Open-Label, Extension Study to Evaluate the Safety of Hyd... | NCT01922739

NCT01922739

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Hydrocodone ER	Experimental	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.	Drug: Hydrocodone ER Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Hydrocodone ER	Drug	Participants were instructed to take hydrocodone ER tablets orally with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.	Hydrocodone ER

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Participants With Adverse Events	An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.	Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)
Participants With Potentially Clinically Significant Abnormal Laboratory Values	Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values. Significance criteria: Blood urea nitrogen: >=10.71 mmol/L Creatinine: >=177 μmol/L Uric acid: M>=625, F>=506 μmol/L Aspartate aminotransferase (AST): >=3* upper limit of normal (ULN) Alkaline phosphatase: >=3* upper limit of normal (ULN) Gamma-glutamyl transpeptidase (GGT): >=3* upper limit of normal (ULN) Serum white blood cells: >=20 * 10^9/L Hemoglobin: M<=115, F<=95 g/dL Hematocrit: M<0.37, F<0.32 L/L Eosinophils: >=10.0 % Platelets: <=75 * 10^9/L Absolute neutrophils: <=1.0 * 10^9/L Urinalysis: Glucose, Ketones, and Total Protein: >=2 unit increase from baseline	End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)
Participants With Potentially Clinically Significant Abnormal Vital Signs Values	Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria Pulse - high: >=120 and increase of >= 15 beats/minute from baseline Pulse - low: <=50 and decrease of >=15 beats/minute Systolic blood pressure - high: >=180 and increase >=20 mmHg Systolic blood pressure - low: <=90 and decrease >=20 mmHg Diastolic blood pressure - high: >=105 and increase of >=15 mmHg Diastolic blood pressure - low: <=50 and decrease of >=15 mmHg

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Worst Pain Intensity (WPI) Scores During the Previous 24 Hours for Each Visit	The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. At each visit, participants selected the number that best described their worst pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patients must have participated in and completed the entire double-blind treatment period on study drug through the final study visit (week 12) of study 3103.

NOTE: Patients who had a final on-treatment visit (i.e. prior to week 12) are not permitted to participate in study 3104.
The patient is able to speak English and is willing to provide written informed consent for study 3104, including re-signing a written opioid agreement, to participate in this study.
Women of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception, agree to continue use of this method for the duration of the study and for 30 days after participation in the study, and have a negative pregnancy test at screening. Acceptable methods of contraception include barrier method with spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method. NOTE: A woman will be considered surgically sterile if she has had a tubal ligation, hysterectomy, bilateral salpingo-oophorectomy or bilateral oophorectomy, or hysterectomy with bilateral salpingo-oophorectomy.
The patient must be willing and able to successfully self-administer the study drug, comply with study restrictions, and return to the study center for scheduled study visits, as specified in the protocol.
The patient must not participate in any other study involving an investigational agent (excluding those who participated in study 3103) while enrolled in the present study.

Exclusion Criteria:

The patient's current source of pain is different from the low back pain the patient was experiencing at entry into study 3103. NOTE: Any additional source of pain for a patient must be discussed with the medical monitor.
The patient has current evidence of alcohol or other substance abuse with the exception of nicotine or caffeine.
The patient has developed, during study 3103, a medical or psychiatric disease (including suicidality) that, in the opinion of the investigator, would compromise collected data.
The patient is expected to have surgery during the study.
The patient is pregnant or lactating.
The patient has developed an active malignancy (excluding basal cell carcinoma) during study 3103.
The patient has known human immunodeficiency virus (HIV).
In the judgment of the investigator, the patient has any clinically significant deviation from normal in the physical examination and/or clinical laboratory test values.
The patient has developed cardiopulmonary disease that would, in the opinion of the investigator, significantly increase the risk of treatment with opioids.
The patient is receiving a monoamine oxidase inhibitor (MAOI).
- Other exclusion criteria apply.

