Clinical Trial Results:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 3-Period Crossover, Positive Control, QT-Evaluation Study of APL-130277 in Patients with Parkinson’s Disease Complicated by Motor Fluctuations ("OFF" Episodes)
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Summary
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EudraCT number |
2016-001762-29 |
Trial protocol |
IT |
Global end of trial date |
21 Dec 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Jan 2019
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First version publication date |
06 Jan 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CTH-201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03187301 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
CTH-201: CTH-201 | ||
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Sponsors
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Sponsor organisation name |
Sunovion Pharmaceuticals Inc.
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Sponsor organisation address |
84 Waterford Drive, Marlboro, United States, 01752
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Public contact |
CNS Medical Director, SUNOVION PHARMACEUTICALS, +01 1-866-503-6351, ClinicalTrialDisclosure@sunovion.com
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Scientific contact |
CNS Medical Director, SUNOVION PHARMACEUTICALS, +01 1-866-503-6351, ClinicalTrialDisclosure@sunovion.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Dec 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Dec 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Dec 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective is to evaluate the effect of APL-130277 compared to placebo on QTc intervals in subjects with Parkinson’s disease (PD) complicated by motor fluctuations.
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Protection of trial subjects |
The study was conducted according to the protocol, ICH Good Clinical Practice (GCP), ICH guidelines, and the ethical principles that have their origin in the Declaration of Helsinki
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
17 Oct 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Italy: 19
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Country: Number of subjects enrolled |
United States: 29
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Worldwide total number of subjects |
48
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EEA total number of subjects |
19
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
26
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From 65 to 84 years |
21
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85 years and over |
1
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Recruitment
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Recruitment details |
Patients with Parkinson’s disease (PD) complicated by motor fluctuations (‘OFF’ episodes) were recruited in 13 study sites in Italy and the United States, starting April 2017. The study was completed in December 2017. Approval was obtained from the Enrollment Adjudication Committee and Sponsor prior to enrollment of each patient. | ||||||||||||||
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Pre-assignment
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Screening details |
Dose Titration Phase: individual responses to single doses of APL 130277 were evaluated at 5 mg increments up to 40 mg and then 10 mg increments up to 60 mg until a full ‘ON’ was achieved. If tolerated, patients were titrated to a supratherapeutic dose (up to 60 mg) which was 1 or 2 levels above the initial dose producing an ‘ON’ response. | ||||||||||||||
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Period 1
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Period 1 title |
Period 1
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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APL-130277 (Titration) | ||||||||||||||
Arm description |
Patients were titrated to an effective and tolerable dose of APL-130277. Patients were dosed with increasing doses of APL 130277 starting with 10 mg at Titration Visit (TV) 1 up to a maximum of 60 mg. Patients who did not achieve a complete and full ‘ON’ response with the 10 mg APL 130277 dose at TV1 restarted their normal PD medications and were asked to return to the clinic the next business day for TV2, to assess the next highest dose. The evaluation continued sequentially with 15 mg (TV2), 20 mg (TV3), 25 mg (TV4), 30 mg (TV5), 35 mg (TV6), 40 mg (TV7), 50 mg (TV8), and 60 mg (TV9) doses of APL-130277 until a full ‘ON’ state was achieved. If tolerated, patients were titrated to a supratherapeutic dose (up to 60 mg) which was 1 or 2 levels above the initial dose producing an ‘ON’ response. If the patient was unable to tolerate 1 or either of the 2 additional dose levels after reaching a full “ON” state patients were randomized to the previous tolerable dose. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
APL-130277
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Investigational medicinal product code |
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Other name |
Apomorphine sublingual film
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Pharmaceutical forms |
Sublingual film
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Routes of administration |
Sublingual use
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Dosage and administration details |
Patients received single doses of APL-130277 from 10 mg to 60 mg sequentially as required to elicit a full ‘ON’ response.
