Clinical trial NCT03187301: A Cardiac Safety Study of an Investigational Drug to See How if Affects the Heart in People With Parkinson's Disease Complicated by Motor Fluctuations "OFF" Episodes
Official title: A Phase 2, Randomized, Double-Blind, Placebo Controlled, 3-Period Crossover, Positive Control, QT-Evaluation Study of APL-130277 in Subjects With Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson's Disease
Off Episodes of Parkinson Disease
Keywords: Parkinson's Disease
Off episodes
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2017-06-14
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: A cardiac safety study of an investigational drug to see how it affects the heart in people with Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)

Detailed description: This multi-center, Phase 2, Randomized, Double-Blind, Placebo Controlled, 3-Period Crossover, Positive Control study designed to evaluate the QT interval prolongation potential of 10 mg to 60 mg doses of APL-130277 compared to placebo and the positive control, 400mg moxifloxacin in subjects with Parkinson's Disease (PD) who experience motor fluctuations ("OFF" episodes) The patient is titrated to the highest tolerated dose from 10mg to 60mg, and then is randomized to one of six crossover sequences. Each sequence includes treatment with the following:

1. Treatment A: APL-130277 at the dose determined in the Dose Titration Phase,
2. Treatment B: Matched placebo,
3. Treatment C: A single 400 mg dose of moxifloxacin

Eligibility criteria: Inclusion Criteria:

* 1) Male or female ≥ 18 years of age. 2) Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria (excluding the "more than one affected relative" criterion).

  3) Clinically meaningful response to Levodopa (L-Dopa). Subjects with or without well defined "OFF" episodes, as determined by the Investigator will be allowed.

  4) Receiving stable doses of L-Dopa/carbidopa (immediate or sustained release) administered at least 3 times per day OR Rytary™ administered 3 times per day, for at least 4 weeks before the initial Screening Visit (SV1). Subjects receiving L-Dopa/carbidopa 3 times a day must also be on stable treatment with adjunctive PD medication regimens. These regimens bust me maintained at a stable dose for at least 4 weeks prior to the initial Screening Visit (SV1) with the exception that MAO-B inhibitors must be maintained at a stable level for at least 8 weeks prior to the initial Screening Visit (SV1).

  5) No planned medication change(s) or surgical intervention anticipated during the course of study.

  6) the subject must be able to have a drug withdrawal induced "OFF" episode.

  7) Stage III or less on the modified Hoehn and Yahr scale in the "ON" state.

  8) Mini-Mental State Examination (MMSE) score \> 21.

  9) If female and of childbearing potential, must agree to use one of the following methods of birth control throughout the study and until at least 30 days after final drug administration:
  * Oral contraceptive
  * 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).

    10)Male subjects must be either surgically sterile, agree to be sexually abstinent or use a barrier method of birth control (e.g., condom) from first study drug administration until at least 30 days after final drug administration

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

    12)Able to understand the consent form, and to provide written informed consent.

    13)Must be approved as a satisfactory candidate by the Enrollment Authorization Committee (EAC) and the Sponsor.

Exclusion Criteria:

