A Phase 3 interventional study of APL-130277 and subcutaneous apomorphine in Motor OFF Episodes Associated With Parkinson's Disease, sponsored by Sumitomo Pharma America, Inc.. Completed at 31 sites in 6 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-12-16.
Sponsored by Sumitomo Pharma America, Inc. · Phase 3, Interventional, and Treatment
A study of an investigational drug to see how it affects the people with Parkinson's Disease complicated by motor fluctuations ("OFF" Episodes) compared to an approved drug used to treat people with Parkinson's Disease complicated by motor fluctuations ("OFF" Episodes)
An Open-Label, Randomized, Crossover Trial utilizing a Single-Blinded Rater to evaluate APL-130277 compared to s.c. Apomorphine in Levodopa Responsive Subjects with Parkinson's Disease Complicated by Motor Fluctuations.
PART A consists of an open label, crossover titration phase where eligible subjects will be randomized to 1 of 2 treatment sequences in a 1:1 ratio to Sublingual APL-130277 followed by subcutaneous apomorphine or subcutaneous apomorphine followed by sublingual APL-130277. Subjects will undergo dose titration with the first study treatment (APL-130277 or sc apomorphine) to tolerance and effect, ie, the tolerable dose that turns the subject from the practically defined "OFF" state to the full "ON" state as determined by both the Investigator and subject. The subject will then be crossed over to the other study treatment (APL-130277 or subcutaneous apomorphine) and similarly titrated to tolerance and effect. These determined doses of APL-130277 and subcutaneous apomorphine will be used during PART B.
PART B consists of an open-label, crossover treatment period where subjects will be randomized to one of the study treatment for 4 weeks, then be crossed over to the other study treatment (APL-130277 or sc apomorphine) for additional 4-weeks of open-label treatment. Subjects return to the clinic for safety and efficacy assessments throughout the treatment period.
This study is designed to test the superiority of sublingually administered APL-130277 against subcutaneously injected apomorphine (APO-go) for the treatment of "OFF" episodes in patients with Parkinson's Disease, as measured by the change from pre-dose to 90 minutes post-dose in MDS UPDRS Part III score in Part B after 4 weeks of dosing in each crossover period.
Exclusion Criteria:
Subjects with type 1 diabetes, or insulin dependent diabetics are excluded. Subjects with type 2 diabetes are eligible for study inclusion if the following conditions are met:
APL-130277: Part A- determine the dose; Part B- 28-day repeat dosing at the dose determined in Part A
Drug: APL-130277
subcutaneous apomorphine , Part A- determine the dose; Part B- 28-day repeat dosing at the dose determined in Part A
Drug: subcutaneous apomorphine
APL-130277: Part A- determine the dose; Part B- 28-day repeat dosing at the dose determined in Part A
Also known as: Apomorphine Hydrochloride
subcutaneous apomorphine Part A- determine the dose; Part B- 28-day repeat dosing at the dose determined in Part A
Also known as: APO-go®
Change From Pre-dose to 90 Mins. Post-dose in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Score After 4 Weeks of Dosing in Each Crossover Period (Assessed by the Blinded-rater In-clinic at Visit 3 and Visit 6 of PART B).
The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. The summary score used in this study for the primary objective and primary efficacy endpoint is Part III motor examination score. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4. The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
Time frame: Pre-dose to 90 minutes post-dose at Week 4 of each treatment period (Visit 3 and 6)
Durability of Effect, Defined as an Investigator Confirmed Full "ON" Within 30 Minutes Post Dose and at 90 Minutes Post-dose, After 4 Weeks of Dosing in Each Crossover Period (Assessed by the Blinded-rater In-clinic at Visit 3 and Visit 6 of PART B).