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Period 2
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Period 2 title |
Period 2
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Is this the baseline period? |
Yes [1] | ||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||
Roles blinded |
Subject, Investigator, Carer | ||||||||||||||
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Arms
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Arm title
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Overall Crossover | ||||||||||||||
Arm description |
Patients who successfully completed the Dose Titration Phase of the study were randomized to 1 of 6 treatment sequences in the single-dose Randomized Crossover Assessment Phase. Following confirmation by both the Investigator and the patient that the patient was in the ‘OFF’ state, the patient was dosed according to the patient’s random treatment assignment with 1. APL-130277 at the dose determined in the Dose Titration Phase; OR 2. Matched placebo APL-130277; OR 3. A single 400 mg dose of moxifloxacin. Patients were randomized in equal numbers to 6 possible sequences of the above 3 study treatments determined by a 3-way balanced crossover design. There was a 3-day washout period between treatment period dosing visits. Dosing of APL-130277 and placebo was double-blinded, and dosing of moxifloxacin was open-label. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
APL-130277
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Investigational medicinal product code |
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Other name |
Apomorphine sublingual film
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Pharmaceutical forms |
Sublingual film
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Routes of administration |
Sublingual use
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Dosage and administration details |
Patients received a single dose of APL-130277 in the relevant treatment period dosing visit.
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Investigational medicinal product name |
Moxifloxacin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Patients received a 400 mg dose of moxifloxacin in the relevant treatment period dosing visit.
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Investigational medicinal product name |
placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Sublingual film
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Routes of administration |
Sublingual use
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Dosage and administration details |
Patients received a single dose of placebo in the relevant treatment period dosing visit.
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| Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: period one was the titration period to get to the baseline period (period 2) |
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| Notes [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The number of subjects in the baseline period, came from the titration period and that is where the 48 subjects came from - 48 were in tritration and 40 were in baseline [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: 1. APL-130277 (Titration): Patients who completed the Dose Titration Phase in Period 1 (N=41) were eligible to proceed to randomization in the crossover phase (Period 2). One patient discontinued prior to receiving any study medication; therefore, a total of 40 patients were dosed with study medication in the crossover phase (Period 2) 2. Overall Crossover: Patients who completed the Dose Titration Phase in Period 1 were randomized to 1 of 6 treatment sequences to receive each of the treatments |
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Baseline characteristics reporting groups
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Reporting group title |
Period 2
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Reporting group description |
Patients who successfully completed the Dose Titration Phase of the study were randomized to 1 of 6 treatment sequences in the single-dose Randomized Crossover Assessment Phase. Following confirmation by both the Investigator and the patient that the patient was in the ‘OFF’ state, the patient was dosed according to the patient’s random treatment assignment with 1. APL-130277 at the dose determined in the Dose Titration Phase; OR 2. Matched placebo APL-130277; OR 3. A single 400 mg dose of moxifloxacin. Patients were randomized in equal numbers to 6 possible sequences of the above 3 study treatments determined by a 3-way balanced crossover design. There was a 3-day washout period between treatment period dosing visits. Dosing of APL-130277 and placebo was double-blinded, and dosing of moxifloxacin was open-label. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
APL-130277 (Titration)
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Reporting group description |
Patients were titrated to an effective and tolerable dose of APL-130277. Patients were dosed with increasing doses of APL 130277 starting with 10 mg at Titration Visit (TV) 1 up to a maximum of 60 mg. Patients who did not achieve a complete and full ‘ON’ response with the 10 mg APL 130277 dose at TV1 restarted their normal PD medications and were asked to return to the clinic the next business day for TV2, to assess the next highest dose. The evaluation continued sequentially with 15 mg (TV2), 20 mg (TV3), 25 mg (TV4), 30 mg (TV5), 35 mg (TV6), 40 mg (TV7), 50 mg (TV8), and 60 mg (TV9) doses of APL-130277 until a full ‘ON’ state was achieved. If tolerated, patients were titrated to a supratherapeutic dose (up to 60 mg) which was 1 or 2 levels above the initial dose producing an ‘ON’ response. If the patient was unable to tolerate 1 or either of the 2 additional dose levels after reaching a full “ON” state patients were randomized to the previous tolerable dose. | ||
Reporting group title |
Overall Crossover
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Reporting group description |
Patients who successfully completed the Dose Titration Phase of the study were randomized to 1 of 6 treatment sequences in the single-dose Randomized Crossover Assessment Phase. Following confirmation by both the Investigator and the patient that the patient was in the ‘OFF’ state, the patient was dosed according to the patient’s random treatment assignment with 1. APL-130277 at the dose determined in the Dose Titration Phase; OR 2. Matched placebo APL-130277; OR 3. A single 400 mg dose of moxifloxacin. Patients were randomized in equal numbers to 6 possible sequences of the above 3 study treatments determined by a 3-way balanced crossover design. There was a 3-day washout period between treatment period dosing visits. Dosing of APL-130277 and placebo was double-blinded, and dosing of moxifloxacin was open-label. | ||
Subject analysis set title |
APL-130277 (Crossover)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.
