| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A progressive disease of the nervous system characterised by tremor, muscular rigidity, and slow, imprecise movement. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of 2 doses of PXT002331 as an adjunct to levodopa in the reduction of OFF time in subjects with PD. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the effects of 2 doses of PXT002331 as an adjunct to levodopa on LID in subjects with PD.
To assess the pharmacokinetic profile of PXT002331 in subjects with PD.
To assess the safety and tolerability of 2 doses of PXT002331 in subjects with PD.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects will be:
1.1. males or females of non-childbearing potential diagnosed after the age of 30 years with idiopathic PD (ie, not induced by drugs or other diseases) as defined by fulfilling Steps 1 and 2 of the United Kingdom (UK) PD Society Brain Bank clinical diagnostic criteria
1.2. between 35 and 85 years of age, inclusive, at the time of signing informed consent
2. Subjects will have:
2.1. a documented medical history of idiopathic PD for at least 3 years
2.2. disease severity of 2 to 4 on the modified Hoehn and Yahr scale when in the OFF state
2.3. been treated with a stable regimen of levodopa-containing therapy and should maintain the stability of their therapy throughout the study according to their usual regimen (dose level and frequency). The maximum allowed total levodopa dose must be ≤1600 mg per day.
2.3.1. subjects who are on an immediate-release formulation of levodopa-containing therapy, NOT including Apodespan PR (or equivalent), must be receiving at least 3 doses per day and must be on a stable dose for at least 2 weeks prior to the first screening visit.
2.3.2. subjects who are on a long-acting formulation of levodopa-containing therapy, including Apodespan PR (or equivalent), must be on a stable dose for at least 6 weeks prior to the first screening visit
2.4. experienced motor fluctuations with wearing off over a period of at least 3 months prior to randomisation, with a minimum daily OFF time of at least 2 hours per 24 hours, while awake (as measured during the Screening Period by subject home diary [Hauser diary] on each of the 3 consecutive days immediately preceding the baseline visit; ≥2 hours OFF time on each of the 3 days)
2.5. experienced predictable OFF periods, as assessed at screening and baseline by a MDS UPDRS Part IV B, Question 4.5 rating of 1 or 2
2.6. experienced LID over a period of at least 3 months prior to randomisation, with a minimum daily ON time with dyskinesia (troublesome and/or non troublesome) lasting at least 2 hours per 24 hours, while awake (as measured during the Screening Period by subject home diary [Hauser diary] on each of the 3 consecutive days immediately preceding the baseline visit; ≥2 hours ON time with dyskinesia on each of the 3 days)
2.7. experienced significant time spent with LID, as assessed at screening and baseline by MDS UPDRS Part IV A, Question 4.1 score ≥1
2.8. experienced impact from LID on daily function, as assessed at screening and baseline by MDS UPDRS Part IV A, Question 4.2 score ≥2
2.9. been on a stable regimen of any additional permitted anti-Parkinsonian drugs (ie, peripheral decarboxylase inhibitors, dopamine agonists [except apomorphine], MAO-B inhibitors [except safinamide] or COMT inhibitors) for at least 4 weeks prior to baseline.
3. Female subjects will be women of non-childbearing potential, defined as follows:
3.1. permanently sterile following hysterectomy, bilateral salpingectomy, bilateral oophorectomy or confirmed tubal occlusion (not tubal ligation)
3.2. postmenopausal, defined as at least 12 months post cessation of menses (without an alternative medical cause)
3.2.1. postmenopausal status will be confirmed with a screening serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL.
4. Subjects must pass a Hauser diary concordance test, defined as at least 75% concordance in ON/OFF ratings between rater and subject over the 4 assessments made over a 2-hour period. Additionally, subjects must be concordant on at least 1 OFF period and 1 ON period across the 4 assessments.
5. If needed, in the opinion of the Investigator, subjects must have a caregiver (eg, family member, social worker, case worker or nurse that spends >4 hours/week with the subject) considered reliable by the Investigator in providing support to the subject to ensure compliance with study drug, assessment visits and protocol procedures.
6. Subjects are able, with or without the help of a caregiver, to understand the purpose and risks of the study and provide signed and dated informed consent and authorisation to use confidential health information in accordance with national and local subject privacy regulations. |
|
| E.4 | Principal exclusion criteria |
Medical conditions and diagnostic tests:
1. Subjects with atypical, secondary or drug-induced Parkinsonism (eg, metoclopramide, flunarizine), metabolic identified neurogenetic disorders (eg, Wilson’s disease), encephalitis, or Parkinson Plus syndromes, or other forms of atypical Parkinsonian syndromes (eg, progressive supranuclear palsy and multiple system atrophy)
2. Subjects with a Mini-Mental State Examination (MMSE) score <25
3. Subjects who have Long QT syndrome or a QTcF >450 ms (males) or >470 ms (females) that is considered clinically significant by the Investigator at screening or baseline
4. Subjects who have, or who have a history of, any clinically significant hepatic or gallbladder disorder, as determined by the Investigator
5. Subjects who have dementia, currently active psychosis or hallucinations. Previous psychotic episodes that were brief and considered drug-induced are not exclusionary; inclusion of such subjects is at the Investigator’s discretion.
