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The purpose of this study was to evaluate the efficacy, safety, and tolerability of single doses of trospium inhalation powder (TrIP) administered to subjects with chronic obstructive pulmonary disease (COPD).
This was a single-center, randomized, double-blind, cross-over, placebo-controlled study. Following screening, each eligible subject was randomized to a dosing sequence. Study subjects received a total of 5 single doses, each separated by a 3- to 14-day washout period. Doses A, B, C, and D were administered in a double-blind fashion, in sequences generated by a 4-period Latin square design. The 4 dosing sequences were: ABCD, BDAC, CADB, and DCBA. Dose E was administered in an open-label fashion as the final dose in each dosing sequence for all subjects.
Subjects reported to the clinic the evening prior to each dose. Protocol assessments were carried out until 24 hours postdose. Pulmonary function testing (via spirometry) was captured at specified timepoints at baseline as well as before and after dosing. Other efficacy and safety outcomes were assessed according to protocol. Blood sampling was performed for assessment of trospium concentrations at specified timepoints.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Represents Dose A in the Dosing Sequence assignments. |
|
| TrIP-2D (100mcg) | Experimental | Represents Dose B |
|
| TrIP-2SS (100mcg) | Experimental | Represents Dose C |
|
| TrIP-2D (400mcg) | Experimental | Represents Dose D |
|
| TrIP-2SS (100mcg) + Foradil (12mcg) | Experimental | Represents Dose E. All subjects received Dose E as their final (5th) dose, after completing their initial 4 single doses according to their sequence assignment. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | Supplied as an empty size-2 capsule and administered as a single dose via C2S inhaler. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Spirometry Parameter: Peak Forced Expiratory Volume in 1 Second(FEV1)in Liters (L) | Following screening, each subject was randomized to a sequence of 5 dosing periods (Doses A, B, C, D, and E). Each period was separated by a 3- to 14-day washout interval. The dosing formulations were as follows: Dose A = placebo Dose B = TrIP-2D (100 μg TrCl formulated in leucine and DPPC) Dose C = TrIP-2SS (100 μg TrCl formulated in leucine and sodium saccharin) Dose D = TrIP-2D (400 μg TrCl) Dose E = TrIP-2SS (100 μg TrCl) + Foradil (12 μg formoterol fumarate) FEV1 (L)was measured at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose. | 15 minutes to 24 hours post-treatment |
| Measure | Description | Time Frame |
|---|---|---|
| FEV1 Response to Treatment | Response was defined as the number of subjects reporting a post-treatment FEV1 of ≥12% (or 200 mL) above baseline. | Up to 24 hours post-treatment |
| Time to Maximum Plasma Concentration (Tmax) of Trospium After Single Administrations of TrIP |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bernard L. Silverman, MD | Alkermes, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Spartanburg Medical Research | Spartanburg | South Carolina | 29303 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Overall Study | Following screening, each subject was randomized to a sequence of 5 dosing periods (Doses A, B, C, D, and E). Each period was separated by a 3- to 14-day washout interval. Doses A, B, C, and D were administered in a double-blind fashion. Dose E was administered in an open-label fashion. The dosing formulations were as follows: Dose A = placebo Dose B = TrIP-2D (100 μg TrCl formulated in leucine and DPPC) Dose C = TrIP-2SS (100 μg TrCl formulated in leucine and sodium saccharin) Dose D = TrIP-2D (400 μg TrCl) Dose E = TrIP-2SS (100 μg TrCl) + Foradil (12 μg formoterol fumarate) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Overall Study | Following screening, each subject was randomized to a sequence of 5 dosing periods (Doses A, B, C, D, and E). Each period was separated by a 3- to 14-day washout interval. Doses A, B, C, and D were administered in a double-blind fashion. Dose E was administered in an open-label fashion. The dosing formulations were as follows: Dose A = placebo Dose B = TrIP-2D (100 μg TrCl formulated in leucine and DPPC) Dose C = TrIP-2SS (100 μg TrCl formulated in leucine and sodium saccharin) Dose D = TrIP-2D (400 μg TrCl) Dose E = TrIP-2SS (100 μg TrCl) + Foradil (12 μg formoterol fumarate) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Spirometry Parameter: Peak Forced Expiratory Volume in 1 Second(FEV1)in Liters (L) | Following screening, each subject was randomized to a sequence of 5 dosing periods (Doses A, B, C, D, and E). Each period was separated by a 3- to 14-day washout interval. The dosing formulations were as follows: Dose A = placebo Dose B = TrIP-2D (100 μg TrCl formulated in leucine and DPPC) Dose C = TrIP-2SS (100 μg TrCl formulated in leucine and sodium saccharin) Dose D = TrIP-2D (400 μg TrCl) Dose E = TrIP-2SS (100 μg TrCl) + Foradil (12 μg formoterol fumarate) FEV1 (L)was measured at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours postdose. | Posted | Mean | Standard Deviation | Liters | 15 minutes to 24 hours post-treatment |
|
Adverse events were monitored continuously from the time the subject signed the consent form until the end of the last dosing period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Overall Study |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (12.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Bernard L. Silverman, MD | Alkermes, Inc. | 781-609-6000 | bernard.silverman@alkermes.com |
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| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| D053120 | Respiratory Aspiration |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
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| ID | Term |
|---|---|
| D000068759 | Formoterol Fumarate |
| ID | Term |
|---|---|
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