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Subject analysis set title |
Placebo (Crossover)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.
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Subject analysis set title |
Moxifloxacin (Crossover)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.
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Subject analysis set title |
10 mg APL-130277 PK subset
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who received a single dose of 10 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
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Subject analysis set title |
15 mg APL-130277 PK subset
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who received a single dose of 15 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
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Subject analysis set title |
20 mg APL-130277 PK subset
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
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Subject analysis set title |
25 mg APL-130277 PK subset
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
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Subject analysis set title |
35 mg APL-130277 PK subset
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
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Subject analysis set title |
50 mg APL-130277 PK subset
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
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End point title |
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) | |||||||||||||||||||||||||||||||||
End point description |
For the primary central tendency analysis, the changes from baseline (ΔQTcF) were compared between APL-130277 and placebo (ΔΔQTcF). Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 minutes (mins) and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. These average values were used in all change from baseline calculations.
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End point type |
Primary
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End point 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.
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Statistical analysis title |
comparison for 15 mins post-dose | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 15 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The mixed model for repeated measurements (MMRM) included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect
Please note: crossover design - total subjects analyzed 40 not 80
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Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | |||||||||||||||||||||||||||||||||
Method |
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Parameter type |
Least Square (LS) Mean Difference (Param | |||||||||||||||||||||||||||||||||
Point estimate |
4
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Confidence interval |
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level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.5 | |||||||||||||||||||||||||||||||||
upper limit |
7.4 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.11
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| Notes [1] - For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% confidence intervals (CIs) for APL-130277 versus placebo fell below 10 msec. In this case, it was concluded that APL-130277 did not prolong the QTc interval to a clinically significant degree. |
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Statistical analysis title |
comparison for 30 mins post-dose | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 30 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
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Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | |||||||||||||||||||||||||||||||||
Method |
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Parameter type |
LS Mean Difference (Parameter dispersion | |||||||||||||||||||||||||||||||||
Point estimate |
3
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Confidence interval |
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level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.5 | |||||||||||||||||||||||||||||||||
upper limit |
6.5 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.11
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| Notes [2] - For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec. In this case, it was concluded that APL-130277 did not prolong the QTc interval to a clinically significant degree. |
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Statistical analysis title |
comparison for 45 mins post-dose | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 45 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
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Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | |||||||||||||||||||||||||||||||||
Method |
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Parameter type |
: LS Mean Difference (Parameter dispers | |||||||||||||||||||||||||||||||||
Point estimate |
3.7
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Confidence interval |
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level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.2 | |||||||||||||||||||||||||||||||||
upper limit |
7.2 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.11
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| Notes [3] - For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec. In this case, it was concluded that APL-130277 did not prolong the QTc interval to a clinically significant degree. |