Investigator will confirm whether subject is "OFF", Full "ON" or Partial "ON" , and note the time the subject changes from "OFF" to Partial "ON" or Full "ON". The Investigator will also record the subject "ON"/"OFF" status (binary variable, Yes / No) prior to performing each MDS-UPDRS Part III assessment. Durability of effect is defined as an Investigator confirmed full "ON" within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each PART B crossover period. Response rate = % of subjects that achived full "ON" within the timeframe
Time frame: Within 30 minutes post-dose and at 90 minutes post-dose at Week 4 of each treatment period (Visit 3 and 6)
Subject Preference for APL Treatment as Measured by the Subject Treatment Preference Questionnaire (TPQ), Planned After the Subject Had Completed Both APL-130277 and sc Apomorphine Treatment Regimens (Assessed In-clinic at Visit 6 of PART B)
The TPQ assessment of subject treatment preference was changed from being based on a visual analogue scale or VAS (Q9b)) to a 5-point Likert scale (Q9a). Subject reported preference for APL or SC was based on question Q9a or Q9b combined. For Q9a, responses were dichotomized as follows for statistical analysis: preference for APL (responses of either definitely or somewhat prefer APL) versus no preference for APL (responses of no preference, or somewhat/definitely prefer sc apomorphine). The VAS score was similarly dichotomized as preference for APL (score of \>0 to 50) versus no preference for APL (-50 to 0). If a subject responded to both Q9a and Q9b, then Q9a only was used.
Time frame: After 8 weeks of treatment (Visit 6)
Subject Confirmed Durability of Effect, Defined as Subject Confirmed Full "ON" Within 30 Minutes Post-dose and at 90 Minutes Post-dose, After 4 Weeks of Dosing in Each Crossover Period (Assessed In-clinic at Visit 3 and Visit 6 of PART B).
Patients will confirm whether he/she is "OFF", Full "ON" or Partial "ON", and the staff will ask the subject to notify the staff when he/she changes from "OFF" to Partial "ON" or Full "ON" (binary variable, Yes / No) . Subject confirmed durability of effect is defined as subject confirmed full "ON" within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed in-clinic at V3 and V6 of PART B). Response rate = % subjects that achived full ON within the timeframe
Time frame: Week 4
Patient Global Impression of Change (PGI-C): Subject Improvement of "OFF" Episodes, Defined as Very Much Better, Much Better or a Little Better After 4 Weeks of Dosing in Each Crossover Period (Assessed In-clinic at Visit 3 and Visit 6 of PART B).
The PGI-C is the patient reported outcome counterpart to the Clinical Global Impressions scale, (CGI), which was published in 1976 by the National Institute of Mental Health (US). It consists of one item taken from the CGI and adapted to the patient. The PGI-C is based on a 7-point scale, where a lower score is associated with higher symptom improvement. The scale is: Very much better Much better A little better No change A little worse Much worse Very much worse Subject improvement of "OFF" episodes is defined as very much better, much better or a little better at Week 4 in each PART B crossover period. Response rate= % of subjects who achieved improvement of "OFF" episodes
Time frame: At Week 4 of each treatment period (Visit 3 and 6, or Early Termination)
| Milestone | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL |
|---|---|---|---|---|---|---|
| Started | 20 | 19 | 19 | 18 | 18 | 19 |
| Safety population | 20 | 18 | 19 | 18 | 18 | 19 |
| Modified intent-to-treat population | 20 | 18 | 19 | 18 | 18 | 19 |
| Completed | 0 | 0 | 16 | 15 | 14 | 15 |
| Not completed | 20 | 19 | 3 | 3 | 4 | 4 |
| Withdrew: Adverse event | 3 | 6 | 1 | 1 | 3 | 1 |
| Withdrew: Lack of efficacy | 13 | 9 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 3 | 3 | 2 | 2 | 1 | 3 |
