Enrollment: 127 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 4, Open-Label, Efficacy and Safety Study of Apokyn® for Rapid and Reliable Improvement of Motor Symptoms in Parkinson Disease Subjects With Delayed Onset of L-Dopa Action
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: APOKYN APOKYN (apomorphine hydrochloride injection) is used as needed to treat off-episode motor symptoms, such as muscle stiffness, slow movements, and difficulty starting movements, in people with advanced Parkinson's disease (PD). In the study, subjects will complete an L-Dopa Baseline Period in which they record daily "time to on" following their regularly scheduled L-Dopa morning dose for 7 days. At the end of the baseline period, patients will start trimethobenzamide therapy during a minimum 3-Day Anti-Emetic Pretreatment Period. Patients determined to remain eligible at the end of the required Anti-Emetic Pretreatment Period will be initiated on APOKYN therapy by an investigator. Once the appropriate dose is identified by a study investigator, patients will inject APOKYN at their regularly scheduled levodopa morning dose time (levodopa will be delayed by 40 minutes) daily during a 7-day APOKYN Treatment Period and record "time to on" following the APOKYN injection.

Drug: APOKYN; Apokyn will be titrated to an optimum dose which reproduces 90% of the subjects' "best on" UPDRS score during the Initiation Period. During the APOKYN Treatment Period, subjects will inject the dose identified in the initiation period once daily at the time of their normal scheduled L-Dopa dose (L-Dopa will be delayed by 40 minutes).; Other Names: apomorphine hydrochloride injection ; Drug: L-dopa; Subjects on a stable L-Dopa regimen will be entered into the study. For the L-Dopa Baseline Period through the Initiation Period, subjects will continue their normal L-Dopa dosing regimen. During the APOKYN Treatment Period, subjects will replace their normally scheduled first morning L-Dopa dose with an APOKYN injection, and then administer their normal first morning L-Dopa dose 40 minutes later.; Other Names: Levodopa, Levodopa/Carbidopa, Sinemet, Sinemet CR, Parcopa ; Drug: Trimethobenzamide; Following the L-Dopa Baseline Period, subjects will initiate trimethobenzamide treatment TID for a minimum of 3 days during a Anti-Emetic Pretreatment Period. Subjects will continue trimethobenzamide therapy TID through the duration of the APOKYN Initiation Period and APOKYN Treatment Period.; Other Names: Tigan

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Average Daily "Time to on" ("TTO") by Subject Diary. [L-Dopa Baseline Days 1-7 and APOKYN Treatment Days 1-7]

   Patients will record daily "time to on" or "TTO" following their regularly scheduled first L-Dopa dose in the baseline period for 7 consecutive days. Following initiation on Apokyn therapy, patients will inject Apokyn at their regularly scheduled L-Dopa time (L-Dopa dosing will be delayed by 40 minutes following Apokyn injection) and record "time to on" or "TTO" from the injection. "Time to on" for both periods will be recorded in a standardized subject diary. Daily "TTO" for the baseline period will be averaged for each subject and compared to the daily "TTO" for the same subject during the treatment period to assess APOKYN's effect on "TTO".

Secondary Outcome Measures

1. Change From Baseline in Gastric Emptying Time [L-Dopa Baseline Days 1-7 and APOKYN Treatment Days 1-8]

   A sub-group of subjects from 1 study site that have symptoms of gastroparesis were admitted to the clinic on 2 occasions to undergo gastroparesis procedures and assessments (once at the conclusion of the baseline L-dopa period and once at the conclusion of the APOKYN treatment period). Note, to do the second gastroparesis assessment, this sub-group of subjects had an extension for one extra day beyond the designated 7 day APOKYN treatment period (i.e., it will be 8 days) in order to keep the 7 day diary recording outpatient scope of work the same as the rest of the subjects in the study. The second inpatient period was also considered the end-of-study visit for this sub group.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female ≥18 years of age.

2. Idiopathic PD.

3. Not currently taking APOKYN and, if previously prescribed APOKYN, did not discontinue therapy due to intolerable side effects/safety reasons.

