Pharmacokinetic Interaction Between SSP-004184 (SPD602) and Midazolam in Healthy Adult Subjects

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01989169
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 1.3
• Patients Per Site Per Month: 22.3

Study Details

Study Description

Brief Summary

A Study to Evaluate the Pharmacokinetic Interaction Between SSP-004184 and Midazolam in Healthy Adult Subjects

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Midazolam; Drug: SSP-004184SS	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 1, Randomized, Open Label, Crossover Study to Evaluate the Pharmacokinetic Interaction Between SSP-004184 (SPD602) and Midazolam in Healthy Adult Subjects
• Actual Study Start Date: Nov 26, 2013
• Actual Primary Completion Date: Jan 6, 2014
• Actual Study Completion Date: Jan 6, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Midazolam Administered as a single oral 6 mg dose on Day 1.	Drug: Midazolam
Experimental: SSP-004184SS + Midazolam Midazolam (6 mg) + SSP-004184SS (30 mg/kg) concomitantly administered as a single oral dose on Day 1.	Drug: Midazolam; Drug: SSP-004184SS; Other Names: SPD602

Outcome Measures

Primary Outcome Measures

1. Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUCinf) of Midazolam [Study Periods 1 & 2: Within 60 minutes pre-dose, and Post-dose 0.167, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 hours.]

   AUCinf is the area under the plasma concentration versus time curve extrapolated from time 0 to infinity, calculated using the observed value of the last non-zero concentration. AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body.

2. Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measureable Concentration (AUClast) of Midazolam [Study Periods 1 & 2: Within 60 minutes pre-dose, and Post-dose 0.167, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 hours.]

   AUClast is the area under the concentration versus time curve from the time of dosing to the last measurable concentration. AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body.

3. Maximum Plasma Concentration (Cmax) of Midazolam [Study Periods 1 & 2: Within 60 minutes pre-dose, and Post-dose 0.167, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 hours.]

   Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Normal healthy male and female volunteers between the ages of 18 and 65, inclusive

• Serum ferritin, hemoglobin and erythrocyte indices within normal range

Exclusion Criteria:

• Evidence of any active or chronic disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Pharmacology of Miami, Inc.	Miami	Florida	United States	33014

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01989169
• Other Study ID Numbers: SPD602-117
• First Posted: Nov 20, 2013
• Last Update Posted: Jun 24, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Midazolam

Study Results

Participant Flow

Arm/Group Title	Midazolam First	Midazolam + SSP-004184SS First
Arm/Group Description	Subjects received Midazolam 6mg in Period 1, followed by Midazolam 6mg and SSP-004184SS 30mg/kg during Period 2.	Subjects received Midazolam 6mg and SSP-004184SS 30mg/kg in Period 1, followed by Midazolam 6mg during Period 2.
Period Title: Period 1
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	15	15
COMPLETED	15	14
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Midazolam First	Midazolam + SSP-004184SS First	Total
Arm/Group Description	Subjects received Midazolam 6mg in Period 1, followed by Midazolam 6mg and SSP-004184SS 30mg/kg during Period 2.	Subjects received Midazolam 6mg and SSP-004184SS 30mg/kg in Period 1, followed by Midazolam 6mg during Period 2.	Total of all reporting groups
Overall Participants	15	15	30
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	37 (10.45)	44.9 (10.53)	41 (11.07)
Age, Customized (Count of Participants)
<=18 years	1 6.7%	0 0%	1 3.3%
Between 18 and 65 years	14 93.3%	15 100%	29 96.7%
Sex: Female, Male (Count of Participants)
Female	4 26.7%	5 33.3%	9 30%
Male	11 73.3%	10 66.7%	21 70%
Region of Enrollment (Count of Participants)
UNITED STATES	15 100%	15 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUCinf) of Midazolam
Description	AUCinf is the area under the plasma concentration versus time curve extrapolated from time 0 to infinity, calculated using the observed value of the last non-zero concentration. AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body.
Time Frame	Study Periods 1 & 2: Within 60 minutes pre-dose, and Post-dose 0.167, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 hours.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set: All subjects who took at least 1 dose of investigational product and for whom the primary pharmacokinetic data were considered sufficient and interpretable.

Arm/Group Title	Midazolam	SSP-004184SS + Midazolam
Arm/Group Description	Administered as a single oral 6 mg dose on Day 1.	Midazolam (6 mg) + SSP-004184SS (30 mg/kg) concomitantly administered as a single oral dose on Day 1.
Measure Participants	29	30
Mean (Standard Deviation) [ng*hr/mL]	103.348 (54.087)	120.1 (38.686)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Midazolam, SSP-004184SS + Midazolam
	Comments	The means of the log-transformed pharmacokinetic parameters were compared between treatments using a mixed-effects model with period and treatment as fixed effects and subject nested within sequence as a random effect. In order to estimate the magnitude of the treatment regimen differences in AUCinf, the geometric mean ratio (i.e., the least squares mean difference in the log-transformed parameters back transformed to the original scale) and their 90% CIs were calculated.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	If the 90% CI of the geometric mean ratios were within the range (0.80, 1.25), then equivalence was assumed and the hypothesis that a drug interaction occurred was rejected. If the 90% CIs were not wholly contained within the range (0.80, 1.25), then a drug interaction was not excluded.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LS Means
	Estimated Value	1.215
	Confidence Interval	(2-Sided) 90%; 1.116 to 1.323
	Parameter Dispersion	Type: Value:
	Estimation Comments	The ratio of geometric LS means and 90% CIs for the geometric mean ratio is for Treatment B to Treatment A.