| Withdrew: Early term at sponsor request | 0 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Protocol violation | 1 | 0 | 0 | 0 | 0 | 0 |
| Milestone | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL |
|---|---|---|---|---|---|---|
| Started | 20 | 19 | 19 | 18 | 18 | 19 |
| Safety population part a | 20 | 18 | 19 | 18 | 18 | 19 |
| Modified intent-to-treat population part a | 20 | 18 | 19 | 18 | 18 | 19 |
| Completed | 2 | 3 | 19 | 18 | 18 | 19 |
| Not completed | 18 | 16 | 0 | 0 | 0 | 0 |
| Withdrew: Adverse event | 3 | 6 | 0 | 0 | 0 | 0 |
| Withdrew: Lack of efficacy | 12 | 6 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 3 | 3 | 0 | 0 | 0 | 0 |
| Withdrew: Early term at sponsor request | 0 | 1 | 0 | 0 | 0 | 0 |
| Milestone | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL |
|---|---|---|---|---|---|---|
| Started | 2 | 3 | 19 | 18 | 18 | 19 |
| Completed | 0 | 0 | 19 | 18 | 18 | 19 |
| Not completed | 2 | 3 | 0 | 0 | 0 | 0 |
| Withdrew: Lack of efficacy | 1 | 3 | 0 | 0 | 0 | 0 |
| Withdrew: Protocol violation | 1 | 0 | 0 | 0 | 0 | 0 |
| Milestone | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL |
|---|---|---|---|---|---|---|
| Started | 0 | 0 | 19 | 18 | 18 | 19 |
| Safety population part b | 0 | 0 | 19 | 18 | 18 | 19 |
| Modified intent-to-treat population part b | 0 | 0 | 19 | 18 | 18 | 19 |
| Completed | 0 | 0 | 16 | 15 | 14 | 15 |
| Not completed | 0 | 0 | 3 | 3 | 4 | 4 |
| Withdrew: Adverse event | 0 | 0 | 1 | 1 | 3 | 1 |
| Withdrew: Withdrawal by subject | 0 | 0 | 2 | 2 | 1 | 3 |
The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. The summary score used in this study for the primary objective and primary efficacy endpoint is Part III motor examination score. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4. The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
| Units on a scale | SC (Subcutaneous Apomorphine) | APL (APL-130277) |
|---|---|---|
| Change From Pre-dose to 90 Mins. Post-dose in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Score After 4 Weeks of Dosing in Each Crossover Period (Assessed by the Blinded-rater In-clinic at Visit 3 and Visit 6 of PART B). | -13.78 (-16.65 to -10.90) | -13.55 (-16.39 to -10.70) |
Investigator will confirm whether subject is "OFF", Full "ON" or Partial "ON" , and note the time the subject changes from "OFF" to Partial "ON" or Full "ON". The Investigator will also record the subject "ON"/"OFF" status (binary variable, Yes / No) prior to performing each MDS-UPDRS Part III assessment. Durability of effect is defined as an Investigator confirmed full "ON" within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each PART B crossover period. Response rate = % of subjects that achived full "ON" within the timeframe
| Percentage of participants | SC (Subcutaneous Apomorphine) | APL (APL-130227) |
|---|---|---|
| Durability of Effect, Defined as an Investigator Confirmed Full "ON" Within 30 Minutes Post Dose and at 90 Minutes Post-dose, After 4 Weeks of Dosing in Each Crossover Period (Assessed by the Blinded-rater In-clinic at Visit 3 and Visit 6 of PART B). | 18.03 | 17.74 |
The TPQ assessment of subject treatment preference was changed from being based on a visual analogue scale or VAS (Q9b)) to a 5-point Likert scale (Q9a). Subject reported preference for APL or SC was based on question Q9a or Q9b combined. For Q9a, responses were dichotomized as follows for statistical analysis: preference for APL (responses of either definitely or somewhat prefer APL) versus no preference for APL (responses of no preference, or somewhat/definitely prefer sc apomorphine). The VAS score was similarly dichotomized as preference for APL (score of \>0 to 50) versus no preference for APL (-50 to 0). If a subject responded to both Q9a and Q9b, then Q9a only was used.
