OTR Tablet 40 mg Fasted-state Bioequivalence Study

• Sponsor: Mundipharma (China) Pharmaceutical Co. Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03398278
• Collaborator: (none)
• Enrollment: 38
• Location: 1
• Arms: 2
• Actual Duration (Months): 8.6
• Patients Per Site Per Month: 4.4

Study Details

Study Description

Brief Summary

This is an open-label, single dose, randomised, cross-over study to confirm the bioequivalence (BE) of OTR tablet 40 mg and OXYCONTIN tablet 40 mg in a fasted state in Chinese subjects with chronic pain

Condition or Disease	Intervention/Treatment	Phase
Chronic Pain	Drug: Oxycodone Tamper Resistant; Drug: OXYCONTIN®	Phase 1

Detailed Description

In this BE study, subjects with histories of chronic pain are chosen as the target population.

Inclusion/exclusion criteria are strictly defined to reduce the potential variation of the PK data.

Single dose design is chosen per Food and Drug Administration (FDA)/WHO guideline on bioavailability (BA)/BE studies for modified-release products.

As a general rule, cross-over design is applied in the study to decrease the inter-individual variations between the two cohorts. A washout period lasting for at least 7 half-lives of the investigational medicine is needed to eliminate the drug residual from the previous period7. The elimination half-life of oxycodone from OTR is 4.5 hours, and a 6-day washout period is sufficient to achieve the aim.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: An Open-label, Single Dose, Randomised, Cross-over Study to Determine the Fasted State Pharmacokinetics of Oxycodone From Oxycodone Tamper Resistant (OTR) Tablet 40 mg and OXYCONTIN® Tablet 40 mg in Chinese Subjects With Chronic Pain
• Actual Study Start Date: Jun 30, 2017
• Actual Primary Completion Date: Oct 15, 2017
• Actual Study Completion Date: Mar 20, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oxycodone Tamper Resistant Oxycodone Tamper Resistant (OTR) Tablet 40 mg	Drug: Oxycodone Tamper Resistant; Orally taking Oxycodone Tamper Resistant 40mg in fast state; Other Names: Oxycodone Tamper Resistant (OTR) Tablet 40 mg
Active Comparator: OXYCONTIN® OXYCONTIN® Tablet 40 mg	Drug: OXYCONTIN®; Orally taking OXYCONTIN® 40mg in fast state; Other Names: OXYCONTIN® Tablet 40 mg

Outcome Measures

Primary Outcome Measures

1. Cmax of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State [up to 32 hours]

   The analysis was for PK parameters Cmax of analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) were used to compare the test and the reference treatments.

2. AUCt of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State [up to 32 hours]

   The analysis was for PK parameters AUCt of analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) were used to compare the test and the reference treatments.

3. AUCINF of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State [up to 32 hours]

   The analysis was for PK parameters AUCINF for analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) was used to compare the test and the reference treatments.

Secondary Outcome Measures

1. Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State [up to 35 days]

   An overall summary of adverse events will be provided by treatment groups. The number and percentage of subjects reporting adverse events will be summarised by the preferred term nested within the System Organ Classification. In addition the number of reported adverse events will be summarised.

2. Number of Lab Tests With Clinical Significance [up to 35 days]

   Clinical laboratory data to be summarised includes haematology, blood chemistry, and urinalysis.Each parameter will be assigned an LNH classification according to whether the value is lower than (L), within (N) or higher than (H) the reference range for that parameter. Results will be summarised using shift tables to evaluate categorical changes from baseline to end of study with respect to reference range values (lower than, within, and higher than).

3. Number of AEs Related to Vital Sign [up to 35 days]

   Vital sign parameters to be summarised include systolic blood pressure, diastolic blood pressure, pulse rate, respiration rate, and axillary temperature. Vital sign results for each parameter will be assigned an LNH classification according to whether the value is lower than (L), within (N), or higher than (H) the reference range for that parameter. Vital sign results will be summarised using shift tables to evaluate categorical changes from baseline to end of study with respect to reference range values (lower than, within, and higher than).

4. Number of AEs Related to ECGs [up to 35 days]

   Twelve-lead ECG was conducted at screening and on Day 4 of Period 2.