4. Prescribed L-dopa therapy at a steady maintenance dose, representing an optimal treatment regimen in the opinion of the Investigator, for at least 4 weeks before study participation.

5. Minimum subject-reported time to turn "on" (TTO) in the early morning (time to end akinetic/ bradykinetic state resulting from delay in L-dopa onset of action) of 45 minutes after the first morning L-dopa dose for a minimum of 3 days/week (as determined with the subject diary at Visit 2).

6. Able to adequately differentiate between and describe variations in "on" and "off" states in the opinion of the Investigator.

7. I to III Modified Hoehn and Yahr stage in the "on" state (Appendix B).

8. Be seeking treatment for early morning akinesia.

9. If female and of childbearing potential, must agree to use one of the following methods of birth control:

• Oral contraceptive;

• Patch;

• Barrier (diaphragm, sponge or condom) plus spermicidal preparations;

• Intrauterine contraceptive system;

• Levonorgestrel implant;

• Medroxyprogesterone acetate contraceptive injection;

• Complete abstinence from sexual intercourse;

• Hormonal vaginal contraceptive ring; or

• Surgical sterilization or partner sterile (must have documented proof).

1. Access to a live-in caregiver, if needed.

2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures to complete the study.

3. Able to verbalize understanding of the consent form, able to provide written informed consent.

The following must be present for inclusion in the single site gastroparesis sub-study:

1. Have symptoms of gastroparesis.

2. Have improvement of at least one Modified Hoehn and Yahr stage from "off" to "on."

3. Currently seeking treatment for delayed L-dopa onset.

4. Have no allergy to eggs.

Exclusion Criteria:

1. Changes in L-dopa dosing regimen 4 weeks before the screening visit.

2. Female who is pregnant or lactating.

3. Contraindications to APOKYN or hypersensitive to apomorphine hydrochloride or any of the ingredients of APOKYN (notably sodium metabisulfite).

4. Participation in any other clinical trial within 14 days of the screening visit.

5. Receipt of any investigational (i.e., unapproved) medication within 30 days of the screening visit.

6. Currently taking, or likely to need to take at any time during the course of the study, any 5HT3 antagonist (i.e., ondansetron, granisetron, dolasetron, palonosetron, alosetron).

7. Currently taking medications for treatment of gastroparesis (e.g., erythromycin, cisapride, metoclopramide).

8. Malignant melanoma or a history of previously treated malignant melanoma within 5 years.

9. Serious medical illness including, but not limited to:

• Liver disease;

• Kidney problems; and

• Heart problems.

1. Psychiatric disorder, including but not limited to dementia or any disorder that, in the opinion of the Investigator requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.

2. Lack of compliance and follow-up.

3. Any other condition, current therapy, or prior therapy (within 30 days of the screening visit), which, in the opinion of the Investigator, would make the subject unsuitable for the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Keck School of Medicine	Los Angeles	California	United States	90033
2	Neurosearch, Inc.	Reseda	California	United States	91335
3	Georgetown University	Washington, D.C.	District of Columbia	United States	20007
4	Parkinson's Disease and Movement Disorders Center of Boca Raton	Boca Raton	Florida	United States	33486
5	Rush University Medical Center	Chicago	Illinois	United States	60612
6	Henry Ford West Bloomfield Hospital	Bloomfield Hills	Michigan	United States	48322
7	Parkinson's Disease and Movement Disorders Center of New York	Commack	New York	United States	11725
8	University of Cincinnati Academic Health Center	Cincinnati	Ohio	United States	45267
9	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
10	The Movement Disorder Clinic of Oklahoma	Tulsa	Oklahoma	United States	74136
11	University of Texas Health Science Center, Houston, Department of Neurology	Houston	Texas	United States	77030
12	Center for Neurological Care and Research	San Antonio	Texas	United States	78240

Sponsors and Collaborators

• USWM, LLC (dba US WorldMeds)

Investigators

• Principal Investigator: Stuart H. Isaacson, MD, Parkinson's Disease and Movement Disorders Center of Boca Raton

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: USWM, LLC (dba US WorldMeds)
• ClinicalTrials.gov Identifier: NCT01770145
• Other Study ID Numbers: USWM-AP1-4001
• First Posted: Jan 17, 2013
• Last Update Posted: Nov 30, 2017
• Last Verified: Oct 1, 2017

• Keywords provided by USWM, LLC (dba US WorldMeds): Motor symptoms; Parkinson's Disease; Delayed Onset; Akinesia; Hypomobility; Unified Parkinson Disease Rating Scale (UPDRS) motor scores; Dopamine agonist; Apomorphine; Apokyn; Levodopa
• Additional relevant MeSH terms: Parkinson Disease; Levodopa; Carbidopa; Carbidopa, levodopa drug combination; Trimethobenzamide; Apomorphine

Study Results

Participant Flow

Arm/Group Title	APOKYN
Arm/Group Description	Subjects will complete an L-Dopa Baseline Period in which they record daily "time to on" following their regularly scheduled L-Dopa morning dose for 7 days. At the end of the baseline period, patients will start trimethobenzamide therapy during a minimum 3-Day Anti-Emetic Pretreatment Period. Patients determined to remain eligible at the end of the required Anti-Emetic Pretreatment Period will be initiated on APOKYN therapy by an investigator. Once the appropriate dose is identified by a study investigator, patients will inject APOKYN at their regularly scheduled levodopa morning dose time (levodopa will be delayed by 40 minutes) daily during a 7-day APOKYN Treatment Period and record "time to on" following the APOKYN injection.
Period Title: Baseline
STARTED	127
COMPLETED	101
NOT COMPLETED	26
Period Title: Baseline
STARTED	101
COMPLETED	97
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	APOKYN
Arm/Group Description	Subjects will complete an L-Dopa Baseline Period in which they record daily "time to on" following their regularly scheduled L-Dopa morning dose for 7 days. At the end of the baseline period, patients will start trimethobenzamide therapy during a minimum 3-Day Anti-Emetic Pretreatment Period. Patients determined to remain eligible at the end of the required Anti-Emetic Pretreatment Period will be initiated on APOKYN therapy by an investigator. Once the appropriate dose is identified by a study investigator, patients will inject APOKYN at their regularly scheduled levodopa morning dose time (levodopa will be delayed by 40 minutes) daily during a 7-day APOKYN Treatment Period and record "time to on" following the APOKYN injection.
Overall Participants	127
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.20 (9.72)
Sex: Female, Male (Count of Participants)
Female	43 33.9%
Male	84 66.1%
Race/Ethnicity, Customized (participants) [Number]
Not Hispanic or Latino	121 95.3%
Hispanic or Latino	6 4.7%
Duration of Parkinson's Disease (years) (participants) [Number]
0-5 years	21 16.5%
6-10 years	48 37.8%
11-15 years	34 26.8%
15+ years	24 18.9%
Duration of Akinesia (years) (participants) [Number]
<2 years	44 34.6%
2-4 years	35 27.6%
5-6 years	16 12.6%
>6 years	28 22%
Unknown	4 3.1%
Average Daily Time to On (minutes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [minutes]	59.13 (18.13)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Average Daily "Time to on" ("TTO") by Subject Diary.
Description	Patients will record daily "time to on" or "TTO" following their regularly scheduled first L-Dopa dose in the baseline period for 7 consecutive days. Following initiation on Apokyn therapy, patients will inject Apokyn at their regularly scheduled L-Dopa time (L-Dopa dosing will be delayed by 40 minutes following Apokyn injection) and record "time to on" or "TTO" from the injection. "Time to on" for both periods will be recorded in a standardized subject diary. Daily "TTO" for the baseline period will be averaged for each subject and compared to the daily "TTO" for the same subject during the treatment period to assess APOKYN's effect on "TTO".
Time Frame	L-Dopa Baseline Days 1-7 and APOKYN Treatment Days 1-7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APOKYN
Arm/Group Description	In the study, subjects will complete an L-Dopa Baseline Period in which they record daily "time to on" following their regularly scheduled L-Dopa morning dose for 7 days. At the end of the baseline period, patients will start trimethobenzamide therapy during a minimum 3-Day Anti-Emetic Pretreatment Period. Patients determined to remain eligible at the end of the required Anti-Emetic Pretreatment Period will be initiated on APOKYN therapy by an investigator. Once the appropriate dose is identified by a study investigator, patients will inject APOKYN at their regularly scheduled levodopa morning dose time (levodopa will be delayed by 40 minutes) daily during a 7-day APOKYN Treatment Period and record "time to on" following the APOKYN injection.
Measure Participants	88
Baseline	60.86 (18.11)
Treatment Period	23.72 (14.55)
Change from Baseline	37.14 (20.51)

2. Secondary Outcome

Title	Change From Baseline in Gastric Emptying Time
Description	A sub-group of subjects from 1 study site that have symptoms of gastroparesis were admitted to the clinic on 2 occasions to undergo gastroparesis procedures and assessments (once at the conclusion of the baseline L-dopa period and once at the conclusion of the APOKYN treatment period). Note, to do the second gastroparesis assessment, this sub-group of subjects had an extension for one extra day beyond the designated 7 day APOKYN treatment period (i.e., it will be 8 days) in order to keep the 7 day diary recording outpatient scope of work the same as the rest of the subjects in the study. The second inpatient period was also considered the end-of-study visit for this sub group.
Time Frame	L-Dopa Baseline Days 1-7 and APOKYN Treatment Days 1-8

Outcome Measure Data

Analysis Population Description

A sub-group of subjects from 1 study site that have symptoms of gastroparesis were admitted to the clinic to undergo gastroparesis procedures and assessments (once at the conclusion of the baseline L-dopa period and once at the conclusion of the APOKYN treatment period)

Arm/Group Title	APOKYN
Arm/Group Description	In the study, subjects will complete an L-Dopa Baseline Period in which they record daily "time to on" following their regularly scheduled L-Dopa morning dose for 7 days. At the end of the baseline period, patients will start trimethobenzamide therapy during a minimum 3-Day Anti-Emetic Pretreatment Period. Patients determined to remain eligible at the end of the required Anti-Emetic Pretreatment Period will be initiated on APOKYN therapy by an investigator. Once the appropriate dose is identified by a study investigator, patients will inject APOKYN at their regularly scheduled levodopa morning dose time (levodopa will be delayed by 40 minutes) daily during a 7-day APOKYN Treatment Period and record "time to on" following the APOKYN injection.
Measure Participants	0