Contacts/Locations Module

Name	Affiliation	Role
Teva Medical Expert, MD	Teva Branded Pharmaceutical Products R&D, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Teva Investigational Site 10412		Birmingham	Alabama		United States
Teva Investigational Site 10426

References Module

No data available

No data is available for this block.

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Hydrocodone ER	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

No data available

No data is available for this block.

Masking Info

Enrolled participants

Arm/Group Information

ID	Title	Description
BG000	Hydrocodone ER - Opioid Naive	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.
BG001	Hydrocodone ER - Opioid Experienced	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Any AE

Title	Measurements
	OG0004 OG0012 OG00234 OG003

Primary

Participants With Potentially Clinically Significant Abnormal Laboratory Values

Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values.

Significance criteria:

Blood urea nitrogen: >=10.71 mmol/L
Creatinine: >=177 μmol/L
Uric acid: M>=625, F>=506 μmol/L
Aspartate aminotransferase (AST): >=3* upper limit of normal (ULN)
Alkaline phosphatase: >=3* upper limit of normal (ULN)
Gamma-glutamyl transpeptidase (GGT): >=3* upper limit of normal (ULN)
Serum white blood cells: >=20 * 10^9/L
Hemoglobin: M<=115, F<=95 g/dL
Hematocrit: M<0.37, F<0.32 L/L
Eosinophils: >=10.0 %
Platelets: <=75 * 10^9/L
Absolute neutrophils: <=1.0 * 10^9/L
Urinalysis: Glucose, Ketones, and Total Protein: >=2 unit increase from baseline

The Full Analysis Set includes all participants who took at least one dose of study drug and who had at least 1 post-baseline efficacy assessment. Participants with a post-baseline result for each test are counted as part of the number of participants analyzed for that test.

Posted

Count of Participants

Participants

End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

ID	Title	Description
OG000	Hydrocodone ER	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.

Primary

Participants With Potentially Clinically Significant Abnormal Vital Signs Values

Data represents participants with potentially clinically significant (PCS) vital sign values.

Significance criteria

Pulse - high: >=120 and increase of >= 15 beats/minute from baseline
Pulse - low: <=50 and decrease of >=15 beats/minute
Systolic blood pressure - high: >=180 and increase >=20 mmHg
Systolic blood pressure - low: <=90 and decrease >=20 mmHg
Diastolic blood pressure - high: >=105 and increase of >=15 mmHg
Diastolic blood pressure - low: <=50 and decrease of >=15 mmHg

The Full Analysis Set includes all participants who took at least one dose of study drug and who had at least 1 post-baseline efficacy assessment. Participants with a post-baseline vital sign result are counted as part of the number of participants analyzed.

Posted

Count of Participants

Participants

Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

ID	Title	Description
OG000	Hydrocodone ER	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.

Primary

Participants With Shifts From Normal to Abnormal in Physical Examination Findings

The endpoint visit or early termination visit was an abbreviated exam. Endpoint refers to the last observation carried forward.

Post-Titration Safety Analysis Set

Posted

Count of Participants

Participants

End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

ID	Title	Description
OG000	Hydrocodone ER	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.

Units	Counts
Participants	OG000

Primary

Shifts From Baseline to Endpoint (Treatment Period) in Electrocardiogram (ECG) Findings

A 12-lead ECG was conducted at the final visit for study 3103 which is used as baseline for this study, and at week 22 of the treatment period [or early termination]). A qualified physician at the study center was responsible for providing interpretation of the ECG.

Endpoint refers to the last observation carried forward.

Post-Titration Safety Analysis Set. Includes participants who have both baseline and endpoint data.

Posted

Count of Participants

Participants

Baseline (final visit for study 3103), End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

ID	Title	Description
OG000	Hydrocodone ER - Opioid Naive	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.
OG001	Hydrocodone ER - Opioid Experienced	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.