| % of participants | Overall |
|---|---|
| Subject Preference for APL Treatment as Measured by the Subject Treatment Preference Questionnaire (TPQ), Planned After the Subject Had Completed Both APL-130277 and sc Apomorphine Treatment Regimens (Assessed In-clinic at Visit 6 of PART B) | 72.2 (61.9 to 82.6) |
Patients will confirm whether he/she is "OFF", Full "ON" or Partial "ON", and the staff will ask the subject to notify the staff when he/she changes from "OFF" to Partial "ON" or Full "ON" (binary variable, Yes / No) . Subject confirmed durability of effect is defined as subject confirmed full "ON" within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks of dosing in each crossover period (assessed in-clinic at V3 and V6 of PART B). Response rate = % subjects that achived full ON within the timeframe
| Percentage of participants | SC (Subcutaneous Apomorphine) | APL (APL-130227) |
|---|---|---|
| Subject Confirmed Durability of Effect, Defined as Subject Confirmed Full "ON" Within 30 Minutes Post-dose and at 90 Minutes Post-dose, After 4 Weeks of Dosing in Each Crossover Period (Assessed In-clinic at Visit 3 and Visit 6 of PART B). | 14.75 | 19.36 |
The PGI-C is the patient reported outcome counterpart to the Clinical Global Impressions scale, (CGI), which was published in 1976 by the National Institute of Mental Health (US). It consists of one item taken from the CGI and adapted to the patient. The PGI-C is based on a 7-point scale, where a lower score is associated with higher symptom improvement. The scale is: Very much better Much better A little better No change A little worse Much worse Very much worse Subject improvement of "OFF" episodes is defined as very much better, much better or a little better at Week 4 in each PART B crossover period. Response rate= % of subjects who achieved improvement of "OFF" episodes
| Percentage of participants | SC (Subcutaneous Apomorphine) | APL (APL-130277) |
|---|---|---|
| Patient Global Impression of Change (PGI-C): Subject Improvement of "OFF" Episodes, Defined as Very Much Better, Much Better or a Little Better After 4 Weeks of Dosing in Each Crossover Period (Assessed In-clinic at Visit 3 and Visit 6 of PART B). | 77.14 | 83.10 |
Collected over 10 weeks (from first dose of study drug to last study visit). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part A Dose Titration: APL (APL-130277) | 0/102 (0%) | 0/102 (0%) | 52/102 (51%) |
| Part A Dose Titration: SC (Subcutaneous Apomorphine) | 0/97 (0%) | 1/97 (1%) | 44/97 (45.4%) |
| Part B Treatment: APL (APL-130277) | 0/71 (0%) | 1/71 (1.4%) | 23/71 (32.4%) |
| Part B Treatment: SC (Subcutaneous Apomorphine) | 0/70 (0%) | 1/70 (1.4%) | 37/70 (52.9%) |
| Event | Part A Dose Titration: APL (APL-130277) | Part A Dose Titration: SC (Subcutaneous Apomorphine) | Part B Treatment: APL (APL-130277) | Part B Treatment: SC (Subcutaneous Apomorphine) |
|---|---|---|---|---|
| Foot fractureInjury, poisoning and procedural complications | 0/102 | 0/97 | 0/71 | 1/70 |
| Intestinal obstructionGastrointestinal disorders | 0/102 | 0/97 | 1/71 | 0/70 |
| Intestinal ischaemiaGastrointestinal disorders | 0/102 | 1/97 | 0/71 | 0/70 |
| Event | Part A Dose Titration: APL (APL-130277) | Part A Dose Titration: SC (Subcutaneous Apomorphine) | Part B Treatment: APL (APL-130277) | Part B Treatment: SC (Subcutaneous Apomorphine) |