1. Atypical or secondary parkinsonism
2. Nausea associated with the use of dopamine agonists that requires treatment with an antiemetic.
3. Previous treatment with any of the following: a neurosurgical procedure for PD; continuous subcutaneous (s.c.) apomorphine infusion; or Duodopa/Duopa.
4. Treatment with any form of s.c. apomorphine within 7 days prior to the initial Screening Visit (SV1). Subjects that stopped s.c. apomorphine for any reason other than systemic safety concerns or lack of efficacy may be considered.
5. Contraindications to moxifloxacin or APOKYN®, or hypersensitivity to apomorphine hydrochloride or any macrolide antibiotic or any of the ingredients of APOKYN® (notably sodium metabisulfite).
6. Female who is pregnant or lactating.
7. Participation in a clinical trial within 30 days prior to the initial Screening Visit (SV1), with the exception of clinical studies related to APL-13077.
8. Receipt of any investigational (i.e., unapproved) medication within 30 days prior to the initial Screening Visit (SV1), with the exception of APL-13077.
9. Any selective 5HT3 antagonists (i.e., ondansetron, granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists (including Tigan \[trimethobenzamide\] and domperidone, but excluding quetiapine or clozapine) or dopamine depleting agents within 30 days prior to initial Screening Visit (SV1).
10. Drug or alcohol dependency in the past 12 months.
11. Subject has a history of malignancy within 5 years prior to SV1, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Pituitary tumors of any duration are excluded.
12. Documented abnormalities with ECGs including, arrhythmias, clinically meaningful interval irregularities, structural heart abnormalities ,myocardial infarction, presence or history of a pacemaker, or any abnormality of the ECG that in the opinion of the Investigator, would interfere with the ability to measure the QT interval, or correct the QT interval for heart rate.
13. Male subjects with a screening corrected QT interval using Fridericia's formula (QTcF) of ≥ 450 ms; female subjects with a screening QT interval ≥ 470 ms. Eligibility will be based on the core laboratory ECG interpretation report.
14. HR at screening \< 45 bpm or \> 100 bpm.
15. QRS duration at screening \>120 ms
16. PR interval at screening \>200 ms.
17. Subjects with a history of cataplexy, unexplained syncope or seizures.
18. Family history of sudden cardiac death.
19. Heart failure (NYHA Class II or greater) and/or a myocardial infarction.
20. Current use of any concomitant mediations that prolong the QT/QTc interval. Refer to https://crediblemeds.org for listing.
21. History of additional risk factors for TdP (i.e., heart failure, hypokalemia, family history of Long QT Syndrome).
22. Clinically significant medical, surgical, or laboratory abnormality in the opinion of the Investigator.
23. Subject has a positive screening laboratory test result for human immunodeficiency virus (HIV).
24. Subject has a positive screening laboratory test result for hepatitis B surface antigen or hepatitis C antibodies and has liver function test results at screening above the ULN for the reference laboratory.
25. Major psychiatric disorder including, but not limited to, dementia, bipolar disorder, psychosis (including Parkinson's disease psychosis), or any disorder that, in the opinion of the Investigator, requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.
26. History of clinically significant impulse control disorder(s).
27. Dementia that precludes providing informed consent or would interfere with participation in the study.
28. Current suicidal ideation within one year prior to the second Screening Visit (SV2) as evidenced by answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 5 years.
29. Donation of blood plasma in the 30 days prior to first dosing.

Primary outcomes:
measure: Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis)
timeFrame: Baseline to 15, 30, 45, 60 mins and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits.
measure: Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis)
timeFrame: Baseline to 60 mins and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits.
Secondary outcomes:
measure: Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277
timeFrame: Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.
measure: Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277
timeFrame: Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.
measure: AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277
timeFrame: Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.
measure: Number of Patients With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From first dose of study medication up to last study visit for Randomized Crossover Assessment Phase, approximately up to 2 weeks
measure: ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase
timeFrame: Baseline and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
measure: Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase
timeFrame: Baseline (pre-dose) and at 30, 60 and 90 minutes after dosing during the Dose Titration Phase.
measure: Median Time to 'ON' During the Dose Titration Phase
timeFrame: Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.
measure: Median Duration of 'ON' During the Dose Titration Phase
timeFrame: Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.
measure: ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase
timeFrame: Baseline and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
measure: ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase
timeFrame: Baseline (pre-dose P1V1) and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
measure: ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase
timeFrame: Baseline and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
measure: ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase
timeFrame: Baseline and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Movement Disorders Center of Arizona
state: Arizona
city: Little Rock
country: United States
facility: Clinical Trials, Inc.
state: Arkansas
city: Fountain Valley
country: United States
facility: The Parkinson's and Movement Disorder Institute
state: California
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Hallandale Beach
country: United States
facility: MD Clinical
state: Florida
city: Orlando
country: United States
facility: Bioclinica Reserach
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Baton Rouge
country: United States
facility: The NeuroMedical Center, PC
state: Louisiana
city: Farmington Hills
country: United States
facility: QUEST Research Institute
state: Michigan
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants
state: Texas
city: Arcugnano
country: Italy
facility: Casa di Cura villa Margherita (Neurologia)
city: Cassino
country: Italy
facility: Centro Ricerche San Raffaele
city: Chieti
country: Italy
facility: Agine Research Center, University Foundahon Chica-Pescara, Behavioral Neurology and Movement Disorders Unit
city: Rome
country: Italy
facility: Neurologia, Policlinico Tor Vergata
city: Rome
country: Italy
facility: IRCCS San Raffaele Pisana,Clinical Trial Center
Study officials:
affiliation: Sunovion Pharmacetuicals Inc.
name: CNS Medical Director
role: STUDY_CHAIR
References:
citation: Stocchi F, Peckham EL, De Pandis MF, Sciarappa K, Kleiman R, Agbo F, Olanow CW, Blum D, Navia B. A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease. Clin Pharmacol Drug Dev. 2022 Sep;11(9):1068-1077. doi: 10.1002/cpdd.1147. Epub 2022 Jul 28.