5. Number of AEs Related to Physical Examination [up to 35 days]

   Physical examination was conducted at screening, and on Day -1, Day 4 in each Period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Chinese male or female subjects with histories of chronic pain regardless of the aetiology, aged 18-55 years both inclusive

2. The average pain over the last 24 hours should be scored < 4 assessed with Numeric Rating Scales (NRS), when not receiving analgesics. The pain condition has been kept stable at least in the past 7 days prior to entering into the screening and is expected to be stable during the study duration

3. Body weight ≥45 kg and a body mass index (BMI) ≥18 and ≤28 kg/m2

4. Karnofsky score of Performance Status ≥70

5. Willing to take all the food supplied while the subject is in the study unit

6. Be able to read, understand, and sign written Informed Consent Form (ICF) prior to study participation and be willing to follow the protocol requirements

7. Willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, some Intrauterine Device (IUD), sexual abstinence, or vasectomised partner

8. Female subjects, including those up to less than one year post-menopausal, must have a negative serum pregnancy test and be non-lactating

Exclusion Criteria:

1. Subjects who are currently taking opioids or have used opioids in the past 14 days prior to receiving the study drug

2. Have hypersensitivity history to any opioids, naltrexone, naloxone, or related compounds or any contraindications as detailed in the OTR and OXYCONTIN tablet Summary of Product Characteristics

3. Histories of or any current conditions that might interfere with drug absorption, distribution, metabolism, or excretion

4. Subjects who are likely to have paralytic ileus or acute abdomen or to require an operation on abdominal regions

5. Subjects with biliary tract diseases, pancreatitis, prostatic hypertrophy, or corticoadrenal insufficiency

6. Subjects with respiratory depression, corpulmonale, or chronic bronchial asthma

7. Any history of seizures or symptomatic head trauma

8. Subjects with abnormal liver function (values exceeding the upper limit of normal (ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin during the Screening Phase) or abnormal renal function (values exceeding the ULN for serum creatinine during the Screening Phase). Note: if the values of ALT, AST or total bilirubin are between 1 to 1.2 times of ULN and confirmed not clinically significant by the Investigators, the subject may be recruited after getting the approval from Sponsor.

9. Any other significant illness other than the primary disease of chronic pain during the 4 weeks preceding the entry into this study

10. Subjects who are unable to stop taking monoamine oxidase inhibitors during this trial period or time lapses less than 2 weeks since drug withdrawal prior to the study drug administration

11. Subjects who are currently taking tricyclic antidepressants or have used tricyclic antidepressants within 4 weeks prior to the study drug administration

12. Subjects who have used any medicinal product which inhibits Cytochrome P450 3A4 (CYP3A4) (e.g. troleandomycin, ketoconazole, gestodene, etc.) or induces CYP3A4 (e.g. glucocorticoids, barbiturates, rifampicin, etc.) within 4 weeks prior to the study drug administration

13. Subjects who have used any medicinal product which inhibits Cytochrome P450 2D6 (CYP2D6) (e.g. fluoxetine, quinidine, ritonavir, etc.) or induces CYP2D6 (e.g. dexamethasone, rifampicin, glutethimide, etc.) within 4 weeks prior to the study drug administration

14. Histories of smoking (being a smoker or an occasional smoker) within 45 days prior to the study drug administration and refusal to abstain from smoking during the study. According to World Health Organization (WHO), a smoker is defined as having smoked at least 1 cigarette per day continuously for more than 6 months and an occasional smoker is defined as having smoked for more than 4 times per week and less than 1 cigarette per day continuously for more than 6 months.

15. Subjects with histories of alcoholism or drug abuse. Alcoholism is defined as regular alcohol consumption exceeding 14 drinks/week (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor)

16. Consumption of alcoholic beverages within 48 hours before study drug administration, and refusal to abstain from alcohol for at least 48 hours after study drug administration

17. Refusal to abstain from food for 10 hours preceding and 4 hours following administration of the study drug and to abstain from caffeine or xanthine entirely during each confinement

18. Positive Hepatitis B Surface Antigen (HBsAg), anti-Hepatitis C Virus (HCV), anti-Human Immunodeficiency Virus (HIV), or syphilis antibody test result

19. Urine screening before study is positive for opioids, barbiturates, amphetamines, cocaine metabolites, methadone, benzodiazepines, phencyclidine, methamphetamine, or cannabinoids. Or alcohol breath test is positive

20. Any history of frequent nausea or emesis regardless of aetiology

21. Blood or blood products donated within 30 days prior to administration of the study drugs or anytime during the study, except as required by this protocol

22. Subjects who participated in a clinical research study within 30 days of study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	West Hospital, Sichuan University	Chengdu	Sichuan	China	610041

Sponsors and Collaborators

• Mundipharma (China) Pharmaceutical Co. Ltd

Investigators

• Principal Investigator: ZHU LUO, PhD, West Hospital, Sichuan University

Study Documents (Full-Text)

• Study Protocol - May 30, 2016
• Statistical Analysis Plan - Mar 16, 2018

More Information

Publications

None provided.