|---|---|---|---|---|
| NauseaGastrointestinal disorders | 32/102 | 22/97 | 10/71 | 11/70 |
| Injection site haematomaGeneral disorders | 0/102 | 2/97 | 0/71 | 19/70 |
| DyskinesiaNervous system disorders | 8/102 | 7/97 | 8/71 | 14/70 |
| SomnolenceNervous system disorders | 9/102 | 13/97 | 3/71 | 4/70 |
| FatigueGeneral disorders | 6/102 | 10/97 | 4/71 | 4/70 |
| DizzinessNervous system disorders | 10/102 | 4/97 | 2/71 | 3/70 |
| Injection site erythemaGeneral disorders | 0/102 | 6/97 | 1/71 | 5/70 |
| Orthostatic hypotensionVascular disorders | 4/102 | 5/97 | 3/71 | 4/70 |
| FallInjury, poisoning and procedural complications | 1/102 | 1/97 | 4/71 | 1/70 |
| YawningRespiratory, thoracic and mediastinal disorders | 3/102 | 5/97 | 0/71 | 1/70 |
| Age, Categorical(Participants) | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL | Total |
|---|---|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 9 | 8 | 8 | 10 | 9 | 8 | 52 |
| >=65 years | 11 | 10 | 11 | 8 | 9 | 11 | 60 |
| Age, Continuous(Years) | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL | Total |
|---|---|---|---|---|---|---|---|
| Mean | 64.9 ± 8.33 | 63.9 ± 9.99 | 65.0 ± 9.80 | 63.2 ± 6.91 | 63.4 ± 9.71 | 65.6 ± 8.69 | 64.4 ± 8.80 |
| Sex: Female, Male(Participants) | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL | Total |
|---|---|---|---|---|---|---|---|
| Female | 7 | 7 | 6 | 1 | 6 | 7 | 34 |
| Male | 13 | 11 | 13 | 17 | 12 | 12 | 78 |
| Ethnicity (NIH/OMB)(Participants) | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL | Total |
|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 3 | 1 | 1 | 2 | 1 | 8 |
| Not Hispanic or Latino | 19 | 15 | 18 | 16 | 16 | 18 | 102 |
| Unknown or Not Reported | 1 | 0 | 0 | 1 | 0 | 0 | 2 |
| Race (NIH/OMB)(Participants) | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL | Total |
|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| White | 20 | 18 | 19 | 18 | 18 | 19 | 112 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Country(Participants) | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL | Total |
|---|---|---|---|---|---|---|---|
| Austria | 1 | 0 | 2 | 1 | 1 | 0 | 5 |
| Germany | 6 | 2 | 8 | 10 | 5 | 10 | 41 |
| Spain | 7 | 8 | 4 | 3 | 5 | 4 | 31 |
| France | 1 | 1 | 0 | 0 | 0 | 1 | 3 |
| United Kingdom | 1 | 1 | 1 | 3 | 2 | 3 | 11 |
| Italy | 4 | 6 | 4 | 1 | 5 | 1 | 21 |
| Baseline Height (cm)(cm) | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL | Total |
|---|---|---|---|---|---|---|---|
| Mean | 168.05 ± 12.626 | 165.62 ± 12.348 | 171.91 ± 10.260 | 174.78 ± 6.632 | 170.94 ± 9.795 | 171.16 ± 9.929 | 170.39 ± 10.652 |
| Baseline Weight (kg)(kg) | APL-SC | SC-APL | APL-SC-APL-SC | APL-SC-SC-APL | SC-APL-APL-SC | SC-APL-SC-APL | Total |
|---|---|---|---|---|---|---|---|
| Mean | 74.25 ± 16.151 | 70.91 ± 18.624 | 78.45 ± 21.893 | 80.31 ± 11.691 | 83.26 ± 24.383 | 77.14 ± 15.284 | 77.34 ± 18.470 |
6 further baseline measures are reported on the registry.
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Individual Patient Data (IPD) for this study may be made available upon request via the Clinical Study Data Request site.
Supporting information: Study protocol, Sap, Csr
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Sumitomo Pharma America, Inc.