Adverse Events

Arm/Group Title	APOKYN
Arm/Group Description	In the study, subjects will complete an L-Dopa Baseline Period in which they record daily "time to on" following their regularly scheduled L-Dopa morning dose for 7 days. At the end of the baseline period, patients will start trimethobenzamide therapy during a minimum 3-Day Anti-Emetic Pretreatment Period. Patients determined to remain eligible at the end of the required Anti-Emetic Pretreatment Period will be initiated on APOKYN therapy by an investigator. Once the appropriate dose is identified by a study investigator, patients will inject APOKYN at their regularly scheduled levodopa morning dose time (levodopa will be delayed by 40 minutes) daily during a 7-day APOKYN Treatment Period and record "time to on" following the APOKYN injection.
All Cause Mortality
	APOKYN
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	APOKYN
	Affected / at Risk (%)	# Events
Total	0/127 (0%)
Other (Not Including Serious) Adverse Events
	APOKYN
	Affected / at Risk (%)	# Events
Total	70/127 (55.1%)
Cardiac disorders
Palpitations	1/127 (0.8%)	1
Ear and labyrinth disorders
Vertigo	1/127 (0.8%)	1
Tinnitus	1/127 (0.8%)	1
Ear Pain	1/127 (0.8%)	1
Eye disorders
Vision blurred	1/127 (0.8%)	1
Ocular hyperaemia	1/127 (0.8%)	1
Eyelid ptosis	1/127 (0.8%)	1
Eye pain	1/127 (0.8%)	1
Diplopia	1/127 (0.8%)	1
Gastrointestinal disorders
Toothache	1/127 (0.8%)	1
Salivary hyper-secretion	1/127 (0.8%)	1
Retching	1/127 (0.8%)	1
Nausea	25/127 (19.7%)	25
Diarrhea	0/127 (0%)	0
General disorders
Chills	6/127 (4.7%)	6
Chest Pain	1/127 (0.8%)	1
Chest Discomfort	2/127 (1.6%)	2
Vomiting	6/127 (4.7%)	6
Oedema	2/127 (1.6%)	2
Injection Site Pruritus	1/127 (0.8%)	1
Injection site erythema	1/127 (0.8%)	1
Injection site bruising	0/127 (0%)	0
Feeling hot	2/127 (1.6%)	2
Fatigue	2/127 (1.6%)	2
Infections and infestations
Urinary Tract Infection	2/127 (1.6%)	2
Tooth Infection	0/127 (0%)	0
Rhinitis	1/127 (0.8%)	1
Herpes Zoster	0/127 (0%)	0
Cellulitis	0/127 (0%)	0
Injury, poisoning and procedural complications
Tooth Injury	0/127 (0%)	0
Stress Fracture	1/127 (0.8%)	1
Laceration	0/127 (0%)	0
Joint Sprain	1/127 (0.8%)	1
Fall	1/127 (0.8%)	1
Excoriation	0/127 (0%)	0
Contusion	1/127 (0.8%)	1
Investigations
Heart rate increased	1/127 (0.8%)	1
Musculoskeletal and connective tissue disorders
Pain in jaw	1/127 (0.8%)	1
Pain in extremity	0/127 (0%)	0
Mobility decreased	1/127 (0.8%)	1
Neck pain	1/127 (0.8%)	1
Limb discomfort	1/127 (0.8%)	1
Nervous system disorders
Syncope	0/127 (0%)	0
Somnolence	7/127 (5.5%)	7
Paraesthesia	1/127 (0.8%)	1
Loss of consciousness	0/127 (0%)	0
Hyposaethesia	1/127 (0.8%)	1
Headache	2/127 (1.6%)	2
Dyskinesia	1/127 (0.8%)	1
Dysgeusia	1/127 (0.8%)	1
Psychiatric disorders
Confusional state	1/127 (0.8%)	1
Anxiety	0/127 (0%)	0
Restlessness	1/127 (0.8%)	1
Delusion	1/127 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Yawning	10/127 (7.9%)	10
Sinus Congestion	1/127 (0.8%)	1
Rhinorrhoea	1/127 (0.8%)	1
Nasal Congestion	1/127 (0.8%)	1
Hiccups	1/127 (0.8%)	1
Dyspnoea	1/127 (0.8%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/127 (2.4%)	3
Erythema	1/127 (0.8%)	1
Cold sweat	1/127 (0.8%)	1
Sneezing	1/127 (0.8%)	1
Vascular disorders
Pallor	3/127 (2.4%)	3
Orthostatic hypotension	1/127 (0.8%)	1
Hypotension	2/127 (1.6%)	2
Hypertension	0/127 (0%)	0
Hot flush	1/127 (0.8%)	1
Flushing	4/127 (3.1%)	4

Limitations/Caveats

Full analysis set (n=88) included patients who completed 5/7 days of diary entries in APOKYN treatment period. The gastroparesis sub-study to assess prevalence and severity of gastroparesis was not analyzed because too few subjects were enrolled.

More Information

Certain Agreements

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

The Sponsor shall have the first right, within nine months following the Sponsor having in its possession all data related to the Study, to publish the Study lead paper. Following the foregoing, the Institution shall have the right, consistent with academic standards, to publish the results of Study provided the Institution provides a publications committee, comprised of at least the Sponsor, with a draft at least thirty (30) days prior to planned submission.