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Statistical analysis title |
comparison for 60 mins post-dose | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 60 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
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Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
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Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [4] | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
: LS Mean Difference (Parameter dispers | |||||||||||||||||||||||||||||||||
Point estimate |
6.2
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
2.7 | |||||||||||||||||||||||||||||||||
upper limit |
9.7 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.11
|
|||||||||||||||||||||||||||||||||
| Notes [4] - For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec. In this case, it was concluded that APL-130277 did not prolong the QTc interval to a clinically significant degree. |
||||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 2 hours post-dose | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for2 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [5] | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
: LS Mean Difference (Parameter dispers | |||||||||||||||||||||||||||||||||
Point estimate |
4.8
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
1.3 | |||||||||||||||||||||||||||||||||
upper limit |
8.3 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.11
|
|||||||||||||||||||||||||||||||||
| Notes [5] - For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec. In this case, it was concluded that APL-130277 did not prolong the QTc interval to a clinically significant degree. |
||||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 3 hours post-dose | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 3 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
|
|||||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Crossover) v APL-130277 (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [6] | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
: LS Mean Difference (Parameter dispers | |||||||||||||||||||||||||||||||||
Point estimate |
1.8
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
-1.7 | |||||||||||||||||||||||||||||||||
upper limit |
5.3 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.12
|
|||||||||||||||||||||||||||||||||
| Notes [6] - For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec. In this case, it was concluded that APL-130277 did not prolong the QTc interval to a clinically significant degree. |
||||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 4 hours post-dose | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 4 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [7] | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
: LS Mean Difference (Parameter dispers | |||||||||||||||||||||||||||||||||
Point estimate |
-0.7
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
-4.2 | |||||||||||||||||||||||||||||||||
upper limit |
2.8 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.12
|
|||||||||||||||||||||||||||||||||
| Notes [7] - For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec. In this case, it was concluded that APL-130277 did not prolong the QTc interval to a clinically significant degree. |
||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
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) | ||||||||||||||||||||||||
End point description |
For the assay sensitivity analysis in support of the primary central tendency analysis, the changes from baseline (ΔQTcF) were compared between moxifloxacin (positive control) and placebo (ΔΔQTcF). Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 60 mins and 2, 3 and 4 hours post-dose for each of the 3 treatment period dosing visits in the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. These average values were used in all change from baseline calculations.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Baseline to 60 mins and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits.
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
comparison for 60 mins post-dose | ||||||||||||||||||||||||
Statistical analysis description |
comparison for 60 mins post-dose: time-matched, baseline-corrected comparison between moxifloxacin and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
|
||||||||||||||||||||||||
Comparison groups |
Placebo (Crossover) v Moxifloxacin (Crossover)
|
||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
non-inferiority [8] | ||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||
Parameter type |
LS Mean Difference (Parameter dispersion | ||||||||||||||||||||||||
Point estimate |
10
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
5.3 | ||||||||||||||||||||||||
upper limit |
14.8 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
2.11
|
||||||||||||||||||||||||
| Notes [8] - The hypothesis of assay sensitivit (difference in QTcF time between moxifloxacin and placebo) was evaluated by observing if any of the 4 post-dose evaluation time points had a one-sided (Bonferroni-corrected)95% lower confidence limit which was equal to, or exceeded, 5 msec. In this case, it was concluded that assay sensitivity(prolongation of QTcF time with moxifloxacin)was demonstrated. The Bonferroni-corrected CIs were calculated by using the two-sided coverage of 0.10/4 = 0.025 for the 4 CIs |
|||||||||||||||||||||||||
Statistical analysis title |
comparison for 2 hours post-dose | ||||||||||||||||||||||||
Statistical analysis description |