Primary

Participants With Clinically Significant (CS) Hearing Changes From Baseline to the Final Visit in Pure Tone Audiometry Test Results

Pure tone audiometry was performed by trained personnel. Hearing loss was classified in degrees of hearing from normal to profound. This classification was determined by the hearing threshold (or the softest sound detected at a specific frequency). The exact ranges that classified hearing loss depended on the exact technique used during testing and on the patient's age. These values were provided by each audiology laboratory that performed the test. For serial audiograms, the criteria for a clinically significant hearing change were based on guidance from the American Speech Language Hearing Association (ASHA 1994, cited in [Konrad-Martin et al 2005]). These criteria included the following: greater than 20 decibels (dB) pure tone threshold shift at 1 frequency; greater than 10 dB shift at 2 consecutive test frequencies; or threshold response shifting to "no response" at 3 consecutive test frequencies.

Safety Analysis Set

Posted

Count of Participants

Participants

Baseline was within two weeks of the final study visit in study 3103; during study exam was within two weeks of the end of trial visit for study 3104 (up to study week 26)

ID	Title	Description
OG000	Hydrocodone ER - Opioid Naive	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.

Secondary

Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Worst Pain Intensity (WPI) Scores During the Previous 24 Hours for Each Visit

The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. At each visit, participants selected the number that best described their worst pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control.

Endpoint refers to the last observation carried forward.

Full Analysis Set includes participants who had at least one post-baseline efficacy assessment. Participants contributing to each time point are counted as part of the number of participants analyzed for that test.

Posted

Mean

Standard Deviation

units on a scale

Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period

ID	Title	Description
OG000	Hydrocodone ER - Opioid Naive	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.
OG001	Hydrocodone ER - Opioid Experienced

Secondary

Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Average Pain Intensity (API) Scores During the Previous 24 Hours for Each Visit

The API was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described their average pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control.

Endpoint refers to the last observation carried forward.

Posted

Mean

Standard Deviation

units on a scale

Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period

ID	Title	Description
OG000	Hydrocodone ER - Opioid Naive	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.
OG001	Hydrocodone ER - Opioid Experienced

Secondary

Percentage of Participants Withdrawn From the Study For Lack of Efficacy

Percentage of patients who withdrew from the study for lack of efficacy, as indicated on the early termination form of the case report form (CRF).

Safety Analysis Set

Posted

Number

percentage of participants

Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

ID	Title	Description
OG000	Hydrocodone ER	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both were followed by an open-label treatment period of 22 weeks.

Units	Counts
Participants	OG000

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Hydrocodone ER - Titration/Adjustment Period	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. The titration/adjustment period lasted 3-4 weeks.			1	182	27	182
EG001	Hydrocodone ER - Open-Label Treatment Period	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful during the Titration/Adjustment period for managing their pain. The Treatment Period lasted 22 weeks.			10	170	20	170

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute myocardial infarction	Cardiac disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA (16.0)	Systematic Assessment	EG0001 events1 affected182 at risk EG0010 events0 affected170 at risk
Chest pain	General disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Cholangitis	Hepatobiliary disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Cholestasis	Hepatobiliary disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Clostridium difficile infection	Infections and infestations	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Staphylococcal infection	Infections and infestations	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Urinary tract infection	Infections and infestations	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Road traffic accident	Injury, poisoning and procedural complications	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Electrocardiogram T wave inversion	Investigations	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Renal failure acute	Renal and urinary disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (16.0)	Systematic Assessment	EG0000 events0 affected182 at risk EG0011 events1 affected170 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Constipation	Gastrointestinal disorders	MedDRA (16.0)	Systematic Assessment		EG0009 events9 affected182 at risk EG00113 events12 affected170 at risk
Nausea	Gastrointestinal disorders	MedDRA (16.0)	Systematic Assessment		EG00019 events19 affected182 at risk EG00112 events10 affected170 at risk

ID	Term
D017116	Low Back Pain

ParticipantsBG002170

Units	Counts
Participants	OG000178

Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.

ID	Term
D001416	Back Pain
D010146	Pain
D009461	Neurologic Manifestations
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms