ASPIRE: Dolutegravir Antiretroviral Strategy to Promote Improvement and Reduce Drug Exposure

• Sponsor: Babafemi Taiwo (Other)
• Overall Status: Completed
• CT.gov ID: NCT02263326
• Collaborator: ViiV Healthcare (Industry)
• Enrollment: 89
• Locations: 7
• Arms: 2
• Duration (Months): 33
• Patients Per Site: 12.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

HIV-1 infected subjects with CD4 nadir > 200 cells/mm3, no history of virologic failure and plasma HIV RNA <50 copies/mL for at least 48 weeks while on any United States Department of Health and Human Services (DHHS) recommended or alternative three-drug antiretroviral regimen will be randomized to dolutegravir (DTG) plus lamivudine (Arm 1) or continuation of their current regimen (Arm 2) for 48 weeks. The primary endpoint is virologic failure defined as confirmed plasma HIV-1 RNA > 50 copies/mL before or at Week 24

Condition or Disease	Intervention/Treatment	Phase
HIV Infection	Drug: dolutegravir; Drug: lamivudine; Drug: Continue current antiretroviral regimen	Phase 3

Detailed Description

DESIGN HIV-1 infected subjects with CD4 nadir > 200 cells/mm3, no history of virologic failure and plasma HIV RNA <50 copies/mL for at least 48 weeks while on any United States Department of Health and Human Services (DHHS) recommended or alternative three-drug antiretroviral regimen will be randomized to dolutegravir (DTG) plus lamivudine (Arm 1) or continuation of their current regimen (Arm 2) for 48 weeks. The primary endpoint is virologic failure defined as confirmed plasma HIV-1 RNA > 50 copies/mL before or at Week 24

All subjects will undergo routine monitoring including plasma HIV-1 RNA, CD4/CD8 count, hematology, chemistry and fasting lipids. Resistance testing will be done in all patients who experience virologic failure. Single-copy HIV-1 assay will be done to quantify residual viremia.

DURATION 48 weeks

SAMPLE SIZE 90 subjects

POPULATION HIV-1-infected men and women, 18 years and older, with CD4 nadir > 200 cells/mm3, no baseline resistance, no history of virologic failure, and HIV RNA <50 copies/mL for at least 48 weeks prior to study entry while on any DHHS recommended or alternative three-drug regimen

REGIMEN Subjects will be randomized (1:1) to:

Arm 1: dolutegravir 50 mg plus lamivudine 300 mg once daily OR Arm 2: Continue current DHHS recommended or alternative three-drug antiretroviral regimen

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Dolutegravir Antiretroviral Strategy to Promote Improvement and Reduce Drug Exposure (ASPIRE) Study
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Jul 1, 2017
• Actual Study Completion Date: Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: dolutegravir plus lamivudine dolutegravir 50 mg plus lamivudine 300 mg once daily	Drug: dolutegravir; 50 mg tablet by mouth once daily for 48 weeks; Other Names: TIVICAY, DTG ; Drug: lamivudine; 300 mg tablet by mouth once daily for 48 weeks; Other Names: EPIVIR, 3TC
Active Comparator: Continue current ART regimen Continue current DHHS recommended or alternative three-drug antiretroviral regimen	Drug: Continue current antiretroviral regimen; Continue current DHHS recommended or alternative three-drug antiretroviral regimen

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants With Treatment Failure [24 weeks]

   Proportion of participants with treatment failure (defined as virologic failure (HIV RNA >50 copies/mL), loss to follow-up, or treatment discontinuation) between those who switch to DTG + lamivudine and those who continue their current ART regimen

Secondary Outcome Measures

1. Proportion of Participants With Virologic Success [48 weeks]

   Proportion of participants with virologic success (<50 copies/mL) based on FDA snapshot definition

2. Change in CD4 Count From Baseline to Week 48 [Baseline and 48 weeks]

   Change in CD4 count between arms will be presented in the attached statistical analysis table

3. Change in Total Cholesterol From Baseline to Week 48 [Baseline and 48 weeks]

   Change in Total Cholesterol between arms will be presented in the attached statistical analysis table

4. Change in LDL Cholesterol From Baseline to Week 48 [Baseline and Week 48]

   Change in Low-density lipoprotein (LDL) cholesterol between arms will be presented in the attached statistical analysis table

5. Change in Creatinine Clearance From Baseline to Week 48 [Baseline and Week 48]

   Change in Creatinine Clearance between arms will be presented in the attached statistical analysis table

6. Drug Resistance Associated Mutations [48 weeks]

   Drug resistance mutations measured by HIV genotyping in patients with confirmed virologic failure

Other Outcome Measures

1. Residual Viremia by HIV-1 Single-copy Assay [48 weeks]

   Difference in HIV-1 detection by the HIV-1 single copy assay between arms will be presented in statistical analysis

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• HIV-1 Infection

• HIV-1 RNA <50 copies/mL on all measurements within 48 weeks prior to study entry while on any DHHS recommended or alternative three-drug antiretroviral regimen. (A history of switching for simplification and/or tolerability is allowed. At least two measurements within the previous 48 weeks are required prior to study screening.)

• No history of virologic failure, defined as consecutive HIV RNA > 50 copies/mL after 12 months of initiating ART. An isolated (non-consecutive) HIV RNA > 50 copies/mL (but less than 400 copies/mL) is permitted after 12 months of initiating ART but not in the 48-week window prior to study entry.

• Screening plasma HIV RNA < 20 copies/mL using the COBAS AmpliPrep/COBAS TaqMan HIV-1 Test V2.0, obtained within 45 days prior to study entry

• Nadir CD4 count >200 cells/mm

• Pretreatment genotype documenting no mutations in the protease or reverse transcriptase genes

• No known resistance to integrase inhibitors

• Laboratory values obtained within 45 days prior to study entry:

ANC >750 Hemoglobin >10 g/dL Platelets >50,000 Calculated creatinine clearance (CrCl) >50 mL/min

• Negative serum or urine pregnancy test

• Men and women age greater or equal to 18 years.

• Ability to continue current regimen (i.e, have uninterrupted access)

• No evidence of chronic hepatitis B

Exclusion Criteria:

• Serious illness or AIDS-related complication within 21 days of screening requiring systemic treatment and/or hospitalization

• Treatment within 30 days prior to study entry with immune modulators

• Vaccination within 7 days

• Active HCV treatment or anticipated need for treatment within study period. (HCV infection alone is not exclusionary)

• Unstable liver disease or severe hepatic impairment

• Known allergy or hypersensitivity to DTG or lamivudine.

• Active drug or alcohol use or dependence that could interfere with adherence to study requirements

• ALT (alanine aminotransferase) >5 x ULN (upper limit of normal) OR ALT >3 x ULN and total bilirubin >1.5 x ULN (with 35% direct bilirubin)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego	San Diego	California	United States
2	Emory University	Atlanta	Georgia	United States
3	Northwestern University	Chicago	Illinois	United States	60611
4	Brigham and Women's Hospital	Boston	Massachusetts	United States
5	Cornell University	New York	New York	United States
6	University of Cincinnati	Cincinnati	Ohio	United States
7	The Ohio State University	Columbus	Ohio	United States

Sponsors and Collaborators

• Babafemi Taiwo
• ViiV Healthcare

Investigators

• Principal Investigator: Babafemi Taiwo, MBBS, Northwestern University

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Jun 25, 2015

More Information

Publications

None provided.

• Responsible Party: Babafemi Taiwo, Professor, Northwestern University
• ClinicalTrials.gov Identifier: NCT02263326
• Other Study ID Numbers: ASPIRE
• First Posted: Oct 13, 2014
• Last Update Posted: Oct 14, 2019
• Last Verified: Oct 1, 2019

• Additional relevant MeSH terms: HIV Infections; Lamivudine; Dolutegravir; Anti-Retroviral Agents

Study Results

Participant Flow

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Period Title: Overall Study
STARTED	44	45
COMPLETED	43	44
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen	Total
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen	Total of all reporting groups
Overall Participants	44	45	89
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	46	50	47
Sex: Female, Male (Count of Participants)
Female	5 11.4%	6 13.3%	11 12.4%
Male	39 88.6%	39 86.7%	78 87.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 18.2%	5 11.1%	13 14.6%
Not Hispanic or Latino	35 79.5%	40 88.9%	75 84.3%
Unknown or Not Reported	1 2.3%	0 0%	1 1.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 4.5%	1 2.2%	3 3.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	19 43.2%	15 33.3%	34 38.2%
White	23 52.3%	29 64.4%	52 58.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
CD4 Cell Count (cells/mm3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm3]	694	646	680
Time on Antiretroviral Therapy (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	5.28	6.03	5.7
Current ART Regimen (Count of Participants)
Integrase Inhibitor	18 40.9%	15 33.3%	33 37.1%
Protease Inhibitor	14 31.8%	15 33.3%	29 32.6%
Nonnucleoside reverse transcriptase inhibitor	12 27.3%	15 33.3%	27 30.3%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants With Treatment Failure
Description	Proportion of participants with treatment failure (defined as virologic failure (HIV RNA >50 copies/mL), loss to follow-up, or treatment discontinuation) between those who switch to DTG + lamivudine and those who continue their current ART regimen
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Measure Participants	44	45
Number [proportion of participants]	0.0682 0.2%	0.0667 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir Plus Lamivudine, Continue Current ART Regimen
	Comments	A sample size of 41 participants per arm provided 80% power to show noninferiority of DTG/3TC to cART based on a 12% noninferiority margin, assuming an estimated treatment failure rate of 5% per arm by week 24 and 5% 1-sided type I error rate.
	Type of Statistical Test	Non-Inferiority
	Comments	We considered DTG/3TC was noninferior to cART if the 90% confidence interval for the difference in proportions, calculated with Miettinen-Nurminen (score) confidence limits, excluded the 12% noninferiority margin.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.0015
	Confidence Interval	(2-Sided) 90%; -0.098 to 0.102
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Participants With Virologic Success
Description	Proportion of participants with virologic success (<50 copies/mL) based on FDA snapshot definition
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Measure Participants	44	45
Number [proportion of participants]	0.9091 2.1%	0.8889 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir Plus Lamivudine, Continue Current ART Regimen
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The difference in virologic outcomes based on the FDA snapshot algorithm at week 48 (HIV RNA <50 copies/mL) was compared between arms, with 95% confidence intervals.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.020
	Confidence Interval	(2-Sided) 95%; -0.126 to 0.165
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in CD4 Count From Baseline to Week 48
Description	Change in CD4 count between arms will be presented in the attached statistical analysis table
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