comparison for 2 hours post-dose: time-matched, baseline-corrected comparison between moxifloxacin and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
|
||||||||||||||||||||||||
Comparison groups |
Placebo (Crossover) v Moxifloxacin (Crossover)
|
||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
non-inferiority [9] | ||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||
Parameter type |
LS Mean Difference (Parameter dispersion | ||||||||||||||||||||||||
Point estimate |
12.3
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
7.5 | ||||||||||||||||||||||||
upper limit |
17.1 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
2.12
|
||||||||||||||||||||||||
| Notes [9] - The hypothesis of assay sensitivit (difference in QTcF time between moxifloxacin and placebo) was evaluated by observing if any of the 4 post-dose evaluation time points had a one-sided (Bonferroni-corrected)95% lower confidence limit which was equal to, or exceeded, 5 msec. In this case, it was concluded that assay sensitivity(prolongation of QTcF time with moxifloxacin)was demonstrated. The Bonferroni-corrected CIs were calculated by using the two-sided coverage of 0.10/4 = 0.025 for the 4 CIs |
|||||||||||||||||||||||||
Statistical analysis title |
comparison for 3 hours post-dose | ||||||||||||||||||||||||
Statistical analysis description |
comparison for 3 hours post-dose: time-matched, baseline-corrected comparison between moxifloxacin and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
|
||||||||||||||||||||||||
Comparison groups |
Placebo (Crossover) v Moxifloxacin (Crossover)
|
||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
non-inferiority [10] | ||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||
Parameter type |
LS Mean Difference (Parameter dispersion | ||||||||||||||||||||||||
Point estimate |
10.9
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
6.1 | ||||||||||||||||||||||||
upper limit |
15.7 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
2.12
|
||||||||||||||||||||||||
| Notes [10] - The hypothesis of assay sensitivit (difference in QTcF time between moxifloxacin and placebo) was evaluated by observing if any of the 4 post-dose evaluation time points had a one-sided (Bonferroni-corrected)95% lower confidence limit which was equal to, or exceeded, 5 msec. In this case, it was concluded that assay sensitivity(prolongation of QTcF time with moxifloxacin)was demonstrated. The Bonferroni-corrected CIs were calculated by using the two-sided coverage of 0.10/4 = 0.025 for the 4 CIs |
|||||||||||||||||||||||||
Statistical analysis title |
comparison for 4 hours post-dose | ||||||||||||||||||||||||
Statistical analysis description |
comparison for 4 hours post-dose: time-matched, baseline-corrected comparison between moxifloxacin and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
Please note: crossover design - total subjects analyzed 40 not 80
|
||||||||||||||||||||||||
Comparison groups |
Placebo (Crossover) v Moxifloxacin (Crossover)
|
||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
non-inferiority [11] | ||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||
Parameter type |
LS Mean Difference (Parameter dispersion | ||||||||||||||||||||||||
Point estimate |
9
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
4.2 | ||||||||||||||||||||||||
upper limit |
13.8 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
2.12
|
||||||||||||||||||||||||
| Notes [11] - The hypothesis of assay sensitivit (difference in QTcF time between moxifloxacin and placebo) was evaluated by observing if any of the 4 post-dose evaluation time points had a one-sided (Bonferroni-corrected)95% lower confidence limit which was equal to, or exceeded, 5 msec. In this case, it was concluded that assay sensitivity(prolongation of QTcF time with moxifloxacin)was demonstrated. The Bonferroni-corrected CIs were calculated by using the two-sided coverage of 0.10/4 = 0.025 for the 4 CIs |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The maximum observed plasma concentration (Cmax) for apomorphine and apomorphine sulfate (metabolite) was determined in patients treated with APL-130277. Pharmacokinetic (PK) parameters were derived using a non-compartmental analysis method. Bioanalysis of apomorphine and apomorphine-sulfate plasma concentration were measured using a validated liquid chromatography-tandem mass spectrometry (LC/MS-MS) method. The calibration range was 0.0200 nanograms per milliliter (ng/mL) to 20.0 ng/mL apomorphine and 10.0 to 1000 ng/mL apomorphine sulfate (metabolite). PK assessments were performed at each period of the Randomized Crossover Assessment Phase (at P1V1, P2V2 and P3V3) and results are presented for each of the APL-130277 doses administered (as determined for each patient during the Dose Titration Phase).
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.
|
||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The time of maximum observed plasma concentration (Tmax) for apomorphine and apomorphine sulfate (metabolite) was determined in patients treated with APL-130277. PK parameters were derived using a non-compartmental analysis method. Bioanalysis of apomorphine and apomorphine-sulfate plasma concentration were measured using a validated LC/MS-MS method. The calibration range was 0.0200 ng/mL to 20.0 ng/mL apomorphine and 10.0 to 1000 ng/mL apomorphine sulfate. PK assessments were performed at each period of the Randomized Crossover Assessment Phase (at P1V1, P2V2 and P3V3) and results are presented for each of the APL-130277 doses administered (as determined for each patient during the Dose Titration Phase).