• Responsible Party: Mundipharma (China) Pharmaceutical Co. Ltd
• ClinicalTrials.gov Identifier: NCT03398278
• Other Study ID Numbers: ONF16-CN-102
• First Posted: Jan 12, 2018
• Last Update Posted: Jan 31, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Chronic Pain; Oxycodone

Study Results

Participant Flow

Recruitment Details	38, from Jun2017 to Oct2017, from patient database, medical clinic, advertisement recruitment and etc.

Arm/Group Title	OTR 40 Mg-OXYCONTIN 40 mg	OXYCONTIN 40 Mg-OTR 40 mg
Arm/Group Description	the treatment sequence is OTR 40 mg dose first and then OXYCONTIN 40 mg dose in fasted state	the treatment sequence is OXYCONTIN 40 mg dose first and then OTR 40 mg dose in fasted state
Period Title: Period 1
STARTED	19	19
COMPLETED	18	19
NOT COMPLETED	1	0
Period Title: Period 1
STARTED	18	19
COMPLETED	16	17
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	OTR 40 Mg-OXYCONTIN 40 mg	OXYCONTIN 40 Mg-OTR 40 mg	Total
Arm/Group Description	the treatment sequence is OTR 40 mg dose first and then OXYCONTIN 40 mg dose	the treatment sequence is OXYCONTIN 40 mg dose first and then OTR 40 mg dose	Total of all reporting groups
Overall Participants	19	19	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.5 (9.61)	40.2 (10.18)	40.8 (9.79)
Sex: Female, Male (Count of Participants)
Female	11 57.9%	14 73.7%	25 65.8%
Male	8 42.1%	5 26.3%	13 34.2%
Race/Ethnicity, Customized (Count of Participants)
HAN	19 100%	19 100%	38 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	57.87 (7.182)	55.19 (8.088)	56.57 (7.650)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	160.4 (9.10)	157.7 (8.21)	159.1 (8.67)
BMI (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	22.52 (2.419)	22.16 (2.433)	22.34 (2.399)

Outcome Measures

1. Primary Outcome

Title	Cmax of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State
Description	The analysis was for PK parameters Cmax of analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) were used to compare the test and the reference treatments.
Time Frame	up to 32 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cmax of OTR 40 mg	Cmax of OXYCONTIN® 40 mg
Arm/Group Description	OTR Tablet 40 mg	OXYCONTIN® Tablet 40 mg
Measure Participants	32	32
Mean (90% Confidence Interval) [ng/mL]	60.98	52.23

2. Primary Outcome

Title	AUCt of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State
Description	The analysis was for PK parameters AUCt of analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) were used to compare the test and the reference treatments.
Time Frame	up to 32 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AUCt of OTR Tablet 40 mg	AUCt of OXYCONTIN Tablet 40 mg
Arm/Group Description	OTR Tablet 40 mg	OXYCONTIN Tablet 40 mg
Measure Participants	32	32
Mean (90% Confidence Interval) [ng*h/ml]	604.5095	588.6874

3. Primary Outcome

Title	AUCINF of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg in a Fasted State
Description	The analysis was for PK parameters AUCINF for analyte oxycodone. Analysis of Variance (ANOVA) with fixed effect terms for treatment, period, sequence, and subject within sequence for ratio of means (using log scale) was used to compare the test and the reference treatments.
Time Frame	up to 32 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AUCINF of OTR Tablet 40 mg	AUCINF of OXYCONTIN Tablet 40 mg
Arm/Group Description	OTR Tablet 40 mg	OXYCONTIN Tablet 40 mg
Measure Participants	32	32
Mean (90% Confidence Interval) [ng*h/ml]	610.9314	612.8057