6. Suicide attempt within 1 year prior to the first screening visit, or severe suicidal ideation within 6 months prior to the first screening visit (ie, the subject answers “yes” to Questions 4 or 5 in the Baseline/Screening C SSRS assessment performed at the first screening visit), or subject is at significant risk of suicidal behaviour in the opinion of the Investigator
7. Subject has a current diagnosis of epilepsy, has a history of seizures as an adult, has a history of stroke or has had a transient ischemic attack within 1 year prior to the first screening visit
8. Subjects who have a known genetic disorder of human UDP-glucoronosyltransferase
9. Any known contraindication to the use of levodopa, including a history of malignant melanoma or a history of narrow-angle glaucoma
10. Subject has cancer, with the exception of the following: basal cell carcinoma or successfully treated squamous cell carcinoma of the skin; cervical carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years
11. Positive serology test (hepatitis B virus surface antigen [HBsAg], hepatitis C virus [HCV] antibody, human immunodeficiency virus [HIV] 1 or 2 antibodies)
12. Subjects who have had a clinically significant illness within 4 weeks of first dose, as determined by the Investigator
13. Subjects with scheduled surgeries during the study period
14. Any advanced, severe or unstable disease (other than PD) that may interfere with the primary and secondary study outcome evaluations
Prior/concomitant medication and surgery:
15. Subjects who have undergone prior neurosurgical operation for PD or transcranial magnetic stimulation
16. Subjects currently taking (or expected to be administered during the course of the study) any of the prohibited medications.
Prior/concurrent clinical study experience:
17. Subjects who are participating in another clinical study (eg, attending follow-up visits) or who have participated in a clinical study involving administration of an investigational drug (new chemical entity) in the past 3 months prior to the baseline visit
18. Subjects who have previously taken part in or withdrawn from this study. Re-screening may be permitted on a case-by-case basis based on approval from the Sponsor. Re-screening may only be
performed once per subject and applies only to screen failures from the study.
Other exclusions:
19. Male subjects who do not agree to use a barrier method of contraception (ie, a condom with spermicide) in addition to a second highly effective method of contraception used by their female partners or to refrain from donating sperm from the time of the first dose until 3 months after the final dosing occasion.
20. Female subjects of childbearing potential
21. Subjects who have donated:
21.1. blood in the 3 months prior to the first screening visit
21.2. plasma in the 7 days prior to the first screening visit
21.3. platelets in the 6 weeks prior to the first screening visit
22. Subjects who have a significant history of alcoholism or drug/chemical abuse, as determined by the Investigator
23. Positive test for ethanol or drugs of abuse at the first screening visit or at the baseline visit. The following items would not necessarily be an exclusion to participation in the study, depending on the subject’s known use and discussion with the Investigator and medical monitor: cannabinoids, benzodiazepines, barbiturates, opiates, nicotine, and amphetamines for treatment of Attention Deficit Hyperactivity Disorder (ADHD). Use of cocaine, phencyclidine, methadone or amphetamines (for non-medical use) is unconditionally exclusionary.
24. Subjects who are pregnant (as determined by positive serum pregnancy test at screening and/or positive urine pregnancy test at baseline), breastfeeding or lactating
25. Subjects who, in the opinion of the Investigator, should not participate in this study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy outcome measure will be change from baseline to end of Treatment Period (Day 28) in the daily awake OFF time based on subject Hauser diary entries (average of 3 consecutive days). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to Day 14
Baseline to Day 28 |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline to end of Treatment Period (Day 28) in the total objective score (Parts 3 and 4) for dyskinesia impairment and disability assessed by Unified Dyskinesia Rating Scale (UDysRS)
• Change from baseline to end of Treatment Period (Day 28) in UDysRS total score
• Proportion of subjects achieving a clinically significant reduction in OFF time (at least 1 hour as defined by Hauser et al.15) from baseline to end of Treatment Period (Day 28) based on subject Hauser diary entries (average of 3 consecutive days)
• Change from baseline to end of Treatment Period (Day 28) in the percentage of daily awake OFF time based on subject Hauser diary entries (average of 3 consecutive days)
• Change from baseline to end of Treatment Period (Day 28) in the daily awake ON time without troublesome dyskinesia (defined as ON time without dyskinesia plus ON time with non-troublesome dyskinesia) based on subject Hauser diary entries (average of 3 consecutive days)
• Change from baseline to end of Treatment Period (Day 28) in the percentage of daily awake ON time without troublesome dyskinesia (defined as ON time without dyskinesia plus ON time with non-troublesome dyskinesia) based on subject Hauser diary entries (average of 3 consecutive days) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Baseline to Day 14
• Baseline to end of Treatment Period (Day 28)
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study will be defined as the date of the final clinical database lock. This provides for a single and conservative definition across all study sites (protocol section 15). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