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.
|
||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The area under the concentration-time curve from time of dosing to the last measurable point (AUClast) for apomorphine and apomorphine sulfate (metabolite) was determined in patients treated with APL-130277. PK parameters were derived using a non-compartmental analysis method. Bioanalysis of apomorphine and apomorphine-sulfate plasma concentration were measured using a validated LC/MS-MS method. The calibration range was 0.0200 ng/mL to 20.0 ng/mL apomorphine and 10.0 to 1000 ng/mL apomorphine sulfate. PK assessments were performed at each period of the Randomized Crossover Assessment Phase (at P1V1, P2V2 and P3V3) and results are presented for each of the APL-130277 doses administered (as determined for each patient during the Dose Titration Phase).
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.
|
||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Number of Patients with Treatment-Emergent Adverse Events (TEAEs) | ||||||||||||||||||||||||||||||||||||
End point description |
AE definition: any untoward medical occurrence in a clinical trial participant. Serious AE definition: an AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in permanent (persistent) disability/incapacity, is a congenital anomaly/birth defect or is an important medical event. Severity of AEs were classified as: mild: causes no limitation of usual activities, moderate: causes some limitation of usual activities; or severe: prevents or severely limits usual activities. The investigator assessed AEs for relatedness to study medication. TEAEs were defined as all AEs that started on or after the first dose of study medication (APL-130277, moxifloxacin or placebo). Results are presented for TEAEs during the Randomized Crossover Assessment Phase.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
From first dose of study medication up to last study visit for Randomized Crossover Assessment Phase.
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
End point title |
ECG Assessments: Mean Change from Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | |||||||||||||||||||||||||||||||||
End point description |
QTcB was defined as QT interval corrected with Bazett’s method. QT was defined as time between start of Q wave and end of T wave. QTcB was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point 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.
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 15 mins post-dose: | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 15 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
Least Square (LS) Mean Difference (Param | |||||||||||||||||||||||||||||||||
Point estimate |
4.4
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
0.3 | |||||||||||||||||||||||||||||||||
upper limit |
8.6 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.54
|
|||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 30 mins post-dose: | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 30 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
Least Square (LS) Mean Difference (Param | |||||||||||||||||||||||||||||||||
Point estimate |
2.5
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
-1.6 | |||||||||||||||||||||||||||||||||
upper limit |
6.7 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.54
|
|||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 45 mins post-dose: | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 45 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
Least Square (LS) Mean Difference (Param | |||||||||||||||||||||||||||||||||
Point estimate |
3.2
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
-0.9 | |||||||||||||||||||||||||||||||||
upper limit |
7.4 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.54
|
|||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 60 mins post-dose: | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 60 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
Least Square (LS) Mean Difference (Param | |||||||||||||||||||||||||||||||||
Point estimate |
3.3
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
-0.9 | |||||||||||||||||||||||||||||||||
upper limit |
7.5 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.54
|
|||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 2 hours post-dose: | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 2 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
Least Square (LS) Mean Difference (Param | |||||||||||||||||||||||||||||||||
Point estimate |
5
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
0.8 | |||||||||||||||||||||||||||||||||
upper limit |
9.2 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.54
|
|||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 3 hours post-dose: | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 3 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
Least Square (LS) Mean Difference (Param | |||||||||||||||||||||||||||||||||
Point estimate |
4.6
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
0.4 | |||||||||||||||||||||||||||||||||
upper limit |
8.8 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.55
|
|||||||||||||||||||||||||||||||||
Statistical analysis title |
comparison for 4 hours post-dose: | |||||||||||||||||||||||||||||||||
Statistical analysis description |
comparison for 4 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect.