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| TrIP-2D | Drug | Trospium inhalation powder containing 100 mcg TrCl (trospium chloride), supplied as dry powder in size-2 capsules and administered as a single dose via C2S inhaler. |
|
| TrIP-2SS | Drug | Trospium inhalation powder containing 100 mcg TrCl (trospium chloride), supplied as dry powder in size-2 capsules and administered as a single dose via C2S inhaler. |
|
| TrIP-2D | Drug | Trospium inhalation powder containing 400 mcg TrCl (trospium chloride), supplied as dry powder in size-2 capsules and administered as a single dose via C2S inhaler. |
|
| TrIP-2SS + Foradil | Drug | Trospium inhalation powder containing 100 mcg TrCl (trospium chloride), plus foradil (12 mcg formoterol fumarate) supplied as dry powder in size-2 capsules and administered as a single dose via C2S inhaler. |
|
Tmax is reported as median (range) of hours to reach maximum trospium concentration in plasma. |
| up to 24 hours post-treatment |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | TrIP-2SS (100mcg) + Foradil (12mcg) | Subjects were administered TrIP (100mcg)plus Foradil (12mcg)over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Foradil (12mcg)and Trospium inhalation powder containing 2% TrCl (100 mcg) formulated in leucine and sodium saccharin, supplied as dry powder in size-2 capsules, was administered via a dry powder inhaler. |
| OG002 | TrIP-2D (100mcg) | Subjects were administered TrIP-2D (100mcg) over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Trospium inhalation powder containing 2% TrCl (100 mcg) formulated in leucine and DPPC; supplied as dry powder in size-2 capsules and administered via dry powder inhaler. One capsule (100 mcg TrCl) or 4 capsules (400 mcg TrCl) were used. A separate inhaler was provided for each capsule. |
| OG003 | TrIP-2D (400mcg) | Subjects were administered TrIP-2D (400mcg)over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Trospium inhalation powder containing 2% TrCl (100 μg) formulated in leucine and DPPC; supplied as dry powder in size-2 capsules and administered via dry powder inhaler. One capsule (100 μg TrCl) or 4 capsules (400 μg TrCl) were used. A separate inhaler was provided for each capsule. |
| OG004 | Placebo | Subjects were administered placebo over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Placebo was supplied as empty Size-2 capsules and administered via a dry powder inhaler. |
|
|
|
| Secondary | FEV1 Response to Treatment | Response was defined as the number of subjects reporting a post-treatment FEV1 of ≥12% (or 200 mL) above baseline. | All 24 randomized subjects were included in the analysis. | Posted | Number | Participants | Up to 24 hours post-treatment |
|
|
|
| Secondary | Time to Maximum Plasma Concentration (Tmax) of Trospium After Single Administrations of TrIP | Tmax is reported as median (range) of hours to reach maximum trospium concentration in plasma. | The PK population consisted of all subjects who received active study medication and had sufficient concentration data to facilitate calculation of the PK parameters or descriptive statistics of concentrations of trospium. | Posted | Median | Full Range | Hours | up to 24 hours post-treatment |
|
|
|
| 0 |
| 24 |
| 6 |
| 24 |
| EG001 | TrIP-2D (100mcg) | Subjects were administered TrIP-2D (100mcg) over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Trospium inhalation powder containing 2% TrCl (100 mcg) formulated in leucine and DPPC; supplied as dry powder in size-2 capsules and administered via dry powder inhaler. One capsule (100 mcg TrCl) or 4 capsules (400 mcg TrCl) were used. A separate inhaler was provided for each capsule. | 0 | 24 | 1 | 24 |
| EG002 | TrIP-2SS (100mcg) | Subjects were administered TrIP (100mcg) over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Trospium inhalation powder containing 2% TrCl (100 mcg) formulated in leucine and sodium saccharin, supplied as dry powder in size-2 capsules, was administered via a dry powder inhaler. | 0 | 24 | 2 | 24 |
| EG003 | TrIP-2D (400mcg) | Subjects were administered TrIP-2D (400mcg)over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Trospium inhalation powder containing 2% TrCl (100 μg) formulated in leucine and DPPC; supplied as dry powder in size-2 capsules and administered via dry powder inhaler. One capsule (100 μg TrCl) or 4 capsules (400 μg TrCl) were used. A separate inhaler was provided for each capsule. | 0 | 24 | 4 | 24 |
| EG004 | TrIP-2SS (100mcg) + Foradil (12mcg) | Subjects were administered TrIP (100mcg)plus Foradil (12mcg)over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Foradil (12mcg)and Trospium inhalation powder containing 2% TrCl (100 mcg) formulated in leucine and sodium saccharin, supplied as dry powder in size-2 capsules, was administered via a dry powder inhaler. | 0 | 24 | 1 | 24 |
| EG005 | Placebo | Subjects were administered placebo over 5 dosing periods, each separated by a 3- to 14 day washout period. Subjects reported to the clinic the evening prior to each dose, and assessments were carried out through 24 hours postdose. A 3- to 14-day washout period was maintained between doses. Placebo was supplied as empty Size-2 capsules and administered via a dry powder inhaler. | 0 | 24 | 1 | 24 |
| Dry mouth | Gastrointestinal disorders | MedDRA (12.0) | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (12.0) | Systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA (12.0) | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA (12.0) | Systematic Assessment |
|
| Viral infection | Infections and infestations | MedDRA (12.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (12.0) | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (12.0) | Systematic Assessment |
|
No individual Investigator may publish results without written agreement from Alkermes. Should an Investigator wish to publish or present the data at a meeting, a copy of the manuscript or abstract must be provided to the Sponsor at least 30 days prior to the submission for review and approval. Any revisions will be negotiated in good faith by the Investigator and Sponsor.
| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012120 | Respiration Disorders |
| D000588 |
| Amines |