4. Secondary Outcome

Title	Adverse Event of OTR Tablet 40 mg and OXYCONTIN Tablet 40 mg, When Given to Chinese Subjects With Chronic Pain in a Fasted State
Description	An overall summary of adverse events will be provided by treatment groups. The number and percentage of subjects reporting adverse events will be summarised by the preferred term nested within the System Organ Classification. In addition the number of reported adverse events will be summarised.
Time Frame	up to 35 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oxycodone Tamper Resistant (OTR)	OXYCONTIN®
Arm/Group Description	Oxycodone Tamper Resistant (OTR) Tablet 40 mg Oxycodone Tamper Resistant: Orally taking Oxycodone Tamper Resistant 40mg in fast state	OXYCONTIN® Tablet 40 mg OXYCONTIN®: Orally taking OXYCONTIN® 40mg in fast state
Measure Participants	35	35
Number of AEs (#)	23	22
Number of TEAEs (#)	23	22
Number of relateda TEAEs	15	16

5. Secondary Outcome

Title	Number of Lab Tests With Clinical Significance
Description	Clinical laboratory data to be summarised includes haematology, blood chemistry, and urinalysis.Each parameter will be assigned an LNH classification according to whether the value is lower than (L), within (N) or higher than (H) the reference range for that parameter. Results will be summarised using shift tables to evaluate categorical changes from baseline to end of study with respect to reference range values (lower than, within, and higher than).
Time Frame	up to 35 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clinical Laboratory Data of OTR Tablet 40 mg	Clinical Laboratory Data of OXYCONTIN Tablet 40 mg
Arm/Group Description	OTR Tablet 40 mg	OXYCONTIN Tablet 40 mg
Measure Participants	35	35
Number [Lab tests with clinical significance]	3	3

6. Secondary Outcome

Title	Number of AEs Related to Vital Sign
Description	Vital sign parameters to be summarised include systolic blood pressure, diastolic blood pressure, pulse rate, respiration rate, and axillary temperature. Vital sign results for each parameter will be assigned an LNH classification according to whether the value is lower than (L), within (N), or higher than (H) the reference range for that parameter. Vital sign results will be summarised using shift tables to evaluate categorical changes from baseline to end of study with respect to reference range values (lower than, within, and higher than).
Time Frame	up to 35 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vital Sign of OTR Tablet 40 mg	Vital Sign of OXYCONTIN Tablet 40 mg
Arm/Group Description	OTR tablet 40 mg	OXYCONTIN tablet 40 mg
Measure Participants	35	35
Number [AEs of vital signs related]	2	4

7. Secondary Outcome

Title	Number of AEs Related to ECGs
Description	Twelve-lead ECG was conducted at screening and on Day 4 of Period 2.
Time Frame	up to 35 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ECG of OTR Tablet 40 mg	ECG of OXYCONTIN Tablet 40 mg
Arm/Group Description	OTR Tablet 40 mg	OXYCONTIN Tablet 40 mg
Measure Participants	35	35
Number [AEs of ECG related]	0	0

8. Secondary Outcome

Title	Number of AEs Related to Physical Examination
Description	Physical examination was conducted at screening, and on Day -1, Day 4 in each Period.
Time Frame	up to 35 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Physical Examination of OTR Tablet 40 mg	Physical Examination of OXYCONTIN Tablet
Arm/Group Description	OTR Tablet 40 mg	OXYCONTIN Tablet 40 mg
Measure Participants	35	35
Number [AEs related to Physical examination]	0	0

Adverse Events

Time Frame	Events will be recorded from the point at which the ICF is signed until 7±1 days after last oxycodone dose in the case of completion/discontinuation from the study. This includes new AEs that are reported within 7±1 days after last oxycodone dosing after the subject's completion/discontinuation visit.
Adverse Event Reporting Description	same with clinicaltrials.gov Definitions.
Arm/Group Title	OTR 40 mg		OXYCONTIN® 40 mg
Arm/Group Description	Oxycodone Tamper Resistant (OTR) Tablet 40 mg Oxycodone Tamper Resistant: Orally taking Oxycodone Tamper Resistant 40mg in fast state		OXYCONTIN® Tablet 40 mg OXYCONTIN®: Orally taking OXYCONTIN® 40mg in fast state
All Cause Mortality
	OTR 40 mg		OXYCONTIN® 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/35 (0%)
Serious Adverse Events
	OTR 40 mg		OXYCONTIN® 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	OTR 40 mg		OXYCONTIN® 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/35 (11.4%)		3/35 (8.6%)
Cardiac disorders
Diastolic blood pressure decreased	2/35 (5.7%)	2	2/35 (5.7%)	2
Gastrointestinal disorders
Nausea	4/35 (11.4%)	4	3/35 (8.6%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.