Primary ObjectiveThe primary objective of the study is to determine the effect of ND0612 on daily *ON* time without troublesome dyskinesia (defined as the sum of "ON" time without dyskinesia and *ON* time with non-troublesome dyskinesia)…
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
DBDD Maintenance Period (DB W12) in the mean daily "ON" time without
troublesome dyskinesia ("GOOD ON") adjusted to subject's waking hours and
normalized to 16 waking hours, based on subject's "ON/OFF" diary assessments on
the 3 consecutive days before the visit.
"GOOD ON" is defined as the sum of "ON" time without dyskinesia and "ON" time
with non-troublesome dyskinesia.
Secondary outcome
The key secondary efficacy endpoint is the change from Baseline to the end of
the DBDD Maintenance Period (DB W12) in the mean daily "OFF"
time adjusted to subject's waking hours and normalized to 16 waking hours,
based on subject's "ON/OFF" diary assessments on the 3 consecutive days before
the visits.
Background summary
Parkinson*s disease (PD) is a neurodegenerative movement disorder characterized
by tremor, bradykinesia, muscular rigidity, and gait impairment as a result of
marked dopamine deficiency in the basal ganglia of the brain due to the loss of
dopaminergic neurons. Dopamine itself does not cross the blood-brain barrier,
but its metabolic precursor, levodopa (LD), can permeate into striatal tissue
and has, therefore, been an important drug in the treatment of the disease. For
the past 40 years, LD (or L-Dopa) has remained the most effective therapy for
the treatment of PD.
Attempts are being made to provide more sustained dopamine concentrations in
the central nervous system, known as continuous dopaminergic stimulation, by
using novel LD preparations. The current available long-acting oral LD
therapies failed to reduce the risk of motor complications in controlled
trials. In contrast, long lasting and dramatic reductions in motor
complications associated with reduced dyskinesias and *OFF* periods (phases
with no response to medication and significant motor symptoms) have been
observed in PD subjects when treated with continuous infusion of LD
(intravenous or intraduodenal) or dopamine agonists. Unfortunately, the
infusion approaches to date have inherent limitations in that they are neither
convenient nor practical treatment options and dopamine agonists fail to reach
the efficacy of LD and bear major adverse effects.
LD and CD have been used extensively in humans by the oral route. NeuroDerm,
Ltd. (NeuroDerm) is developing an LD/CD solution for continuous subcutaneous
(SC) administration via infusion pump system for the treatment of idiopathic
PD. The LD/CD solution ND0612 contains 60 mg/mL LD and 7.5 mg/mL of CD. ND0612
is being developed for patients with LD-responsive PD who do not have
satisfactory control of debilitating motor fluctuations and hyper/dyskinesia
despite optimized treatment with commercially available PD products.
Non-clinical and clinical studies to date support the continued evaluation of
ND0612 as a way to provide continuous and stable sources of LD for transport to
the brain for the treatment of PD.
Study objective
Primary Objective
The primary objective of the study is to determine the effect of ND0612 on
daily *ON* time without troublesome dyskinesia (defined as the sum of "ON" time
without dyskinesia and *ON* time with non-troublesome dyskinesia) using
subject-completed *ON/OFF* diary assessments of motor function in subjects with
Parkinson*s disease (PD) experiencing motor fluctuations.
Secondary Objectives
Key secondary objective of the study is to determine the effect of ND0612 on
daily *OFF* time in subjects with PD experiencing motor fluctuations using
subject completed *ON/OFF* diary assessments of motor function.
Other secondary objectives are to determine the effect of ND0612 on:
• Movement Disorder Society-Unified Parkinson*s Disease Rating Scale
(MDS-UPDRS) Part II (Motor Aspects of Experiences of Daily Living [M-EDL]).
• Patient Global Impression of Change (PGIC).
• Clinical Global Impression of Improvement (CGI-I).
• MDS-UPDRS Part III (Motor Examination), measured in the *OFF* state or
approximately 15 minutes before the next encapsulated oral dose (LD/CD or
placebo).
• Daily *ON* time without dyskinesia (troublesome or non-troublesome) using
subject-completed *ON/OFF* diary assessments of motor function.
• Proportion of responders in *OFF* time.
• Parkinson*s disease Quality of Life (QoL) based on the 39-item PD Quality of
Life questionnaire (PDQ-39).
• The Parkinson*s Disease Sleep Scale (PDSS).
Study design
This study is comprised of 6 periods:
(1) a Screening Period (1-4 weeks);
(2) an open-label oral IR-LD/CD Adjustment Period (6 weeks) composed of 4 weeks
titration and 2 weeks of stable oral IR-LD/CD dose
(3) an open-label ND0612 Conversion Period (6 weeks) composed of 4 weeks
titration and 2 weeks of stable ND0612 and oral IR-LD/CD dose.