Population with CD4 count data available at baseline and week 48

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Measure Participants	40	43
Median (Inter-Quartile Range) [cells/mm^3]	39	28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir Plus Lamivudine, Continue Current ART Regimen
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.866
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Change in Total Cholesterol From Baseline to Week 48
Description	Change in Total Cholesterol between arms will be presented in the attached statistical analysis table
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

Population with total cholesterol data available at baseline and week 48

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Measure Participants	40	43
Median (Inter-Quartile Range) [mg/dL]	0	-1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir Plus Lamivudine, Continue Current ART Regimen
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.613
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Change in LDL Cholesterol From Baseline to Week 48
Description	Change in Low-density lipoprotein (LDL) cholesterol between arms will be presented in the attached statistical analysis table
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Population with LDL cholesterol data available at baseline and week 48

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Measure Participants	40	43
Median (Inter-Quartile Range) [mg/dL]	2	-3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir Plus Lamivudine, Continue Current ART Regimen
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.420
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Change in Creatinine Clearance From Baseline to Week 48
Description	Change in Creatinine Clearance between arms will be presented in the attached statistical analysis table
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Population with creatinine clearance data available at baseline and week 48

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Measure Participants	41	43
Median (Inter-Quartile Range) [ml/min]	-4	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir Plus Lamivudine, Continue Current ART Regimen
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Drug Resistance Associated Mutations
Description	Drug resistance mutations measured by HIV genotyping in patients with confirmed virologic failure
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Measure Participants	44	45
Count of Participants [Participants]	0 0%	0 0%

8. Other Pre-specified Outcome

Title	Residual Viremia by HIV-1 Single-copy Assay
Description	Difference in HIV-1 detection by the HIV-1 single copy assay between arms will be presented in statistical analysis
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

Participants with HIV-1 single copy assays performed at baseline and week 48 timepoints

Arm/Group Title	Dolutegravir Plus Lamivudine	Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks	Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Measure Participants	36	36
Mean (Standard Deviation) [copies/mL]	4.7 (7.0)	4.2 (6.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dolutegravir Plus Lamivudine, Continue Current ART Regimen
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -3.0 to 4.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	48 weeks
Adverse Event Reporting Description	After study entry, all laboratory values greater than or equal to Grade 3, any laboratory values that lead to a change in study treatment, and all renal, liver function tests, and lipid values, regardless of grade, were reported. All Grade ≥3 signs/symptoms, any signs/symptoms regardless of grade that lead to a change in treatment, or that meet Expedited Adverse Event (EAE), SAE, or ICH guidelines.
Arm/Group Title	Dolutegravir Plus Lamivudine		Continue Current ART Regimen
Arm/Group Description	dolutegravir 50 mg plus lamivudine 300 mg once daily dolutegravir: 50 mg tablet by mouth once daily for 48 weeks lamivudine: 300 mg tablet by mouth once daily for 48 weeks		Continue current DHHS recommended or alternative three-drug antiretroviral regimen Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
All Cause Mortality
	Dolutegravir Plus Lamivudine		Continue Current ART Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/45 (0%)
Serious Adverse Events
	Dolutegravir Plus Lamivudine		Continue Current ART Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/44 (2.3%)		2/45 (4.4%)
Cardiac disorders
Grade 4 myocardial infarctions	0/44 (0%)	0	2/45 (4.4%)	2
Infections and infestations
Grade 4 viral syndrome	1/44 (2.3%)	1	0/45 (0%)	0
Other (Not Including Serious) Adverse Events
	Dolutegravir Plus Lamivudine		Continue Current ART Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		3/45 (6.7%)
Hepatobiliary disorders
Grade 3 bilirubinemia	0/44 (0%)	0	3/45 (6.7%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.