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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

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ClinicalTrials.gov Identifier: NCT03187301
Recruitment Status : Completed
First Posted : June 14, 2017
Last Update Posted : November 19, 2018
Sponsor:
Information provided by (Responsible Party):
Sunovion

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)

Condition or disease Intervention/treatment Phase
Parkinson's Disease Off Episodes of Parkinson Disease Drug: APL-130277 Drug: Placebo Drug: Moxifloxacin Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double blind period
Primary Purpose: Treatment
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)
Actual Study Start Date : August 3, 2017
Actual Primary Completion Date : December 21, 2017
Actual Study Completion Date : December 21, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: APL-130277
APL-130277 at the dose determined in the dose titration phase
Drug: APL-130277
APL-130277 single dose

Placebo Comparator: Placebo
Placebo
Drug: Placebo
Placebo single dose

Active Comparator: moxifloxacin
moxifloxacin at a single 400mg dose
Drug: Moxifloxacin
moxifloxacin 400mg single dose




Primary Outcome Measures :
  1. Time-matched change from baseline in QTc, placebo-adjusted and corrected for HR based on the Fridericia correction method (QTcF) method (ΔΔQTcF). Assay sensitivity will be demonstrated by inclusion of a positive control, moxifloxacin. [ Time Frame: Up to 24 hours ]
    Time-matched change from baseline in QTc, placebo-adjusted and corrected for HR based on the Fridericia correction method (QTcF) method (ΔΔQTcF). Assay sensitivity will be demonstrated by inclusion of a positive control, moxifloxacin.


Secondary Outcome Measures :
  1. Cmax [ Time Frame: Day 1 ]
    Cmax

  2. Tmax [ Time Frame: Day 1 ]
    Tmax

  3. AUC0-T [ Time Frame: Day 1 ]
    AUC0-T

  4. Safety and tolerability as measured primarily by number of subjects with treatment emergent AEs [ Time Frame: up to end of study ]
    including AEs reported as a result of clinically significant laboratory tests, 12-lead ECGs, physical examinations, vital signs (including BP, HR, RR, body temperature and weight) , SAEs, and AE leading to discontinuation.

  5. ECG assessments including QTc with Bazett correction (QTcB), heart rate, PR interval, QRS interval, Uncorrected QT interval [ Time Frame: upto 4 weeks ]
    ECG assessments including QTc with Bazett correction (QTcB), heart rate, PR interval, QRS interval, Uncorrected QT interval, ECG morphology and presence of cardiac arrahythmias such as ventricular tachycardia or Torsade de Pointes (TdP)

  6. MDS-UPDRS Part III change from pre-dose to 30, 60, 90 minutes after dosing during the Titration Phase at the highest tolerated APL-130277 dose level and the lowest APL-130277 dose resulting in a full "ON" [ Time Frame: upto 4 weeks ]
    The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III is a scale used to assess motor function.

  7. Time to "ON" during Titration Phase at the highest tolerated APL-130277 dose level and the lowest APL-130277 dose resulting in a full "ON" [ Time Frame: upto 4 weeks ]
    Time to "ON" during Titration Phase at the highest tolerated APL-130277 dose level and the lowest APL-130277 dose resulting in a full "ON"

  8. Duration of "ON" during Titration Phase at the highest tolerated APL-130277 dose level and the lowest APL-130277 dose resulting in a full "ON". [ Time Frame: upto 4 weeks ]
    Duration of "ON" during Titration Phase at the highest tolerated APL-130277 dose level and the lowest APL-130277 dose resulting in a full "ON".



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03187301


Locations
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United States, Arizona
Movement Disorders Center of Arizona
Scottsdale, Arizona, United States, 85258
United States, Arkansas
Clinical Trials, Inc.
Little Rock, Arkansas, United States, 72205
United States, California
The Parkinson's and Movement Disorder Institute
Fountain Valley, California, United States, 92708
United States, Florida
Parkinson's Disease and Movement Disorders Center of Boca Raton
Boca Raton, Florida, United States, 33486
MD Clinical
Hallandale Beach, Florida, United States, 33009
Bioclinica Reserach
Orlando, Florida, United States, 32806
United States, Georgia
Atlanta Center for Medical Research
Atlanta, Georgia, United States, 30331
United States, Louisiana
The NeuroMedical Center, PC
Baton Rouge, Louisiana, United States, 70810
United States, Michigan
QUEST Research Institute
Farmington Hills, Michigan, United States, 48334
United States, Texas
Central Texas Neurology Consultants
Round Rock, Texas, United States, 78681
Italy
Casa di Cura villa Margherita (Neurologia)
Arcugnano, Italy, 36057
Centro Ricerche San Raffaele
Cassino, Italy, 03043
Agine Research Center, University Foundahon Chica-Pescara, Behavioral Neurology and Movement Disorders Unit
Chieti, Italy
Neurologia, Policlinico Tor Vergata
Rome, Italy, 00133
IRCCS San Raffaele Pisana,Clinical Trial Center
Rome, Italy, 00163
Sponsors and Collaborators
Sunovion
Investigators
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Study Chair: CNS Medical Director Sunovion Pharmacetuicals Inc.

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Responsible Party: Sunovion
ClinicalTrials.gov Identifier: NCT03187301     History of Changes
Other Study ID Numbers: CTH-201
2016-001762-29 ( EudraCT Number )
First Posted: June 14, 2017    Key Record Dates
Last Update Posted: November 19, 2018
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sunovion:
Parkinson's Disease
Off episodes

Additional relevant MeSH terms:
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Apomorphine
Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Emetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Dopamine Agonists
Dopamine Agents