(4) a randomized, double-blind, double-dummy, active-controlled Maintenance
Period (12 weeks);
(5) an optional open-label Treatment Extension Period (1 year); and
(6) a Safety Follow-up Period (up to 4,5 years).
All subjects must have a named study partner (e.g., spouse, relative, friend,
neighbor, or
caregiver) who is willing and able to support the subject during the study
Intervention
Subjects will be randomized in a 1:1 ratio at the Randomization visit (ND
D42/DB D1) to 1 of 2 treatment groups:
• Test Group (Group A): ND0612 infusion + placebo IR-LD/CD (white) + active
IR-LD/CD (grey)
• Control Group (Group B): IR-LD/CD (white) + placebo infusion + placebo
IR-LD/CD (grey)
Study burden and risks
Patients are expected to:
-Complete questionnaires:
-Parkinson*s Disease Sleep Scale (5x)
-Quality of Life in Parkinson*s Disease (5x)
-EuroQol 5-dimensions, 5-levels Quality of Life Questionnaire (5x)
-keep a diary
-Provide urine samples (8x)
-have an ECG (5x)
-physical and neurological examination (5x)
-have blood draws 8x
- have subcutaneous placements of the infusion pump each day (with help of a
study partner). Patient and partner will need to spend time training to learn
how to operate the infusion pump. This will take at least 4 sessions with a
minimum of 6 hours in total.
The patient will have approximately 22 scheduled visits to the hospital and 9
telephone visits. If patients choose to participate in the optional treatment
extension period they will have an additional 20 hospital and 9 telephone
visits during up to 4,5 years.
Continuous infusion of LD/CD with Duodopa/Duopa has proven efficacious in Phase
3 clinical trials and is marketed across the world. Duodopa/Duopa is
administered directly to the jejunum via a PEG-J tube, and thus requires
surgical intervention, and is associated with potentially
serious surgical and gastrointestinal complications, including bezoar, ileus,
implant site erosion/ulcer, intestinal hemorrhage, intestinal ischemia,
intestinal obstruction, perforation of the intestine or adjacent anatomical
structures, pancreatitis, pneumoperitoneum and postoperative wound infection.
Some of these adverse events have resulted in serious outcomes, including
prolonged hospitalization, surgery and/or death.
ND0612 treatment is administered subcutaneously, therefore avoiding the side
effects and burden of a surgical intervention. Data accumulated to date
suggests that continuous ND0612 infusion is associated with a more benign
safety profile that relates mainly to infusion site infections (cellulitis and
abscess) that have been treated successfully with antibiotics and /or drainage
and have resolved without any sequala, and transient local effects including
subcutaneous nodules, infusion site erythema, edema, pain, and hematomas that
resolve spontaneously.
Due to the above, the overall risk benefit balance for study ND0612-317 is
considered to be favorable.
Ruhrberg Science building, Pekeris St. 3
Rehovot 7670212
IL
Ruhrberg Science building, Pekeris St. 3
Rehovot 7670212
IL
Listed location countries
Age
Inclusion criteria
1. Male and female subjects with PD of any race at least 30 years of age who
sign an Institutional Review Board/Ethics Committee-approved informed consent
form (ICF).
2. Parkinson*s disease diagnosis consistent with the UK Brain Bank Criteria.
3. Modified Hoehn and Yahr scale in *ON* stage <= 3.
4. Subjects must experience motor fluctuations and experience an average of at
least 2.5 hours daily (with a minimum of 2 hours every day) in the *OFF* state
during the waking hours as confirmed by an adequately completed *ON/OFF* diary
over 3 days.
5. Subject treatment should be at least 4 doses/day of LD/ Dopa Decarboxylase
Inhibition (DDI) (or at least 3 doses/day of extended release LD/DDI, e.g.,
Rytary) and at least 400 mg/day of LD, or equivalent according to the
conversion table, and, according to the Investigator*s judgement, the subject
experiences motor fluctuations that cannot be further improved by adjusting
anti-PD medications.
6. Subjects and/or study partners have no impediment that may prevent them from
operating the pump system.
7. Subjects and/or study partners must demonstrate ability to keep accurate
diary entries of PD symptoms (*ON/OFF* diaries) with at least 75% concordance
with the the Blinded Efficacy Rater by the end of the diary training session
during the Screening Period, including at least 1 *OFF* assessment.