2. Primary Outcome

Title	Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measureable Concentration (AUClast) of Midazolam
Description	AUClast is the area under the concentration versus time curve from the time of dosing to the last measurable concentration. AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body.
Time Frame	Study Periods 1 & 2: Within 60 minutes pre-dose, and Post-dose 0.167, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 hours.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set: All subjects who took at least 1 dose of investigational product and for whom the primary pharmacokinetic data were considered sufficient and interpretable.

Arm/Group Title	Midazolam	SSP-004184SS + Midazolam
Arm/Group Description	Administered as a single oral 6 mg dose on Day 1.	Midazolam (6 mg) + SSP-004184SS (30 mg/kg) concomitantly administered as a single oral dose on Day 1.
Measure Participants	29	30
Mean (Standard Deviation) [ng*h/ml]	100.935 (54.014)	116.902 (37.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Midazolam, SSP-004184SS + Midazolam
	Comments	The means of the log-transformed pharmacokinetic parameters were compared between treatments using a mixed-effects model with period and treatment as fixed effects, and subject nested within sequence as a random effect. In order to estimate the magnitude of the treatment regimen differences in AUClast, the geometric mean ratio (i.e., the least squares mean difference in the log-transformed parameters back transformed to the original scale) and their 90% CIs were calculated.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	If the 90% CI of the geometric mean ratios fell within the range (0.80, 1.25), then equivalence was assumed and the hypothesis that a drug interaction occurred was rejected. If the 90% CIs were not wholly contained within the range (0.80, 1.25), then a drug interaction was not excluded.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LS Means
	Estimated Value	1.216
	Confidence Interval	(2-Sided) 90%; 1.115 to 1.327
	Parameter Dispersion	Type: Value:
	Estimation Comments	The ratio of geometric LS means and 90% CIs for the geometric mean ratio is for Treatment B to Treatment A.

3. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of Midazolam
Description	Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated.
Time Frame	Study Periods 1 & 2: Within 60 minutes pre-dose, and Post-dose 0.167, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72 hours.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set: All subjects who took at least 1 dose of investigational product and for whom the primary pharmacokinetic data were considered sufficient and interpretable.

Arm/Group Title	Midazolam	SSP-004184SS + Midazolam
Arm/Group Description	Administered as a single oral 6 mg dose on Day 1.	Midazolam (6 mg) + SSP-004184SS (30 mg/kg) concomitantly administered as a single oral dose on Day 1.
Measure Participants	29	30
Mean (Standard Deviation) [ng/mL]	35.124 (12.532)	48.29 (12.605)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Midazolam, SSP-004184SS + Midazolam
	Comments	The means of the log-transformed pharmacokinetic parameters were compared between treatments using a mixed-effects model with period and treatment as fixed effects, and subject nested within sequence as a random effect. In order to estimate the magnitude of the treatment regimen differences in Cmax, the geometric mean ratio (i.e., the least squares mean difference in the log-transformed parameters back transformed to the original scale) and their 90% CIs were calculated.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	If the 90% CI of the geometric mean ratios fell within the range (0.80, 1.25), then equivalence was assumed and the hypothesis that a drug interaction occurred was rejected. If the 90% CIs were not wholly contained within the range (0.80, 1.25), then a drug interaction was not excluded.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LS Means
	Estimated Value	1.383
	Confidence Interval	(2-Sided) 90%; 1.282 to 1.491
	Parameter Dispersion	Type: Value:
	Estimation Comments	The ratio of geometric LS means and 90% CIs for the geometric mean ratio is for Treatment B to Treatment A.

Adverse Events

Arm/Group Title	Midazolam Alone		Midazolam + SSP-004184SS
Arm/Group Description	Administered as a single oral 20 mg dose on Day 1.		Midazolam (6 mg) + SSP-004184SS (30 mg/kg) administered concomitantly as a single oral dose on Day 1.
All Cause Mortality
	Midazolam Alone		Midazolam + SSP-004184SS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Midazolam Alone		Midazolam + SSP-004184SS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Midazolam Alone		Midazolam + SSP-004184SS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/29 (20.7%)		10/30 (33.3%)
Nervous system disorders
Dizziness	2/29 (6.9%)	2	5/30 (16.7%)	5
Somnolence	4/29 (13.8%)	4	5/30 (16.7%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.