|
|||||||||||||||||||||||||||||||||
Comparison groups |
APL-130277 (Crossover) v Placebo (Crossover)
|
|||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
80
|
|||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority | |||||||||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||||||||
Parameter type |
Least Square (LS) Mean Difference (Param | |||||||||||||||||||||||||||||||||
Point estimate |
2.6
|
|||||||||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||||||||
level |
90% | |||||||||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||||||||
lower limit |
-1.6 | |||||||||||||||||||||||||||||||||
upper limit |
6.9 | |||||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||||||||||||||
Dispersion value |
2.56
|
|||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
ECG Assessments: Mean Change from Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Heart rate was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.
|
||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
ECG Assessments: Mean Change from Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
PR interval was defined as time from the onset of the P wave to the start of the QRS complex. PR interval was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.
|
||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
ECG Assessments: Mean Change from Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
QRS interval was defined as the time of QRS complex (Q, R, and S waves). QRS interval was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.
|
||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
ECG Assessments: Mean Change from Baseline to Post-Baseline Value for Uncorrected QT Interval during Randomized Crossover Assessment Phase | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Uncorrected QT interval was defined as time between start of Q wave and end of T wave. QT interval was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.
|
||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||
End point title |
Median Time to ‘ON’ During the Dose Titration Phase | ||||||||||||
End point description |
The time to ‘ON’ was calculated as minutes from the time when the patient received APL-130277 until the time the patient turned fully ‘ON’, as assessed by the Investigator. Data was censored at 90 minutes.
The median time to a full ‘ON’ response during the Dose Titration Phase following the highest tolerated APL-130277 dose level (indicated as Day 2) and the lowest APL-130277 dose resulting in a full ‘ON’ (indicated as Day 1) are presented. The median time to ‘ON’ on Day 1 and Day 2 was calculated using the Kaplan-Meier method.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Median Duration of ‘ON’ During the Dose Titration Phase | ||||||||||||
End point description |
The duration of ‘ON’ was calculated as minutes from the time when the patient turned fully ‘ON’ until the time when the patient turned ‘OFF’, as assessed by the Investigator. If the patient did not turn fully ‘ON’ within 90 minutes the duration of ‘ON’ was defined as zero minutes. If the patient turned fully ‘ON’ and did not turn ‘OFF’ by 90 minutes, the data was censored at 90 minutes minus the time when the patient turned fully ‘ON’.
The median duration of a full ‘ON’ response during the Dose Titration Phase following the highest tolerated APL-130277 dose level (indicated as Day 2) and the lowest APL-130277 dose resulting in a full ‘ON’ (indicated as Day 1) are presented. The median duration of ‘ON’ on Day 1 and Day 2 was calculated using the Kaplan-Meier method.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||
End point title |
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 | ||||||||||||||||||||
End point description |
The Motor Function section (Part III) of the MDS-UPDRS was administered by the Investigator, and included 33 scores based on 18-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range was from 0 to 132, with a lower score indicating better motor function and a higher score indicating more severe motor symptoms.
The least squares mean change in the MDS-UPDRS Part III score from pre-dose to 30, 60 and 90 minutes post-dose during the Dose Titration Phase at the highest tolerated APL-130277 dose level (indicated as Day 2) and the lowest APL-130277 dose resulting in a full ‘ON’ (indicated as Day 1) are presented.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline (pre-dose) and at 30, 60 and 90 minutes after dosing during the Dose Titration Phase.
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Dose Titration Phase (up to 28 days): all AEs that started on/after the first dose of APL-130277 but before the first dose of study medication during the Randomized Crossover Assessment Phase.
Randomized Crossover Assessment Phase (up to 18 days): all
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All AEs were collected for each patient. Patients were queried in a non-leading manner, without specific prompting. TEAEs are presented for the Dose Titration Phase (APl-130277 [titration]) and for the Randomized Crossover Assessment Phase (APL-130277 [crossover], Placebo [crossover] and Moxifloxacin [crossover]).
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
APL-13077 (titration)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
APL-13077 (Crossover)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (crossover)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Moxifloxacom (crossover)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