8. Mini Mental State Examination (MMSE) score >= 24.
9. Female subjects must be surgically sterile (hysterectomy, bilateral
oophorectomy, or tubal ligation); postmenopausal (defined as cessation of
menses for at least 1 year); or willing to practice a highly effective method
of contraception. All female subjects must be non-lactating and not pregnant
and have a negative urine pregnancy test at Screening and at Enrollment (IR1
D1). Female subjects of childbearing potential must practice a highly effective
method of contraception (such methods include combined [estrogen and
progestogen containing] hormonal contraception associated with inhibition of
ovulation: oral / intravaginal; transdermal / progestogen-only hormonal
contraception associated with inhibition of ovulation: oral / injectable;
implantable / intrauterine device [IUD] / intrauterine hormone-releasing system
[IUS]/ bilateral tubal occlusion / vasectomized partner/ sexual abstinence)
from 1 month before Enrollment (IR D1 /V2) until 1 month after the last dose of
study treatment. Alternatively, true abstinence is acceptable when it is in
line with the subject*s preferred and usual lifestyle. If a subject is usually
not sexually active but becomes active, the subject and sexual partner must
comply with the contraceptive requirements detailed above.
10. Willingness and ability to comply with study requirements.
11. Subjects must have a named study partner that signed the ICF.
12. Approval for entry into the study by an independent EAC.
Exclusion criteria
1. Atypical or secondary Parkinsonism.
2. Acute psychosis or troublesome hallucinations in the past 6 months.
3. Subjects with clinically significant or unstable medical, surgical, or
psychiatric condition or laboratory abnormalities which, in the opinion of the
Investigator or the EAC, represents a safety risk, makes the subject unsuitable
for study entry, or potentially unable to complete all aspects of the study.
4. Clinically significant ECG abnormalities.
5. Renal or liver dysfunction that may alter drug metabolism including
Screening Visit serum levels of creatinine > 1.5 mg/dL, aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 2 × upper limit of
normal, and total bilirubin > 2.5 mg/dL.
6. Any malignancy in the 5 years before enrollment, except basal cell carcinoma
of the skin, squamous cell carcinoma in situ, or cervical carcinoma in situ
that have been successfully treated.
7. Use of subcutaneous (SC) apomorphine injections, sublingual apomorphine, or
inhaled LD within 4 weeks before the enrollment.
8. Concomitant therapy or within 28 days before enrollment with:
metoclopramide, reserpine, methylphenidate, or amphetamines, well as
neuroleptics; exception in case of Quetiapine and Pimavanserin use: (1) allowed
only in case it had been used for a period of at least 3 months before
enrollment, (2) subject is on stable therapy for at least 3 months (3)
underlying psychosis to be under control and anticipating no changes to the
dosage of the medication throughout the study.
9. Subjects with a history of alcohol or substance abuse within the past 12
months.
10. Subjects who have taken experimental medications within 30 days before
enrollment.
11. Subjects who have previously participated in studies ND0612H-006 and/or
ND0612H-012.
12. Subjects who have previously undergone treatment for PD with a surgical
intervention (e.g., pallidotomy, thalamotomy, transplantation, deep brain
stimulation procedures), gene therapy, Duodopa®/Duopa®, or continuous
dopaminergic or apomorphine infusion. Subjects who have discontinued Duodopa®/
Duopa® treatment at least 6 months before enrollment and have undergone stoma
closure surgery at least 6 months before enrollment, may be included in this
study. Subjects who are planning to undergo treatment for PD with a surgical
intervention will be enrolled at the Investigator*s discretion.
13. Subjects with severe disabling dyskinesias, based on Investigator's
discretion.
14. History of significant skin conditions or disorders (e.g., psoriasis,
atopic dermatitis, etc.) or evidence of different lesions (e.g., sunburn, acne,
scar tissue, tattoo, open wound, branding, or pigmentation) that, in the
Investigator's opinion, would interfere with the infusion of the study drug or
could interfere with study assessments.
15. Subjects who do not have sufficient SC tissue for SC infusion treatment.
16. Use of non-selective monoamine oxidase inhibitors (e.g., phenelzine,
isocarboxazid, tranylcypromine) within 4 weeks before enrollment.
17. Use of monoamine-depleting agents (e.g., reserpine, tetrabenazine,
deutetrabenazine, valbenazine, xenazine) within 4 weeks before enrollment.
18. Current or previous diagnosis of Dopamine Dysregulation Syndrome or Impulse
Control Disorder.
19. Impulse control disorder within the past 2 years, if considered clinically
significant by the investigator.
20. Subjects who answered "yes" to questions 4 or 5 of the C-SSRS within the
last 5 years.
21. Known allergy to the study drug or placebo or any of their excipients.
22. Subjects with narrow angle glaucoma
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-004156-37-NL |
| CCMO | NL71718.018.19 |